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RECENT PUBLICATIONS ON RESIDUAL RISK

2017

Is FGF21 a potential target in hypertriglyceridaemia?

Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. The wealth of data relating to this peptide suggests that it may be an excellent target in therapeutic management of diabetes and cardiovascular disease associated with obesity. While a novel agent targeting FGF21, the analogue PF-05231023, reduced plasma triglycerides this was also associated with increased blood pressure and heart rate.
This study enrolled 107 obese, hypertriglyceridaemic subjects treated with atorvastatin, with or without type 2 diabetes. These individuals were randomly allocated to PF-05231023 or placebo intravenously once-weekly for 4 weeks. At day 25, PF-05231023 treatment was associated with reduction in plasma triglycerides (by 33-43%) and an increase in high-density lipoprotein cholesterol concentration (by 15-28%), without significant changes in body weight. However, treatment was also associated with dose-related increases in blood pressure and heart rate. These results call into question the potential of this therapeutic approach for managing elevated triglycerides associated with obesity.
Once-weekly administration of a long-acting FGF21 analogue modulates lipids, bone turnover markers, blood pressure, and body weight differently in obese hypertriglyceridemic subjects and in non-human primates.

Kim AM, Somayaji VR, Dong JQ et al.

Remnant lipoproteins and cardiovascular risk

This new review discusses recent advances in the field of remnant lipoproteins and remnant cholesterol, specifically focused in their role in cardiovascular disease risk. There is now accumulating evidence from observational, genetic, and mechanistic studies linking remnant lipoproteins with the development of atherosclerotic cardiovascular disease, suggesting that this could be a contributor to lipid-related residual cardiovascular risk. While there are encouraging findings from small studies and post hoc analyses, large prospective studies are still needed to definitively evaluate whether reduction in remnant cholesterol levels translates to reduction in cardiovascular risk.

Are triglycerides causal in cardiovascular disease?

Insights from genetic studies have proved critical in investigating the causality of triglycerides in cardiovascular disease risk. This new review discusses the evidence from recent Mendelian randomization studies.
Meta-analyses of cohorts and population-based sequencing studies have investigated whether genes for lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and the angiopoietin-like proteins 3 and 4, are associated with cardiovascular disease risk. The evidence to date shows that triglyceride-raising variants of these genes showed generally strong associations with clinical cardiovascular endpoints. However, these findings are confounded by the association of elevated triglycerides with low high-density lipoprotein cholesterol (HDL-C). Thus, while the evidence from these genetic studies points to a potential causal association with cardiovascular risk, further study is needed to tease out this confounding with low HDL-C. Ultimately, what is needed to resolve this uncertainty is outcomes studies with novel agents specifically aimed at targeting elevated triglycerides via inhibition of apoCIII or angiopoietin-like protein 3. This week’s Landmark study offers new hope.
Genetics of triglycerides and the risk of atherosclerosis.

Dron JS, Hegele RA.

Atherogenic dyslipidaemia is predictive of incident CHD in China

This Chinese study highlights the importance of triglycerides and high-density lipoprotein cholesterol (HDL-C), components of atherogenic dyslipidaemia, as well as apolipoprotein B (apoB) levels as independent predictors of coronary heart disease (CHD) in individuals referred for coronary angiography. This cross-sectional study included 1,941 patients of whom 1,363 patients had confirmed evidence of CHD. After adjustment for age, sex, body mass index, diabetes, hypertension, smoking and alcohol intake, in nonstatin users there was an independent association between triglycerides, HDL-C and apoB levels and incident CHD (p for trend = .001, .005, and .003, respectively). Given the relatively high prevalence of hypertriglyceridaemia and low HDL-C concentration in this region (both lipid abnormalities were observed in 22% of patients in this study), the study highlights the need to consider appropriate lipid-modifying strategies beyond low-density lipoprotein cholesterol to reduce incident CHD.
Serum triglyceride, high-density lipoprotein cholesterol, apolipoprotein B, and coronary heart disease in a Chinese population undergoing coronary angiography.

Ling Y, Jiang J, Wu B, Gao X.

Does road traffic noise/air pollution play a role in cardiometabolic disease risk?

The results from this study based on data from two large European cohorts (HUNT3, Lifelines, 144,082 individuals aged at least 20 years) suggests that this may be the case. The authors modelled road traffic noise exposure for 2009 using a simplified version of the Common Noise Assessment Methods in Europe. Annual ambient air pollution (particulate matter 10 (PM10), nitrogen dioxide) was estimated for 2007 using a Land Use Regression model. Based on pooled data, higher day-time noise (by interquartile range 5.1 dB) was associated with higher high-sensitivity C-reactive protein, triglycerides, and high-density lipoprotein cholesterol (HDL-C); the association with HDL-cholesterol was robust after adjustment for air pollution. Additionally, higher particulate matter (2.0 µg/m3) or nitrogen dioxide concentration (7.4 µg/m3) was associated with higher triglycerides (by 1.9%, 95% confidence interval 1.5-2.4% and 2.2%, 95% confidence interval 1.6-2.7%, respectively), independent of adjustment for noise. In conclusion, these findings suggest that long-term exposure to road traffic noise and ambient air pollution was associated with detrimental changes in blood biochemistry, including higher triglycerides, suggesting a link with cardiometabolic disease risk.
Long-term exposure to road traffic noise, ambient air pollution, and cardiovascular risk factors in the HUNT and lifelines cohorts.

Cai Y, Hansell AL, Blangiardo M et al.

Gender disparity in lipid targets for men and women in the Arabian Gulf

Women living in the Arabian Gulf, especially those at very high cardiovascular risk, were much less likely to attain recommended lipid goals according to this analysis of the Centralized Pan-Middle East Survey on the undertreatment of hypercholesterolemia (CEPHEUS). The analysis included 4,384 high and very high risk patients (mean age 57±11 years and 40% women) on lipid lowering therapy in six Arabian Gulf countries. Compared with male patients, females in this study were at higher cardiometabolic risk, as shown by a higher prevalence of diabetes (84% vs 71%; p<0.001) and metabolic syndrome (49% vs 35%; p<0.001), but were less likely to achieve their recommended lipid goals, for low-density lipoprotein cholesterol (LDL-C) (28% vs 32%; p = 0.002), high-density lipoprotein cholesterol (HDL-C) (42% vs 50%; p<0.001), and apolipoprotein B (38% vs 42%; p = 0.015). Among the very high risk cohort, only 1 in five women attained LDL-C goal and about 1 in three attained non-HDL-C goals, significantly lower than in men. These data, from a large prospective study, highlight an unmet clinical need to improve lipid management in high risk patients of both sexes, but especially very high risk women, in this region.
Gender disparity in lipid target achievements in high and very high atherosclerotic cardiovascular disease risk patients in the Arabian Gulf.

Al-Zakwani I, Shehab A, Al-Hinai AT et al.

HDL-cholesterol and triglycerides linked with insulin secretion in non-diabetic individuals

Although experimental studies suggest that lipoproteins directly affect beta cell function, evidence from clinical studies is less consistent. This question was investigated in a cross sectional, observational prospective multicentre study including 1,016 non-diabetic subjects (aged 30-60 years and with body mass index 20.0-39.9 kg/m2). The study measured fasting lipids, fasting insulin and Oral Glucose Tolerance Test (OGTT)-induced insulin secretion and clearance, and peripheral insulin sensitivity (by the euglycemic clamp) at baseline and after 3.5 years. There was no association between low-density lipoprotein cholesterol levels and fasting or stimulated insulin secretion or clearance. However, low levels of high-density lipoprotein (HDL) cholesterol and elevated triglycerides were associated with abnormalities in insulin secretion characteristic of the pre-diabetic state, independent of changes in body weight or plasma glucose.
Plasma HDL-cholesterol and triglycerides, but not LDL-cholesterol, are associated with insulin secretion in non-diabetic subjects

Natali A, Baldi S, Bonnet F et al.

Do peroxisome proliferator-activated receptor targeted treatments have a role in fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) encompasses the spectrum of diseases ranging from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), and ultimately cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain.
 
This timely review discusses the potential of novel therapies targeting peroxisome proliferator-activated receptors (PPARs) for modulation of NAFLD. Notably, PPAR-alpha is closely linked to the transcription of genes related to hepatic beta-oxidation, such as CPT-1 and is highly expressed in the liver. In experimental studies, activation of PPAR-alpha by fenofibrate markedly ameliorated hepatic insulin resistance due to upregulation of enzymes involved with beta-oxidation, and upregulation of genes involved in hepatic lipid oxidation, as well as inhibition of de novo lipogenesis and gluconeogenesis enzymes, resulting in a significant decrease in hepatic steatosis. Whether these experimental findings translate to the clinical setting merits further evaluation.
The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease.

Sun X, Zhang Y, Xie M

Pemafibrate (K-877) add-on to statin: More trials report

Two new trials add to evidence of robust reduction in triglycerides when this new selective peroxisome proliferator-activated receptor alpha (SPPARMalpha) agonist is added to statin therapy. In one trial, 188 patients treated with pitavastatin were randomized to add-on treatment with pemafibrate 0.1, 0.2, and 0.4 mg/day for 12 weeks; the other trial evaluated pemafibrate either as a fixed dose of 0.2 mg/day, or with the possibility of up-titration (0.2 mg/kg increasing to 0.4 mg/day) in combination with any statin for 24 weeks in 423 patients. Compared with statin monotherapy, pemafibrate add-on therapy was associated with reduction in triglycerides, remnant cholesterol and apolipoprotein B48 by about 50%, as well as improvement in the atherogenic lipoprotein profile. Pemafibrate also appeared to be well tolerated with no signal for any increase in unexpected adverse events compared with statin monotherapy.
Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor ? modulator (SPPARM?), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia.

Arai H, Yamashita S, Yokote K et al.

Is inflammation a key determinant of the atherogenicity of remnant cholesterol?

Attention has refocused on remnant cholesterol, transported by triglyceride-enriched precursors to low-density lipoproteins, as a contributor to cardiovascular risk. There is compelling evidence from several Mendelian randomization studies that remnant cholesterol is causal in atherosclerotic cardiovascular disease, as well as supportive findings from cross-sectional and prospective studies. There is also biological plausibility for such a link, given that at least some of the group of remnant lipoproteins, such as intermediate density lipoproteins, which contain far more cholesterol per particle than LDL, are able to traverse the arterial wall to elicit changes that predispose to or exacerbate atherosclerosis. Added to this, new evidence indicates that there is an important inflammatory component to the atherogenicity of remnant cholesterol.
 
This study evaluated arterial wall inflammation and bone marrow activity using 18F-FDG PET/CT (18F- fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography) and monocyte phenotype with flow cytometry in 17 patients with familial dysbetalipoproteinaemia (characterized by increased total cholesterol and triglyceride levels) and 17 matched controls. Compared with controls, there was a 20% increase in 18F-FDG uptake in the arterial wall, as well as increased lipid accumulation and higher expression of surface integrins (CD11b, CD11c, and CD18) in patients with familial dysbetalipoproteinaemia. In addition, data from the Copenhagen General Population Study validated the correlation between remnant levels and hematopoietic activity, as well as the strong correlation with leukocyte counts. These findings support an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in these patients.
Remnant cholesterol elicits arterial wall inflammation and a multilevel cellular immune response in humans.

Bernelot Moens SJ, Verweij SL, Schnitzler JG et al

Congress News : 66th Annual Scientific Sessions of the American College of Cardiology, Washington DC, 17-19 March
PCSK9 Inhibition tops the bill; HDL fails again

This year’s ACC Sessions highlighted PCSK9 inhibition, with evidence from two studies with PCSK9 monoclonal antibody therapy - FOURIER and SPIRE-2 with the prematurely terminated bococizumab – that lowering low-density lipoprotein cholesterol (LDL-C) levels far beyond current LDL-C targets reduces cardiovascular events in very high risk patients (1,2). As shown by the SPIRE-2 study, the magnitude of benefit appeared to be greater in patients with higher LDL-C levels at baseline, and thus at higher LDL-related risk, consistent with the regression line shown for statin therapy in the Cholesterol Treatment Trialists’ Collaboration meta-analysis (3). While FOURIER was an event-driven trial, the short duration of follow-up (median 2.2 years) has led to some controversy regarding the lack of benefit on cardiovascular mortality. Additionally, it is relevant that adding evolocumab to maximally tolerated lipid lowering therapy did not eliminate the risk of cardiovascular events in very high risk patients, thus underlying the importance of other risk factors, both lipid and non-lipid related, that contribute to this residual risk. Data are also awaited on subgroup analyses evaluating the effects of evolocumab added to maximal lipid-lowering therapy in diabetes patients.
 
Regarding other lipids and lipoproteins, there was disappointing news (yet again) for targeting high-density lipoprotein (HDL) from the proof-of concept CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) study (4). Short-term treatment with the HDL mimetic CER-001 did not produce a significant effect on coronary disease progression, as measured by intravascular ultrasonography (IVUS), against a background of contemporary therapy in the acute coronary syndrome (ACS) setting. Thus these findings from CARAT suggest that CER-001 is not a promising strategy for ACS patients. Whether HDL-targeted therapy can impact plaque or clinical events remains a persistent question for researchers.
 
References
1. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017 Mar 17. doi: 10.1056/NEJMoa1615664. [Epub ahead of print]
2. Ridker PM, Revkin J, Amarenco P et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017 Mar 17. doi: 10.1056/NEJMoa1701488. [Epub ahead of print]
3. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016 Nov 19;388(10059):2532-56.
4. Nicholls SJ, Andrews J, Kastelein JJP et al. Results of the CARAT Study. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic on coronary atherosclerosis. Available at http://clintrialresults.org/Slides/ACC2017/CARAT_Nicholls.pdf

Increased burden of coronary artery disease with elevated BMI

Data from the Partners Healthcare CT Registry in consecutive patients undergoing enhanced cardiac computed tomography angiography (CTA) at the Massachusetts General Hospital or the Brigham and Women’s Hospital from 2004–2011, showed an increased prevalence, extent, and severity of coronary artery disease (CAD) for individuals with body mass index (BMI) > 25 kg/m2. This analysis included data from 1,118 individuals (mean age 57 years, 58% male, 40% with diabetes and 33% with metabolic syndrome). Over a median follow-up of 3.2 (interquartile range 1.9–4.5) years, there were 46 (4.1%) all-cause deaths, 21 (1.9%) cardiovascular deaths, 13 (1.2%) non-fatal myocardial infarction (MI), 13 (1.2%) unstable angina without revascularization, and 34 (3.1%) late coronary revascularizations. Univariate analysis showed that BMI was associated with the presence, extent, and severity of CAD. There was a 3% increase in risk of any CAD for each 1 kg/m2 increase in BMI (odds ratio 1.03, 95% CI 1.01–1.05, p = 0.012), although in multivariable analyses adjusted for age, gender, smoking and each individual metabolic syndrome component, this was no longer significant. In multivariable analyses, both BMI and the presence of the metabolic syndrome were significantly associated with major cardiovascular events (hazard ratios 1.04, 95% CI 1.01–1.08, p=0.02; and 1.88, 95% CI 1.15–3.08, p=0.01, respectively). Thus, while BMI is a marker of CAD risk, this is mostly mediated by the presence of other metabolic risk factors.
Obesity, metabolic syndrome and cardiovascular prognosis: from the Partners coronary computed tomography angiography registry.

Hulten EA, Bittencourt MS, Preston R et al.

Call for action for dyslipidaemia in Middle East

This call for action paper from a panel of experts from Iraq, Kuwait, Lebanon, Oman, Saudi Arabia and United Arab Emirates (UAE) has highlighted the high prevalence of atherogenic dyslipidaemia in this region, affecting up to 70% of individuals. Experts make the case for research in this region to obtain better understanding of this often neglected dyslipidaemia; education of public and healthcare professionals; preventive programmes for dyslipidaemia and other cardiovascular risk factors; as well as the development of local guidelines relevant to this region.
Dyslipidaemia in the Middle East: Current status and a call for action.

Al Rasadi K, Almahmeed W, AlHabib KF et al.

Abdominal adiposity and risk for type 2 diabetes and coronary heart disease

A report in JAMA supports a causal association between abdominal adiposity and the development of type 2 diabetes and coronary heart disease (CHD). This Mendelian randomization study (a ‘natural’ randomized trial) investigated whether a genetic predisposition to increased waist-to-hip ratio adjusted for body mass index (BMI) was associated with cardiometabolic quantitative traits (i.e., lipids, insulin, glucose, and systolic blood pressure), type 2 diabetes and CHD, using a polygenic risk score based on 48 single-nucleotide polymorphisms for these cardiometabolic traits. Estimates for cardiometabolic traits were based on a combined data set from 4 genome-wide association studies including up to 322,154 participants, as well as individual-level, cross-sectional data from the UK Biobank including 111,986 individuals. The study showed that a 1-standard deviation increase in waist-to-hip ratio mediated by this risk score was associated with 27 mg/dL higher triglyceride levels, 4.1 mg/dL higher 2-hour glucose levels, and 2.1 mmHg higher systolic blood pressure (each p?<0.001), and more than 50% higher risk of type 2 diabetes (odds ratio 1.77 [95% CI, 1.57-2.00]) and CHD (odds ratio 1.46 [95% CI, 1.32-1.62]). These findings suggest that body fat distribution, beyond BMI, may explain part of the variation in risk of type 2 diabetes and CHD observed in different populations, such as South Asians.
Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease.

Emdin CA, Khera AV, Natarajan P et al.

What can we look forward to at the 66th Annual Scientific Sessions of the American College of Cardiology, Washington DC, 17-19 March, 2017?

Among the highlights, the R3i has identified key sessions:

  • FOURIER – In the Opening Late-Breaking Clinical Trials Session on March 17th, this long-awaited cardiovascular outcomes study evaluating the PCSK9 inhibitor evolocumab will report its results. In a press release earlier this month,1 the Sponsor (Amgen) announced that treatment with evolocumab met both its primary composite endpoint (cardiovascular death, non-fatal myocardial infarction [MI], non-fatal stroke, hospitalization for unstable angina or coronary revascularization) and the key secondary composite endpoint (cardiovascular death, non-fatal MI or non-fatal stroke). No new safety issues were observed. Additionally, EBBINGHAUS, a cognitive function study of patients enrolled in the FOURIER trial showed no differences between evolocumab and placebo;1 full details will be reported at the Late Breaking Clinical Trials session on March 18th. 1. Amgen Announces Repatha® (Evolocumab) Significantly Reduced The Risk Of Cardiovascular Events In FOURIER Outcomes Study. Available at https://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/

  • CARAT study: The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is an imaging trial investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome. The primary endpoint is the nominal change in percent atheroma volume. This trial will be reported at a Late-Breaking Clinical Trials Session on March 18th.

  • CVD-REAL Study: There will also be a report of real-world data on rates for hospitalization for heart failure among new users of SGLT-2 inhibitors in a Featured Clinical Research III session on Sunday 19th March.
66th Annual Scientific Sessions of the American College of Cardiology

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2016

Impairment of HDL function in post-infarct patients

This report shows that the functionality of high-density lipoproteins (HDL) was impaired in the acute post myocardial infarction (MI) setting. This prospective study included 111 patients, 41 with non-ST-segment elevation MI (NSTEMI), 37 with STEMI and 37 non-MI patients. In vitro HDL functionality was evaluated using standard experimental approaches, notably measurement of cholesterol efflux from macrophage foam cells; the ability of HDL to prevent low-density lipoprotein oxidation; and the ability of HDL to inhibit TNF-?-induced vascular adhesion molecule-1 expression in endothelial cells. HDL from STEMI patients exhibited reduced cholesterol efflux and decreased anti-inflammatory functionalities (p<0.001), although antioxidative properties were not significantly modified. This reduced HDL function was associated with significant increases in MI risk; patients in the fourth quartile had more than 5-fold increase in MI risk compared with those in lower quartiles (odds ratio [OR], 5.66; 95% confidence interval [CI], 1.26-25.00; p = 0.024; and 5.53; 95% CI, 1.83-16.73; p = 0.002, respectively). These findings may offer some explanation for the lack of benefit observed in the dal-OUTCOMES trial with the cholesteryl ester transfer protein inhibitor dalcetrapib.
HDL function is impaired in acute myocardial infarction independent of plasma HDL cholesterol levels.

Annema W, Willemsen HM, de Boer JF et al.

Dyslipidaemia may precede peripheral insulin resistance

Results from this Chinese study reinforce the importance of targeting atherogenic dyslipidaemia earlier. The study evaluated data from a longitudinal cohort of 3,325 subjects (aged 20–74 years) followed for a mean of 4.2 years. Data for fasting blood lipids, and fasting and 2-hour serum glucose and insulin, were obtained at two time points. The researchers used cross-lagged path analysis to assess the temporal relationship between dyslipidaemia and insulin resistance (IR). According to this model, if the relationship between dyslipidaemia and IR was bidirectional, they would predict each other, and their cross-lagged path coefficients would not differ significantly. However, if IR and dyslipidaemia have an underlying causal relationship, the causal variable should predict the consequent variable, and the cross-lagged path coefficient of the causal variable should be significantly greater. The analysis showed that the path coefficients from baseline triglycerides and high-density lipoprotein cholesterol (HDL-C) to follow-up 2-hour insulin were significantly greater than those from baseline 2-hour insulin to follow-up triglycerides and HDL-C (p<0.001 for each analysis). These findings provide strong evidence that dyslipidaemia probably precedes peripheral IR, and should therefore be targeted sooner.
Changes in triglycerides and high-density lipoprotein cholesterol may precede peripheral insulin resistance, with 2-h insulin partially mediating this unidirectional relationship: a prospective cohort study.

Han T, Cheng Y, Tian S et al.

Economic benefits of targeting both cholesterol and triglycerides

Results from this study indicate economic benefit from treating diabetic patients with combination lipid therapy targeting both elevated cholesterol and elevated triglycerides compared with statin monotherapy. The researchers used data from an observational cohort study of 184,932 patients with diabetes mellitus with 2 triglycerides measurements (between January 2012 and June 2013, with a follow-up measurement 3 to 15 months later) to identify 4 therapy groups: statin monotherapy, triglyceride-specific monotherapy, statin/triglyceride-specific combination therapy, or no therapy. These groups were stratified by percent change in triglycerides (increase ?5%, ?4.9%, decrease 5% to 29%, or decrease ?30%). After adjustment for covariates, the greatest cost reduction was seen among patients on statin/triglyceride-specific combination therapy who had ?30% reduction in triglycerides (decrease by $2,859). Therefore, not only is there clinical evidence for targeting elevated triglycerides, in addition to high cholesterol, but these findings also provide an economic rationale for the benefits of this approach.
Effect of combination cholesterol-lowering therapy and triglyceride-lowering therapy on medical costs in patients with type 2 diabetes mellitus.

Nichols GA, Reynolds K, Olufade T et al.

Triglycerides:HDL ratio predicts worse outcomes after acute ischaemic stroke

A lower triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL-C) was a predictor of poorer outcome at 3 months after ischaemic stroke, according to this study. In total, 1,006 patients (median age 68.5 years; 58% male) admitted with acute ischaemic stroke (2011-2014) were included in this analysis. Three end-points were defined according to the modified Rankin scale (mRS) score at 3 months after symptom onset: excellent outcome, mRS 0-1; good outcome, mRS 0-2; and death, mRS 6. Higher TG, non-HDL-C and TG/HDL-C were strongly associated with the three end-points after adjustment: excellent [odds ratio (OR) = 1.39, OR 1.89 and OR 2.34, respectively] and good (OR 1.48, OR 2.90 and OR 4.12) outcomes, and death (OR 0.59, OR 0.29 and OR 0.26). Patients with a TG/HDL-C <0.87 had about 3-fold higher risk of death (95% confidence interval 1.89-4.55) compared with those with a TG/HDL-C ?0.87.
Triglyceride to high-density lipoprotein cholesterol ratio predicts worse outcomes after acute ischaemic stroke.

Deng QW, Wang H, Sun CZ et al.

Residual cardiovascular risk in a real-world setting

One in eight very high risk patients remain at high risk of cardiovascular events despite statin therapy, according to this report using real-world data. This retrospective observational study analyzed data from 27,330 patients treated with statins (50% male, mean age 68 years). Of these, 770 patients attained a low-density lipoprotein-cholesterol (LDL-C) value below current recommended goals. Despite this, these patients remained at high risk of a cardiovascular event, with incidence rates of 1.3±1.0 per patient per year for moderate cardiovascular risk, 4.1±2.6 for high risk, and 12.5±11.0 for very high risk patients. Compared with moderate risk patients, very high risk patients with a controlled LDL-C value had about 5-fold increase in risk of a (recurrent) event (hazard ratio 4.97, 95% confidence interval 1.36-18.2). Despite the limitations of a retrospective design, these findings highlight the high residual cardiovascular risk that persists in statin-treated patients with controlled LDL-C levels in a real-world setting.
Residual cardiovascular risk in patients who received lipid-lowering treatment in a real-life setting: retrospective study.

Perrone V, Sangiorgi D, Buda S, Degli Esposti L

News from American Heart Association Scientific Sessions 2016, 11-15 November, New Orleans, USA

Lipids were very much in the news at this year’s meeting. Not only was there a report from GLAGOV, the first intravascular ultrasound study evaluating the effects of treatment with a PCSK9 monoclonal antibody on top of statin on progression of coronary atherosclerosis (see Landmark study), but there was also news of other approaches to targeting PCSK9. In the ORION study in high risk patients with elevated low-density lipoprotein cholesterol (LDL-C), 1 or 2 subcutaneous injections of the PCSK9 RNA interference agent inclisiran reduced LDL-C levels by 55-60%. This approach has obvious benefits for adherence, offering the possibility in the future of a single depot injection per year to manage elevated LDL-C levels.
 
On the downside, there were disappointing results from the MILANO-PILOT Study. In this study, infusion of the apoA-IMilano high-density lipoprotein (HDL) mimetic did not significantly change the percent atheroma volume (PAV) in acute coronary syndrome patients, leading to termination of this agent. However, some may question why the placebo response in this study differed with that observed in GLAGOV; in the MILANO-PILOT Study there was -0.8% change in PAV (vs. -0.5% with active drug) whereas in GLAGOV, there was +0.05% change with placebo vs. -0.95% with active drug. Perhaps a case of throwing the baby out with the bathwater?
 
Furthermore, there were early clinical (Phase I) data with Ionis-angptl3-lRx, an antisense inhibitor to angiopoietin-like protein 3 (ANGPTL3). Genetic studies have previously identified ANGPTL3 variants that were associated with very low plasma levels of LDL-C, triglycerides and HDL cholesterol. Together with other evidence, there was a strong rationale that ANGPTL3 may be a novel target for managing dyslipidaemia, with multiple beneficial effects on lipoprotein metabolism. These findings were the catalyst for the development of Ionis-angptl3-lRx. In a phase I study in healthy volunteers with elevated triglycerides, there were significant mean reductions in triglycerides (by 66%), apolipoprotein CIII (by 68%), and LDL-C (by 35%). Safety data were also encouraging.
Late-Breaking Clinical Trials & Clinical Science: Special Reports Scientific Sessions 2016, New Orleans, Louisiana

A link between APOC3, triglycerides and coronary disease via miR-4271 binding?

Emerging evidence shows that loss-of-function mutations in the gene encoding apolipoprotein CIII (APOC3), are associated with a decrease in plasma triglycerides levels and clinical benefit in patients at high cardiovascular risk. This study provides molecular evidence for this association. The authors identified a common APOC3 variant (rs4225) in the microRNA-binding site (miR-4271 binding) which affects its expression and the risk of coronary heart disease. The T allele but not the G allele of this variant suppressed APOC3 by facilitating miR-4271 binding. Furthermore, individuals with the TT genotype not only had lower plasma triglycerides than those with the GG allele (p=0.03), but also evidence from a case-control study suggested that the TT genotype was associated with 11% (2-23%) reduction in coronary heart disease risk [p?=?0.009]. These findings add to accumulating evidence for apolipoprotein CIII or APOC3 as a potential therapeutic targets.
An APOC3 3'UTR variant associated with plasma triglycerides levels and coronary heart disease by creating a functional miR-4271 binding site.

Hu SL, Cui GL1 Huang J, Jiang JG, Wang DW.

Peripheral artery disease associated with increased cardiovascular risk

In this analysis of the PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study, major peripheral artery disease (lower-extremity ulceration or amputation, and peripheral revascularization) increased the risk of all-cause mortality and cardiovascular events in patients with type 2 diabetes. In addition, lower-extremity ulceration or amputation was associated with an increased risk of severe retinopathy. These findings underline the close associations between macrovascular and microvascular risk in type 2 diabetes.
In this report, 11,140 type 2 diabetes patients were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Overall, 516 (4.6%) patients had major peripheral arterial disease at baseline; 300 (2.7%) had lower-extremity chronic ulceration or amputation alone, 190 (1.7%) had peripheral revascularization alone, and 26 (0.2%) had both presentations. Over the follow-up period, 2265 (20.3%) died (all causes), 2166 (19.4%) had major cardiovascular events of whom 988 (8.9%) died, and 807 (7.2%) had major clinical microvascular events. Overall, major peripheral artery disease was associated with 35% (15-60%) increased risk of death (p = 0.0004), 47% (23-75%) increased risk of major cardiovascular events (p <0.0001), 75% (39-221%) increased risk of cardiovascular death (p < 0.0001), and 58% (19-209%) increased risk of myocardial infarction (p = 0.001). There was also a trend toward an association between baseline peripheral artery disease and risk of major clinical microvascular events [hazard ratio 1.31, 95% CI 0.96–1.78, p = 0.09], specifically diabetic retinopathy. In conclusion, these findings emphasize that type 2 diabetes patients with major peripheral artery disease have poor survival and cardiovascular outcomes and underline the need for routine screening for peripheral artery disease to improve prognosis.
Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study.

Mohammedi K, Woodward M, Hirakawa Y et al.

New analysis highlights need for aggressive lipid mana

This post hoc pooled analysis of three randomized trials of serial coronary intravascular ultrasound (REVERSAL, ASTEROID and SATURN) suggests that women with coronary disease derive greater benefit from high intensity statin therapy than male patients. The analysis evaluated data from 451 women and 1190 men. On-treatment levels of mean low-density lipoprotein cholesterol [LDL-C] (68 ± 24 vs. 67 ± 22 mg/dl) and apolipoprotein B (77 ± 23 vs. 76 ± 20 mg/dL) were similar in both sexes, although triglycerides were higher in women than men [median (interquartile range):122 (95, 158) vs. 114 (89, 154) mg/dl, p=0.012]. Additionally, C-reactive protein was also higher in women than men [1.7 (0.9, 3.8) vs. 1.1 (0.6, 2.7) mg/l, p < 0.001]. While women had significantly lower baseline percent atheroma volume (PAV) than men (34.8 ± 8.7 vs. 38.3 ± 8.8%, p < 0.001), they derived significantly greater regression in atheroma (Change in PAV -1.07 ± 0.26 vs. -0.66 ± 0.23%, p=0.02), especially with on-treatment levels of LDL-C <64 mg/dl, apolipoprotein B <73 mg/dl, and non-high-density lipoprotein cholesterol [non-HDL-C] <88.8 mg/dl. Furthermore, these apparent sex-related differences in plaque regression with high intensity treatment seem to relate more to lower achieved atherogenic lipoprotein levels (as typified by LDL-C and non-HDL-C) than lower inflammatory levels (as typified by C-reactive protein). These findings emphasize the need for aggressive lipid lowering strategies in women with established atherosclerosis.
Coronary atheroma progression rates in men and women following high-intensity statin therapy: A pooled analysis of REVERSAL, ASTEROID and SATURN.

Stegman B, Shao M, Nicholls SJ et al.

Dyslipidaemia management in type 2 diabetes still far from optimal

In the German DIVE (DIabetes Versorgungs-Evaluation) and the DPV (Diabetes-Patienten-Verlaufsdokumentation) database including more than 350,000 individuals, only a minority (26.7%) were treated with lipid modifying therapy, highlighting the need for further action to address this issue. <
 
This analysis included data from 363,949 individuals with type 2 diabetes. Of those who received lipid modifying treatment, the most commonly prescribed was statin (84%). While control of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) was significantly better (p<0.001) in these patients than in those not on a statin (median LDL-C 100.5 vs. 114.0 mg/dl in those not treated, and non-HDL-C 131.0 vs. 143.1 mg/dl, respectively), plasma triglycerides were significantly higher (160.3 vs. 152.0 mg/dl; p < 0.001). Thus, despite the availability of multiple guidelines, lipid management, particularly of triglycerides, lags behind in this high risk group.
Dyslipidaemia and its treatment in patients with type 2 diabetes - a joint analysis of the German DIVE and DPV registries.

Bramlage P, Lanzinger S, Rathmann W et al.

Hot off the Press: Topline results for GLAGOV with the PCSK9 inhibitor evolocumab look good

According to a press release, GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound), a serial intravascular ultrasound imaging study, met its primary endpoint, showing significant change in percent atheroma volume from baseline to week 78 with evolocumab compared to placebo. There were also significant changes in secondary outcomes of atheroma measurement. GLAGOV is due to be presented at this year’s Scientific Sessions of the American Heart Association.

Is the polypill a cost-effective option to reduce residual cardiovascular risk?

In the Spanish healthcare setting, the polypill (aspirin 100 mg, atorvastatin 20 mg, ramipril 10 mg) is a cost-effective approach to reducing residual cardiovascular risk in adults with a history of myocardial infarction, compared with individual monotherapies. Using Markov modelling, use of the cardiovascular polypill instead of its monocomponents would avoid 46 nonfatal and 11 fatal cardiovascular events per 1000 patients treated over a 10-year period. Moreover, this analysis showed that the polypill would be a cost-effective strategy compared with multiple monotherapy at a willingness-to-pay threshold of 30 000 euros per quality-adjusted life year.
Usefulness of a cardiovascular polypill in the treatment of secondary prevention patients in Spain: A cost-effectiveness study

Barrios V, Kaskens L, Castellano JM et al.

SPIRE outcomes studies with bococizumab

Although statins significantly reduce vascular event rates, lipid-related residual cardiovascular risk remains high in many patient groups. The SPIRE outcomes studies will offer the opportunity to test whether the level of low-density lipoprotein cholesterol (LDL-C) at study entry is a determinant of clinical benefit with the PCSK9 inhibitor bococizumab. There are two outcomes studies with bococizumab: SPIRE-1 (NCT01975376) and SPIRE-2 (NCT01975389). These event-driven studies will assess the efficacy and safety of bococizumab in reducing the residual risk of cardiovascular events in high-risk patients on statin, with and without clinical cardiovascular disease, and with LDL-C levels ?70 mg/dL or 1.8 mmol/L (SPIRE-1, n = 17,000) or ?100 mg/dL or 2.6 mmol/L (SPIRE-2, n = 11,000). SPIRE-2 has now completed recruitment. These trials, together with the outcomes studies with alirocumab and evolocumab, will test whether lowering LDL-C levels by PCSK9 inhibition beyond current targets will provide significant reduction in the residual risk of cardiovascular events in patients receiving best evidence-based treatment including statins.
Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials

Ridker PM, Amarenco P, Brunell R et al

Controversy about lipid fractions and risk for CAD and diabetes

A study using Mendelian randomization highlighted an association between elevated triglycerides and increased coronary artery disease risk; in contrast, higher triglycerides were associated with lower risk of type 2 diabetes. The study used data from genome-wide association studies, comprising 130 single-nucleotide polymorphisms (SNPs) for low-density lipoprotein cholesterol (LDL-C), 140 SNPs for triglycerides and 140 SNPs for high-density lipoprotein cholesterol (HDL-C), to construct genetic risk scores. A 1 standard deviation (SD) genetic increase in LDL-C levels (~38 mg/dL) and triglyceride levels (~89 mg/dL) increased coronary artery disease risk by 68% (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.51-1.87) and 28% (OR 1.28, 95% CI, 1.13-1.45), respectively. In contrast, 1 SD increase in HDL-C (~ 16-mg/dL) decreased risk by 5% (OR 0.95, 95% CI, 0.85-1.06). However, the study showed that all three lipid traits were associated with a lower risk of type 2 diabetes, decreasing risk by 21% (for LDL-C), 17% for HDL-C and 17% for triglycerides per 1 SD increase. These genetic data raise a number of questions for the design of studies evaluating the effects of therapeutic modulation on risk for diabetes and cardiovascular disease.
Association of lipid fractions with risks for coronary artery disease and diabetes

White J, Swerdlow DI, Preiss D et al.

News from ESC Congress 2016 Rome
Triglyceride/HDL ratio predicts multivessel coronary artery disease in ACS

A triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio ?1.76 is an independent predictor for multivessel coronary artery disease in patients with acute coronary syndrome (ACS), according to this report from a national ACS registry in Portugal.
 
The investigators included 9,345 patients in this registry between June 2011 and November 2015; 2,163 were excluded from this analysis because of previous coronary artery disease. Among evaluable patients who underwent angiography, 45.5% had multivessel coronary artery disease. Patients with a TG/HDL ratio ?1.76 were younger, had a higher body mass index and were more frequently males, smokers, diabetics and had more hyperlipidaemia. These individuals also had a significantly higher incidence of multivessel disease (47.5% vs. 37.6%, p<0.001), even after adjustment for other predictors (odds ratio 1.59, 95% CI 1.38–1.83, p<0.001).
Impact of triglycerides/HDLcholesterol ratio on coronary artery disease severity and in shortterm outcome of patients with acute coronary syndromes

Timoteo AT, Rosa SA, Nogueira MA et al

Eur Heart J 2016;37(Abstract Supplement): 1390.

News from ESC Congress 2016 Rome
Mendelian randomization study shows the benefit of targeting multiple risk factors

In a key Hotline session, the effects of higher levels of systolic blood pressure (SBP) and low density lipoprotein cholesterol (LDL-C) were shown to be independent and cumulative, providing a clear rationale for targeting both simultaneously.
 
Using a 2x2 factorial Mendelian randomization study, the investigators incorporated genetic and cardiovascular risk-factor data from 102,773 subjects included in 14 prospective cohort or case-control studies. These data were used to calculate genetic risk scores for each patient based on single nucleotide polymorphisms known to be associated with LDL-C or SBP. Combined exposure to lower LDL-C and lower SBP was significantly greater than the effect of lower LDL-C alone (P=1.4x10-14) and significantly greater than the effect of lowering blood pressure alone (P=1.8x10-23). Combined exposure to 1 mmol/L lower LDL-C and 10 mm Hg lower SBP was associated with an 86.1% lower risk of cardiovascular disease events, as well as an 84% reduction in coronary heart disease mortality. The effect was similar in men and women, smokers and nonsmokers, people with and without diabetes, as well as those with normal blood pressure and cholesterol levels.
A naturally randomized trial comparing the effect of long-term exposure to lower LDL-C, lower SBP, or both on the risk of cardiovascular disease.

Ference B et al.

ESC Congress 2016 - Abstract 3163

News from ESC Congress 2016 Rome
Updated ESC/EAS dyslipidaemia guidelines launched

An update to the 2011 Joint Guidelines for management of Dyslipidemia was launched at this year’s Congress. The key messages for clinicians are:
• Lifestyle is the fundamental first step in cardiovascular disease prevention and should be supported by clinicians
• Low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for intervention to reduce cardiovascular risk; the guidelines give both targets and per cent reduction required for high and very high risk patients
• Nonfasting lipid measurement is recommended for routine screening.
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).

Catapano AL, Graham I, De Backer G et al.

Association of microvascular and macrovascular diabetic complications

The R3i has previously discussed the proposal that the presence of microvascular complications is predictive of cardiovascular events (1). This report adds to this argument, showing that coronary atherosclerosis and plaque vulnerability are more severe in individuals with diabetic retinopathy.
 
This study evaluated the extent and severity of coronary atherosclerosis in 57 diabetes patients with coronary artery disease, either with (n=15) or without (n=42) diabetic retinopathy. The extent of coronary atherosclerosis (yellow plaques) in at least one coronary artery was quantitated, and the severity assessed by colour rating (1 = light yellow; 2 = yellow, or 3 = intense yellow). Over a mean follow-up of 7.1 ± 3.3 years, patients with diabetic retinopathy not only had more coronary atherosclerosis (mean yellow plaques per vessel 2.08 ± 1.01 vs.1.26 ± 0.77, p = 0.002), but also more severe coronary atherosclerosis (mean rating 2.40 ± 0.74 vs. 1.90 ± 0.82, p = 0.044) compared with those without. In addition, the incidence of acute coronary syndromes (ACS) was significantly higher in those with diabetic retinopathy (p = 0.004), with nearly 7-fold higher risk of ACS (adjusted hazard ratio 6.943, 95% confidence interval, 1.267–38.054; p = 0.026). The finding that coronary atherosclerosis is more prevalent and more severe in patients with diabetic retinopathy suggests a link between diabetes-related microvascular complications and macrovascular plaque vulnerability.
 
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.
Impact of diabetic retinopathy on vulnerability of atherosclerotic coronary plaque and incidence of acute coronary syndrome.

Kurihara O, Takano M, Mizuno K et al.

Anagliptin may mediate benefit via reduction in remnant cholesterol

The gliptins or dipeptidyl peptidase 4 (DPP4) inhibitors, are widely accepted therapy for the management of type 2 diabetes, although their effects on cardiovascular outcomes so far remains uncertain. In this small cohort, one of these agents, anagliptin, was shown to have beneficial effects on arterial stiffness in patients with type 2 diabetes, independent of glucose lowering effects. This study included 50 patients (mean age 72.5±9.5 years, 66% male) who were randomized to treatment with anagliptin (n=26) or glimepiride (n=24) for 6 months. Arterial stiffness was measured by the cardio-ankle vascular index at baseline and the end of treatment. Anagliptin significantly reduced both low-density lipoprotein cholesterol and remnant-like particle cholesterol, as well as hepatic enzymes (alanine aminotransferase). Multiple regression analysis showed that the absolute change in remnant cholesterol was an independent predictor of the change from baseline to 6 months in the cardio-ankle vascular index. These findings suggest a potential benefit of anagliptin on arterial stiffness, possibly mediated by reduction in atherogenic remnant cholesterol.
Anagliptin, a dipeptidyl peptidase-4 inhibitor ameliorates arterial stiffness in association with reduction of remnant-like particle cholesterol and alanine transaminase levels in type 2 diabetic patients.

Tahara N1, Yamagishi SI, Bekki M et al.

NIPPON DATA 90: Non-HDL cholesterol is a predictor of long-term coronary mortality

Follow-up of the NIPPON DATA 90 prospective general population cohort study showed an association between non-high-density lipoprotein cholesterol (non-HDL cholesterol) and risk for death from coronary heart disease.
 
NIPPON-DATA 90 (National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005) is a large cohort study of cardiovascular disease in the general population in Japan. This report investigated whether non-HDL cholesterol, which includes low-density lipoprotein (LDL) cholesterol, was predictive of cardiovascular mortality in 8383 subjects followed up for 20 years. In 6701 subjects with lipid data aged <75 years and without a history of cardiovascular disease, 69 died from coronary heart disease and 112 from stroke over this period. Compared with subjects with non-HDL cholesterol <3.9 mmol/L, the risk of coronary heart disease death increased by 27% with non-HDL cholesterol levels of 3.9-4.3 mmol/L (hazard ratio 1.27, 95% confidence interval 0.65-2.49), by 81% in those with levels of 4.4-4.8 mmol/L (hazard ratio 1.81, 95% confidence interval 0.92-3.55), and by 240% in those with levels ?4.9 mmol/L (hazard ratio 2.40, 95% confidence interval 1.30-4.43). This association remained significant after adjustment for other cardiovascular risk factors (P trend=0.010). However, there was no significant association between non-HDL cholesterol and stroke.
 
These findings reaffirm the importance of non-HDL cholesterol as a predictor of future coronary heart disease death, as reported from analyses in Caucasian subjects.
Relationship between non-high-density lipoprotein cholesterol and the long-term mortality of cardiovascular diseases: NIPPON DATA 90

Ito T, Arima H2, Fujiyoshi A1 et al.

Targeting atherogenic dyslipidaemia: the next lipid frontier

This timely perspective highlights the unmet clinical need due to non-low-density lipoprotein abnormalities that contribute to residual cardiovascular risk in high risk patients. In particular, the report highlights the marked increase in the prevalence of atherogenic dyslipidaemia, characterised by hypertriglyceridaemia, low plasma concentration of high-density lipoprotein (HDL) cholesterol, and qualitative changes in LDL particles. The increase in the prevalence of this dyslipidaemic profile has been especially notable in Latin and South America and South East Asia, in line with adoption of a sedentary lifestyle and Westernised diet on top of high habitual carbohydrates intake. This review discusses the underlying pathophysiology contributing to the development of this dyslipidaemia, current therapeutic options, as well as novel therapeutic strategies that target elevated triglyceride-rich lipoprotein particles which may offer promise in reducing the high residual cardiovascular risk.
Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol.

Xiao C, Dash S, Morgantini C et al

Volanesorsen: favourable effects on atherogenic dyslipidaemia in type 2 diabetes

Volanesorsen, a second generation antisense inhibitor of apolipoprotein (apo) CIII, substantially reduced plasma apoC-III and triglycerides in type 2 diabetes patients with elevated triglycerides (>200 and <500 mg/dL). Treatment was also associated with marked improvement in insulin sensitivity. This randomized, double-blind, placebo-controlled trial enrolled 15 type 2 diabetes patients (mean age 56.5 years, 73% women, mean HbA1c 7.9%, baseline triglycerides 249 mg/dL). Patients were allocated to treatment with volanesorsen 300 mg or placebo administered subcutaneously on days 1, 3, 5, 8, 15, 22, 29, 35, 42, 49, 56, 63, 70, 78, and 85 (15 doses). Insulin sensitivity was assessed using a two-step hyperinsulinaemic-euglycaemic clamp procedure, before and after study treatment. Eleven of the 15 patients received all 15 doses. Compared with placebo, treatment with volanesorsen resulted in significant reductions in apoCIII by 88% and triglycerides by 69% (p<0.05), and also increased high-density lipoprotein cholesterol by 42% (p<0.05). Intriguingly, there was also significant improvement in whole-body insulin sensitivity (by 57%, p<0.001), in relation to changes in both apoCIII and triglycerides (p=0.03 and p=0.01, respectively). On the strength of these findings, albeit in a small sample of patients treated for a short duration, further investigation of the efficacy of volanesorsen to better define those patients most likely to benefit from treatment is merited.
Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes

Digenio A, Dunbar RL, Alexander VJ et al.

AIM-HIGH: should we refocus on HDL subfractions?

AIM-HIGH failed to show that targeting high-density lipoprotein cholesterol (HDL-C) reduced cardiovascular events. This secondary analysis suggests that refocusing on HDL subclass, specifically HDL3-C (very-small and denser HDL) may be more relevant in explaining the link between HDL-C and cardiovascular risk.
 
In AIM-HIGH, subjects with cardiovascular disease and low baseline HDL-C concentration were randomized to treatment with simvastatin plus placebo or simvastatin plus extended release niacin 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain on-treatment low-density lipoprotein cholesterol (LDL-C) levels in the range of 40–80 mg/dL. The primary endpoint of the study was a composite of death from coronary disease, nonfatal myocardial infarction, ischaemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. This secondary analysis evaluated baseline levels of HDL-C, HDL3-C, small dense LDL-C and LDL-triglycerides in 3,094 study subjects on statin therapy before entering the study. The investigators showed that baseline HDL3-C was protective against cardiovascular events (hazard ratio 0.84, p = 0.043). None of the other baseline lipid parameters were associated with risk for cardiovascular events.
Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial.

Albers JJ, Slee A, Fleg JL et al.

Fitness and atherogenic dyslipidaemia

Maintaining fitness over the long-term protects against the development of atherogenic dyslipidaemia, according to this report. This study evaluated data from subjects who completed at least three comprehensive medical examinations, including at least one maximal treadmill test, between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Over an average follow-up of 8.85 years, 193 subjects developed atherogenic dyslipidaemia, defined as low plasma concentration of high-density lipoprotein cholesterol <40 mg/dL, triglycerides ?200 mg/dL, and low-density lipoprotein cholesterol ?160 mg/dL. Individuals who maintained a high level of fitness over this period were 44% less likely to develop atherogenic dyslipidaemia compared with those with reduced fitness, even after adjustment for baseline confounders and changes in other established cardiovascular risk factors (odds ratio 0.56; 95% confidence interval 0.34-0.91). These findings provide another reason why maintaining fitness over time improves cardiovascular health.
The impact of cardiorespiratory fitness levels on the risk of developing atherogenic dyslipidemia

Breneman CB, Polinski K, Sarzynski M et al.

Positive data with apolipoproteinCIII antisense agent

In type 2 diabetes patients, the apolipoprotein(apo) CIII antisense agent volanesorsen reduced plasma triglycerides and apoC-III, and also improved insulin sensitivity and glycaemic control. In this phase II double-blind, placebo-controlled study, 15 type 2 diabetes patients with elevated triglycerides (>200 and <500 mg/dl) were randomized to weekly subcutaneous treatment with volanesorsen 300 mg or placebo (2:1) for 13 weeks. Compared with the placebo group, treatment with volanesorsen reduced plasma triglycerides by 69% (p=0.02), apoCIII by 88% (p = 0.02) and raised high-density lipoprotein cholesterol by 42% (p = 0.03). In addition, volvanesorsen treatment led to improvement in whole-body insulin sensitivity by 57% (p < 0.001). This improved insulin sensitivity was associated with reduction in both plasma apoCIII (r = ?0.61, p = 0.03) and triglycerides (r = ?0.68, p = 0.01). There were also improvements in markers of glycaemic control, including glycated albumin, haemoglobin A1c and fructosamine at the end of the study. The adverse event profile in each group was similar and there were no clinically relevant changes in safety parameters including haematology, clinical chemistry or urinalysis values. These findings suggest another agent with promise for the management of type 2 diabetes patients with atherogenic dyslipidaemia.
Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes

Digenio A, Dunbar RL, Alexander VJ.

HDL cholesterol paradox in residual cardiovascular risk

Data from the prospective Second Manifestations of ARTerial disease (SMART) cohort suggested that higher levels of high-density lipoprotein (HDL) cholesterol at baseline are associated with increased cardiovascular risk in type 2 diabetes patients with controlled low-density lipoprotein (LDL) cholesterol concentration. In total, 1,829 type 2 diabetes patients (mean age 60 years, 70% men, 60% on lipid lowering therapy) were included. Over a median follow-up of 7 years, there were 335 new cardiovascular events (myocardial infarction [MI], ischaemic stroke, vascular death) and 385 patients died. In all patients, the risk of MI decreased by 7% per 0.1 mmol/L increase in HDL cholesterol concentration (adjusted hazard ratio 0.93, 95% confidence interval 0.87–1.00); there was no association with any other endpoint. However, baseline plasma HDL cholesterol concentration was not associated with risk of cardiovascular events (hazard ratio 0.97, 95% confidence interval 0.93–1.01) or all-cause death (hazard ratio 0.99, 95% confidence interval 0.96–1.03). Subgroup analyses did suggest that LDL cholesterol concentration may modify the association between HDL cholesterol and cardiovascular events or all-cause death. Indeed, the risk of cardiovascular events was 10% higher (hazard ratio 1.10, 95% confidence interval 1.07–1.21), and all-cause mortality 14% higher (hazard ratio 1.14, 95% confidence interval 1.07–1.21), in individuals with high baseline HDL cholesterol levels and plasma LDL cholesterol concentration <2.0 mmol/L. There was no association in individuals with higher LDL cholesterol levels. These findings may lend some credence to the proposal that an increase in HDL cholesterol concentration is not always beneficial (as shown by dal-OUTCOMES), possibly attributable to modification of HDL functionality and/or distribution changes within HDL subclasses. Additionally, whereas low HDL cholesterol concentration has been shown to be a cardiovascular risk factor, supported by extensive evidence, raising HDL cholesterol levels with HDL-targeted therapies has not been shown to reduce cardiovascular events. Taken together, these findings raise questions about the relevance of HDL cholesterol to residual cardiovascular risk that persists in high-risk patients despite well controlled LDL cholesterol levels.
HDL cholesterol as a residual risk factor for vascular events and all-cause mortality in patients with type 2 diabetes.

Sharif S, van der Graaf Y, Nathoe HM et al.

ACCORDION: Benefit of fenofibrate on diabetic retinopathy did not persist long-term

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study showed significant benefit with fenofibrate on diabetic retinopathy in type 2 diabetes patients treated with simvastatin, reducing disease progression by about one-third over 4 years. The question posed by clinicians was whether this benefit persisted long-term, beyond the clinical trial.
 
As part of the ACCORD Follow-On (ACCORDION) Eye Study (2010–2014), patients were re-evaluated 4 years after the close of the ACCORD trial. The effect of fenofibrate did not persist long-term; progression of diabetic retinopathy was reported for 11.8% of patients allocated fenofibrate versus 10.2% with placebo (adjusted odds ratio 1.13, 95% confidence interval 0.71–1.79, p=0.60). In contrast, the effects of intensive glycaemic control (which did show significant benefit on retinopathy progression in ACCORD-Eye), were even greater than observed during the trial, with 58% reduction in disease progression (5.8% of patients allocated intensive glycemic treatment versus 12.7% with standard treatment showing progression, adjusted odds ratio 0.42, 95% confidence interval 0.28–0.63, p<0.0001). This benefit persisted despite both groups having similar haemoglobin A1c levels. As in the main trial, intensive blood pressure treatment had no benefit (7.5% with intensive blood pressure treatment versus 6.0% on standard treatment showing progression, adjusted odds ratio 1.21, 95% confidence interval 0.61–2.40, p=0.59).
 
As highlighted by the authors, this is the first study to show that previous intensive glycaemic control in patients with type 2 diabetes for at least 10 years and established cardiovascular disease led to a decrease in diabetic retinopathy progression. However, the effects of fenofibrate in reducing diabetic retinopathy progression did not persist beyond the main trial after the drug was discontinuated. This lack of lipid-modification lowering legacy benefit might suggest that previous lipid modification may be less relevant in the long-term for mechanism(s) underlying the pathophysiology of diabetic retinopathy.
Persistent effects of intensive glycemic control on retinopathy in type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study.

The Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Study Group

Homocysteine levels are not associated with an atherogenic lipid profile

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease, although the underlying mechanism is not clear. Previous reports have suggested an association between hyperlipidaemia and hyperhomocysteinaemia. According to this report from the Very Large Database of Lipids, however, elevated plasma levels of homocysteine were not associated with an atherogenic lipid profile. The study included data from 18,297 U.S. adults with lipid measurements (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL-C, very low-density lipoprotein and remnant-lipoprotein cholesterol). For subjects in the highest homocysteine quartile, levels of LDL-C, non-HDL-C and HDL-C (p<0.001) were 7-10% lower, and triglyceride-rich lipoproteins were 2-6% higher, in unadjusted analyses. However, these associations were abolished after adjusting for age, sex, HbA1c, insulin, creatinine, and blood urea nitrogen.
Serum homocysteine is not independently associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-21) study.

Lupton JR, Quispe R, Kulkarni K et al.

Lipid-lowering for primary cardiovascular prevention in type 1 diabetes

Findings from the Swedish National Diabetes Register show the importance of lipid-lowering therapy (LLT) in the primary prevention setting for individuals with type 1 diabetes, reducing the risk of cardiovascular disease by 22–44%.
 
People with type 1 diabetes are at increased risk of cardiovascular events compared with the general population, despite recent advances in care. Recent guidelines have recommended statin therapy for type 1 diabetes individuals aged more than 40 years. However, the data for this recommendation, (based on older individuals, half of whom had cardiovascular disease), do not take account of subsequent changes in diabetes management, and thus may not be generalizable to the primary prevention setting.
 
Investigators used propensity scores for treatment with LLT, which were based on 32 baseline clinical and socioeconomic variables, to estimate the effect of LLT in the overall cohort (n=24,230 with type 1 diabetes). Over the mean follow-up of 6 years, 18,843 individuals received no treatment and 5,387 were treated with LLT (97% statins). Compared with untreated individuals, those receiving LLT had a 40% reduction in cardiovascular mortality (hazard ratio [HR] 0.60, 95% CI 0.50–0.72), 44% reduction in stroke (HR 0.56, 95% CI 0.46–0.70), and 22% reduction in myocardial infarction (HR 0.78, 95% CI 0.66–0.92). This study, the first large observational study to explore the effect of LLT in people with type 1 diabetes without previous CVD, highlights the importance of primary prevention with LLT to reduce cardiovascular risk.
Association Between Use of Lipid-Lowering Therapy and Cardiovascular Diseases and Death in Individuals With Type 1 Diabetes

Hero C, Rawshani A, Svensson AM et al.

Triglycerides predictive of arterial stiffness

Arterial stiffness is strongly predictive of atherosclerotic cardiovascular disease. In this community-based, longitudinal cohort from China, lower triglyceride levels were significantly associated with decreases in carotid-femoral pulse wave velocity, indicative of improved arterial function. The study measured carotid-femoral pulse wave velocity [PWV] and carotid-radial PWV in 1,447 subjects (mean age, 61.3 years). Over a median follow-up of 4.8 years, they showed that plasma triglycerides were independently associated with carotid-femoral and carotid-radial PWV (both p<0.001). This association was even stronger in older individuals (>65 years). Using multivariate logistic regression analysis, the investigators showed that every 1 standard deviation increase in plasma triglycerides was associated with a 1.296-increased likelihood of the presence of carotid-femoral PWV (odds ratio 1.296; 95 % CI 1.064 - 1.580; p = 0.01). The investigators concluded that lowering plasma triglycerides offers the potential for improvement in arterial stiffness in individuals with atherosclerotic disease.
Triglycerides are a predictive factor for arterial stiffness: a community-based 4.8-year prospective study

Wang X, Ye P, Cao R, Yang X, Xiao W, Zhang Y, Bai Y, Wu H

HDL mimetic peptide CER-522 improves left ventricular diastolic dysfunction

In this experimental study in rabbits, the HDL mimetic CER-522 improved left ventricular diastolic dysfunction as well as decreasing macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodeling. Experimental left ventricular dysfunction was induced in rabbits fed a cholesterol- and vitamin D2-enriched diet. Subsequently, the rabbits were treated with 10 mg/kg or 30 mg/kg CER-522 infusions 6 times over 2 weeks, or saline infusions (control). Serial echocardiograms and left ventricular histology showed that CER-522 reduced a number of variables indicative of left ventricular diastolic dysfunction, including early filling mitral deceleration time, deceleration rate, and the left ventricular diastolic dysfunction score. Furthermore, CER-522 infusion also reduced macrophage accumulation in the left ventricle, levels of apoptotic cardiomyocytes, as well as atheromatous plaques in the coronary arteries. The results of this study merit further study of CER-522.
HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits.

Merlet N, Busseuil D, Mihalache-Avram T et al.

ASGR1; the next PCSK9 story?

This study, involving data from 2636 Icelandic subjects, focused on the ASGR1 gene, which codes for a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. Researchers identified two loss-of-function ASGR1 variants (del12 and p.W158X) that had significant effects on non-HDL-C. When these data were imputed to the Icelandic population, it was shown that individuals who were heterozygous for the del12 mutation (0.8% of the study population) had 15.3 mg/dL (0.40 mmol/L) lower non-HDL-C levels than noncarriers. Furthermore, these heterozygous individuals also had a 34% reduction in risk for coronary artery disease (p=4.0×10?6). Carriers also had lower triglyceride levels, although the effect was weaker than for non-HDL-C. The other loss-of-function variant (p.W158X, found in 1 in 1,850 people) was associated with 24.9 mg/dL decrease in non-HDL-C levels and 35% decrease in coronary risk, although this was not statistically significant (p=0.24). Replication testing in 42,524 case patients and 249,414 controls from five European ancestry populations confirmed the findings. These variants, which disrupt ASGR1 function, therefore represent a link between the sialylation pathway and atherosclerotic disease. In an accompanying editorial,1 Professor Anne Tybjaerg-Hansen (University of Copenhagen, Denmark) suggested that the findings may offer new therapeutic potential, although elucidation of the underlying mechanism(s) is needed. Indeed, given the magnitude of the effects of coronary risk versus lipids compared with other loss-of-function variants (such as PCSK9), this might suggest that the mutation also impacts non-lipid pathways, such as those involving inflammatory mediators. Research is ongoing to identify the target molecule with the aim of developing novel therapies.
 
1. Tybjærg-Hansen A. The sialylation pathway and coronary artery disease. N Engl J Med. 2016 May 18. [Epub ahead of print].
Variant ASGR1 associated with a reduced risk of coronary artery disease.

Nioi P, Sigurdsson A, Thorleifsson G et al.

Fibroblast growth factor 21: potential for diagnosis of early stage diabetic retinopathy?

This study suggests that elevated serum fibroblast growth factor 21 (FGF21) levels (>135.5 pg/ml) may be a novel diagnostic biomarker in the initial stages of diabetic retinopathy in individuals with type 2 diabetes.
 
This cross-sectional study included 142 type 2 diabetes patients, with and without diabetic retinopathy. Compared with healthy controls, serum FGF21 levels were elevated in subjects with type 2 diabetes but without retinopathy (mean [SD] 103.50 [75.75] pg/ml versus 99.00 [126.75] pg/mL), and even higher across different stages of diabetic retinopathy (233.00 [109.00] pg/ml for nonproliferative diabetic retinopathy and 215.00 [122.00] pg/ml for proliferative diabetic retinopathy). After adjustment for potential confounders, FGF21 was shown to be the only significant factor associated with diabetic retinopathy in type 2 diabetes patients.
Serum fibroblast growth factor 21 concentrations in type 2 diabetic retinopathy patients.

Esteghamati A, Momeni A, Abdollahi A, Khandan A, Afarideh M, Noshad S, Nakhjavani M.

Study identifies novel variant for triglycerides

In this study, fine gene mapping from 95 lipid genome wide association studies (GWAS) loci in people with extremely high and low to normal plasma lipid levels led to the identification of one new coding variant associated with elevated triglycerides.
 
GWAS for plasma lipid levels have mapped numerous genomic loci, with each region often containing many protein-coding genes. Targeted re-sequencing of exons is a strategy to pinpoint causal variants and genes. The study used this approach in individuals with extremely high as well as low to normal levels of low-density lipoprotein cholesterol (n = 311), triglycerides (n = 308), and high-density lipoprotein cholesterol (n = 684), and tested whether coding sequence variants, individually or aggregated within a gene, were associated with plasma lipid levels. Findings were replicated by sequencing in independent participants (n = 6,424). Overall, the study identified 6 variants with significant associations with plasma lipids; however, only one of these had a novel association with triglycerides (p.Ser147Asn variant in APOA4, 14.3% frequency).
 
In conclusion, these results provide further insight into the genetic control of lipid traits, specifically elevated triglycerides. Fine mapping GWAS loci may, however, have limitations in studying the cause of these signals.
Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution

Patel AP, Peloso GM, Pirruccello JP, Johansen CT, Dubé JB, Larach DB, Ban MR, Dallinge-Thie GM, Gupta N, Boehnke M, Abecasis GR, Kastelein JJP, Hovingh GK, Hegele RA, Rader DJ, Kathiresan S.

HDL characteristics beyond HDL cholesterol concentration: marker or mediator of coronary atherosclerosis?

Findings from this study in patients with coronary artery disease suggest that high-density lipoprotein (HDL) particle size and function may act as markers, or even mediators, of coronary atherosclerosis in humans.
 
The study included 80 patients with non-obstructive (<30% stenosis) coronary artery disease. Assessments included endothelial dysfunction, defined as <50% change in coronary blood flow in response to intra-coronary infusions of acetylcholine during diagnostic coronary angiograph; as well as cholesterol efflux capacity and HDL particle concentration (HDL-P). Whereas cholesterol efflux capacity and HDL-P were both significantly and inversely predictive of endothelial dysfunction (p<0.001 and 0.005, respectively), HDL cholesterol concentration was not informative. Therefore, this report supports the value of other measures beyond HDL cholesterol concentration as markers, or potentially mediators of atherosclerosis in patients with established coronary disease.
Patients with coronary endothelial dysfunction have impaired cholesterol efflux capacity and reduced HDL particle concentration.

Monette JS, Hutchins PM, Ronsein GE, Wimberger J, Irwin AD, Tang C, Sara JD, Shao B, Vaisar T, Lerman A, Heinecke JW

Triglyceride/HDL-C ratio: indicator of risk of sleep apnoea syndrome

The ratio of serum triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) may have potential in estimating the risk of sleep apnoea syndrome, according to this study in non-overweight Japanese men. This cross-sectional study included 1,528 men aged 30-69 years being evaluated for sleep apnoea syndrome, diagnosed as a 3% oxygen desaturation index (ODI) of ?15 events/hour. In total, 241 were diagnosed with sleep apnoea syndrome, independent of conventional risk factors, such as elevated body mass index (BMI). In subjects with a BMI <25 kg/m2, the TG/HDL-C ratio was significantly and positively associated with sleep apnoea syndrome; this was not the case in those with a BMI ?25 kg/m2. The risk of sleep apnoea syndrome was 2-fold higher in individuals with an elevated TG/HDL-C ratio and BMI <25 kg/m2, driven by high triglycerides (multivariable adjusted odds ratio per Log TG-HDL: 2.03, 95 % CI 1.36-3.03). br> 
Taken together, these findings suggest that the TG/HDL-C ratio could have potential in estimating the risk of sleep apnoea syndrome in these individuals, although further study is also merited.
Serum triglyceride levels in relation to high-density lipoprotein cholesterol (TG-HDL) ratios as an efficient tool to estimate the risk of sleep apnea syndrome in non-overweight Japanese men

Shimizu Y, Yoshimine H, Nagayoshi M, Kadota K, Takahashi K, Izumino K, Inoue K, Maeda T.

Death knell for CETP inhibition? More details on ACCELERATE with evacetrapib

Treatment with evacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, did not reduce cardiovascular events, despite substantially raising high-density lipoprotein cholesterol (HDL-C, increase by 130%) and lowering low-density lipoprotein cholesterol (LDL-C, decrease by 37%).
 
ACCELERATE was a phase 3, multicenter randomized, double-blind trial involving 12,092 patients (mean age 65 years, 23% female, mean body mass index 30.2 kg/m2 and 68% with diabetes) with either an acute coronary syndrome, cerebrovascular atherosclerotic disease, peripheral vascular disease or diabetes with coronary artery disease. Patients were randomized 1:1 to evacetrapib 130 mg daily (n=6,038) or placebo (n=6,054) in addition to standard medical therapy. Almost all (96%) patients were treated with a statin at baseline, although only 46% were treated with high-intensity statin. The total duration of follow-up was 30 months (following termination due to futility). At baseline, mean HDL-C was 45 mg/dl and mean LDL-C was 81 mg/dl.
 
The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization and unstable angina. There was no difference in the incidence of the primary outcome over the follow-up period (12.8% for the evacetrapib group vs. 12.7% for placebo, p = 0.85). Similarly, there was no significant effect for any of the individual components of the primary outcome. All-cause mortality was lower in the evacetrapib group but this was not significant (3.8% vs. 4.1% on placebo, p = 0.06).
 
In terms of lipids, mean HDL-C at the end of follow-up was 104 mg/dl vs. 46 mg/dl on placebo (p<0.001); mean LDL-C was 55 mg/dl vs. 84 mg/dl (p < 0.001).
 
There was no difference between the two groups with respect to treatment discontinuation due to adverse events (8.6% in the evacetrapib group vs. 8.7% on placebo, p = 0.86).
 
The reasons for the lack of benefit of evacetrapib in ACCELERATE are so far unclear. The functionality of HDL particles generated by CETP inhibition was also questioned with respect to reverse cholesterol transport and/or other beneficial characteristics. The accumulating evidence suggests that CETP inhibition may not be a good strategy to mitigate residual cardiovascular risk; results are awaited from the ongoing outcomes trial with anacetrapib (REVEAL).
Death knell for CETP inhibition? More details on ACCELERATE with evacetrapib

Dr. Stephen J. Nicholls

The American College of Cardiology Annual Scientific Session, Chicago, IL, April 3, 2016.

HDL cholesterol implicated in hypertension

Both low and high HDL cholesterol concentration was associated with risk for development of hypertension in a Japanese working-age male population, according to this report.
  The study included data from 14,215 non-hypertensive male workers (mean age 38±9 years) who were followed up for new-onset hypertension, defined as blood pressure ?140/90 mm Hg or use of antihypertensive medication. Over a median of 4 years, 1,483 subjects developed hypertension. After adjustment for conventional cardiovascular risk factors, including age, body mass index, impaired fasting glucose/diabetes, baseline blood pressure, alcohol intake, smoking, exercise, and parental history of hypertension, the study reported a U-shaped relationship for HDL cholesterol concentration and risk of hypertension, with increased risk confined to the lowest and highest HDL cholesterol quartiles (increase in risk of developing hypertension by 22% and 34%, respectively). In contrast, only elevated total, low-density lipoprotein cholesterol and non-HDL cholesterol were associated with increased risk of developing hypertension in this Japanese cohort.
Dyslipidemia and the risk of developing hypertension in a working-age male population.

Otsuka T, Takada H, Nishiyama Y et al

Isolated low HDL cholesterol prevalent in Peru

Isolated low plasma HDL cholesterol concentration was the predominant lipid profile in this analysis of the PERU MIGRANT study, which aimed to investigate the effect of migration on cardiovascular risk profiles and mortality in Peru.
 
This report included data from 988 migrants in Peru, 201 in a rural setting, 598 who moved from rural-to-urban setting and 199 urban subjects. Baseline data (collected in 2007 to 2008) were used for cross-sectional analyses and 5-year follow-up data (2012-2013) were used in the longitudinal analysis. Overall, low HDL cholesterol was prevalent, in 56% of cases, with isolated low HDL cholesterol the predominant phenotype (36% of cases). Multivariable analysis showed that isolated low HDL cholesterol was more prevalent in urban than rural migrants, and in women than men. Elevated body mass index was associated with both isolated and non-isolated low HDL cholesterol concentrations. However, only non-isolated HDL cholesterol was associated with increased cardiovascular mortality, increasing risk by more than 3-fold.
Low HDL cholesterol as a cardiovascular risk factor in rural, urban, and rural-urban migrants: PERU MIGRANT cohort study

Lazo-Porras M, Bernabe-Ortiz A, Málaga G et al

Low HDL cholesterol and risk for chronic kidney disease

Low HDL cholesterol has already been shown to be an independent risk factor for the development of diabetic kidney disease in the ADVANCE study.1 This study investigated whether this association extended to a wider population including patients with and without diabetes.
 
Researchers used survival models to investigate the association between HDL cholesterol and the risk of incident chronic kidney disease (CKD) and CKD progression, based on a cohort of 1,943,682 male US veterans. Progression of CKD was defined as doubling of serum creatinine, estimated glomerular filtration rate (eGFR) decline of ?30%, or a composite outcome of end-stage renal disease, dialysis, or renal transplantation. The models were adjusted for demographics, comorbid conditions, eGFR, body mass index, lipid parameters, and statin use over a median follow-up of 9 years. Compared with individuals with an HDL concentration of ?40 mg/dl, those with low HDL-C, defined as <30 mg/dl, had a 20% higher risk of incident CKD (odds ratio 1.20, 95% CI 1.18-1.22), and were also at higher risk of CKD progression, as defined by doubling of serum creatinine (odds ratio 1.14, 95% CI 1.12-1.15) GFR decline of ?30% (odds ratio 1.13, 95% CI 1.12-1.14), and the composite renal end point (odds ratio 1.08, 95% CI 1.06-1.11). In summary, the analysis showed that low HDL cholesterol was associated with increased risk of incident CKD and CKD progression, suggesting the need for its incorporation within risk factor screening panel.
 
1. Morton J, Zoungas S, Li Q et al. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy. Diabetes Care 2012;35:2201–6.
Low levels of high-density lipoprotein cholesterol increase the risk of incident kidney disease and its progression.

Bowe B, Xie Y, Xian H et al.

VADT: Higher HDL cholesterol decreases risk of progression of diabetic retinopathy

Continuing on the HDL theme, this report from the Veterans Affairs Diabetes Trial (VADT) showed that individuals in the intensive glycaemic arm with higher plasma levels of HDL cholesterol had a lower risk for progression of diabetic retinopathy. VADT was a randomized unblinded clinical trial in patients with type 2 diabetes, comparing tight glycaemic control (HbA1C ~7%) with standard glycaemic control (HbA1c 8-9%). In this report, the incidence and progression of diabetic retinopathy (DR) were assessed in 858 of 1,791 subjects with 7-field stereoscopic fundus photographs at baseline and follow-up 5 years later. At 5 years, the risk of DR progression was reduced by ~40% in individuals in the intensive glycaemic arm with lower levels of total cholesterol (?140 mg/dl, p ? 0.024) or triglycerides (?120 mg/dl, p = 0.004), and higher HDL cholesterol concentration (?40 mg/dl, p< 0.007). After adjustment for covariates, including conventional cardiovascular risk factors, both lower total cholesterol at 5 years, and higher HDL cholesterol during the study were associated with reduction in the risk of DR progression in the intensive glycaemic control arm. High HDL cholesterol plasma concentration was also associated with a better response to intensive glycaemic treatment.
Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT).

Azad N, Bahn GD, Emanuele NV et al

Not all HDL cholesterol is good

Low plasma concentration of high-density lipoprotein (HDL) cholesterol is recognized as a risk factor for cardiovascular disease, supported by an extensive epidemiologic evidence-base. However, trials investigating the potential of HDL-targeted therapy have so far proved negative. The results of a new report add to the mystifying HDL story. Individuals with a rare genetic variant for scavenger receptor BI (SR-BI), which results in the receptor being unable to take up HDL, not only had higher HDL cholesterol levels but also a higher risk of coronary disease.
 
Using targeted gene sequencing of plasma samples from 328 individuals with high HDL cholesterol levels (mean 106.8 mg/dL), researchers identified a homozygote for a loss-of-function variant in SCARB1, the gene encoding SR-BI (P376L). This P376L variant was shown to impair the function of the SR-BI receptor resulting in reduced HDL cholesterol uptake in in vitro cell systems. Subsequently, in a meta-analysis of 16 population-based genotyping studies including 300,00 individuals, this rare variant was also identified (minor allele frequency 0.0003). Individuals who were heterozygous for this P376L variant had significantly elevated plasma HDL cholesterol concentration, with no impact on levels of low-density lipoprotein cholesterol or triglycerides. Moreover, carriage of the P376L variant was also associated with 79% increased risk for coronary heart disease (p=0.02). HDL biology is complex, with emerging evidence suggesting that HDL function and cholesterol flux may be more important than absolute plasma levels. The twists and turns of the HDL story continue…..
Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Zanoni P, Khetarpal SA, Larach DB et al; CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium.

Triglyceride-rich lipoproteins and cardiovascular disease: bringing the story together

This timely review brings together latest findings from epidemiological and genetic studies which make the case for reconsideration of triglyceride-rich lipoproteins in cardiovascular disease (CVD) management guidelines. There is now accumulating evidence that triglyceride-rich lipoproteins (for which high triglycerides are a marker), are strong and independent predictors of atherosclerotic cardiovascular vascular disease (ASCVD) and that the cholesterol or remnant cholesterol content of these lipoproteins are strong predictors of ASCVD. The relevance of these findings are underscored by the increasing prevalence of hypertriglyceridaemia (and by association, elevated remnant cholesterol), as a result of the ongoing obesity pandemics. For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) versus those with levels of 0.8 mmol/L (70 mg/dL), the risk for myocardial infarction was more than 5-fold higher, ischaemic heart disease or ischaemic stroke more than 3-fold higher, and all-cause death more than 2-fold higher. There is also genetic evidence to suggest that an important part of inflammation in atherosclerosis and ASCVD is due to degradation and uptake of triglyceride-rich lipoproteins and their remnants into macrophage foam cells in the arterial intima. Thus, triglyceride-rich lipoproteins may contribute to both lipid-related risk as well as other components of residual cardiovascular risk.
Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology.

Nordestgaard BG.

SPIKE: a role for dipeptidyl peptidase 4 inhibitors in atheroma regression

Treatments that attenuate atheroma progression may offer potential for reduction in cardiovascular risk. This is pertinent when considering results from the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). SPIKE was a prospective, randomised, open-label, blinded end point study in 282 insulin-treated patients with type 2 diabetes and without a history of overt cardiovascular disease at baseline. Patients were randomly allocated to sitagliptin (n = 142) or control (n = 140). The primary outcomes were changes in mean and maximum common carotid intima-media thickening (CIMT), as measured by echography at the end of a 104-week treatment period. Sitagliptin treatment was associated with significant attenuation of the mean and left maximum CIMT, but not right maximum CIMT versus control (mean [standard error [SE]: ?0.029 [0.013] vs. 0.024 [0.013] mm, p = 0.005; ?0.065 [0.027] vs. 0.022 [0.026] mm p = 0.021; ?0.007 [0.031] vs. 0.027 [0.031] mm, p = 0.45], respectively). However, whether this effect of treatment translates to reduction in cardiovascular outcomes is uncertain. With a lack of major adverse cardiovascular events in Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) (1) and other recent dipeptidyl peptidase 4 inhibitors CV safety trials (such as saxagliptin (SAVOR-TIMI) and alogliptin (EXAMINE)), further study is warranted. 1. Green JB, Bethel A, Armstrong PW et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373:232-42.
Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). A randomized controlled trial.

Mita T, Katakami N, Shiraiwa T et al; on behalf of the Collaborators on the Sitagliptin Prevention Study of Intima-Media Thickness Evaluation (SPIKE) Trial

Apolipoprotein B predicts subclinical atherosclerosis

Apolipoprotein (apo) B may be an important predictor of coronary risk in young adult life, given its association with the development of coronary artery calcification in later life, according to results from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Data on apoB, cardiovascular risk stratification, and coronary artery calcium score after 25 years from 2,794 adults (recruited at age 18 to 30 years, mean age: 25 ± 3.6 years; 44% male) were evaluated. The presence of coronary artery calcium was defined by a positive, nonzero Agatston score on computed tomography. Discordance analysis, in which biologically linked variables are analysed by groups of concordance or discordance between their relative distributions, was used to avoid predictive capacity in the discordant groups attenuating correlation between the markers of risk in concordant groups. A key finding was that individuals in the middle or high apoB tertile were at higher odds of developing coronary artery calcium at 25 years than those in the lowest apoB tertile, with adjustment for conventional cardiovascular risk factors (odds ratio [OR] 1.53 and 2.28, respectively). The odds of coronary artery calcium at 25 years was highest for individuals with high apoB/high low-density lipoprotein (LDL) cholesterol (OR 1.55) and high apoB/high non–high-density lipoprotein cholesterol (OR 1.45), representing the highest numbers of apoB particles and/or small-dense LDL. As well as being associated with both of these lipid parameters, apoB was also directly related to triglyceride levels (a marker for triglyceride-rich apoB-containing lipoproteins). Taken together, these data suggest that measurement of apoB levels may have value as a predictor of future cardiovascular risk.
Discordance between apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery calcification. The CARDIA Study.

Wilkins JT, Li RC, Sniderman A, Chan C, Lloyd-Jones DM.

Mechanistic insights into how FGF21 lowers triglycerides

Fibroblast growth factor 21 (FGF21), an endocrine factor secreted mainly by the liver in response to peroxisome proliferator-activated receptor-? (PPAR?) activation, exerts favourable effects on glucose and lipid metabolism in animal models and humans. This study proposes a dual mechanism to explain the triglyceride-lowering effects of FGF21, balancing effects in white adipose tissue (WAT, predominantly involved in energy storage and mobilisation) and brown adipose tissue (BAT, involved in non-shivering body thermogenesis). In a murine model, treatment with FGF21 led to reduction in plasma non-esterified fatty acids, hepatic triglyceride content, and very low-density lipoprotein -triglyceride secretion. Metabolic turnover studies provided insights into how FGF21 achieved these changes, by favourable effects on the catabolism of triglyceride-rich lipoproteins in WAT and BAT. In transgenic mice deficient in lipoprotein lipase, these effects were attenuated. Additionally, insulin resistance shifted the FGF21 responses from WAT to BAT. These findings merit further investigation in animal and human studies.
FGF21 lowers plasma triglycerides by accelerating lipoprotein c atabolism in white and brown adipose tissues.

Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, Brenner MB, Heeren J, Scheja L.

Legacy effects of statins: WOSCOPS

Long-term follow-up of the West of Scotland Coronary Prevention Study (WOSCOPS) showed persistent clinical benefits and reduction in the burden of cardiovascular disease associated with 5 years of statin therapy. The study results reaffirm the benefit of low-density lipoprotein (LDL) cholesterol lowering in a primary prevention setting. However, it is important to note that statin treatment does not eliminate the risk of a cardiovascular event in this population, reinforcing the case for targeted intervention of multiple risk factors. WOSCOPS was one of the early large-scale statin studies, in which 6,595 middle-aged men with an average baseline LDL cholesterol of 4.9 mmol/L (190 mg/Dl) and no existing cardiovascular disease were randomised to treatment with pravastatin 40 mg/day or placebo. Results of the 5-year outcomes study showed a 31% reduction in the relative risk of cardiovascular death or myocardial infarction (MI). As the Scottish national healthcare system captures data relating to the utilisation of medical services, analysis of 20-year outcomes in former study subjects was possible. The only treatment difference between the two original study arms was that the pravastatin group had been on statin therapy for an additional 5 years. After 20 years, patients allocated to pravastatin in the original trial had a 21% reduction in cardiovascular death (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69-0.90, p=0.0004), which contributed to 13% reduction in all-cause death (HR 0.87, 95% CI 0.80-0.94, p=0.0007). Thus, these individuals gained an average of 5 extra years free of nonfatal MI or cardiovascular death over this time. Additionally, while the trial showed no benefit on heart failure, 20-year follow-up indicated a 35% reduction in the incidence of hospitalisation for heart failure (p=0.002), an important contributor to the clinical and socioeconomic burden of cardiovascular disease. There was no effect of statin on non-cardiovascular death or cancer death. Given the time frame of follow-up, the findings imply improvement in lifetime benefit associated with 5 years of statin treatment in middle-age. However, it is also important to bear in mind an obvious study limitation; i.e. that information on lipid regulating therapy during the last 10 years of follow-up was not available.
Long term safety and efficacy of lowering LDL cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study

Ford I, Murray H, McCowan C, Packard CJ

Diet superior to exercise for improving dyslipidaemia in high risk patients

Diet, weight loss, and physical activity are fundamental to the management of dyslipidaemia and prevention of cardiovascular disease. This study compared the effects of dietary intervention and intensive exercise training on the atherogenicity of the lipid profile and low-grade inflammation in high risk patients with established coronary artery disease. In total, 70 non-diabetic patients (body mass index 28-40 kg/m2, aged 45-75 years) were randomised to aerobic interval training (85-90% of peak heart rate 3 times/week) or a low energy diet (800-1000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet. The total duration of each intervention was 12 weeks. Lipoprotein particle size and density profiling were assessed to define the atherogenicity of the lipid profile before and after treatment. Low-grade inflammation was evaluated by tumour necrosis factor alpha (TNF?), C-reactive protein, interleukin 6 and soluble urokinase plasminogen activator receptor levels. Among patients who completed the 12-week study period (26 on aerobic exercise training and 29 on diet), both interventions were shown to significantly reduce total and low-density lipoprotein (LDL) cholesterol. However, the dietary intervention was superior to the exercise intervention for decreasing the atherogenicity of the lipid profile, as reflected by increased LDL (p = 0.003) and high-density lipoprotein (P = 0.026) particle size and a decreased proportion of total lipoprotein constituted by the small, dense LDL subfraction (p = 0.004). The dietary intervention alone also decreased TNF? (p = 0.009). In conclusion, the findings from this small study indicate that this dietary intervention was superior in decreasing the atherogenicity of the lipid profile, with limited effect on low-grade inflammation.
Weight loss is superior to exercise in improving the atherogenic lipid profile in a sedentary, overweight population with stable coronary artery disease: A randomized trial.

Pedersen LR, Olsen RH, Anholm C et al.

Empowering the diabetic patient improves cardiovascular and microvascular outcomes

In obese type 2 diabetes patients without pre-existing cardiovascular disease, a structured diabetes education programme (Patient Empowerment Programme [PEP]), is effective in reducing the first occurrence of cardiovascular or microvascular diabetes-related complications. The study enrolled 6, 372 patients allocated to the programme, who were matched one-to-one with controls (non-PEP patients), using a propensity score method with respect to their baseline covariates. Over a median duration of 31.5 months, 350 (PEP/non-PEP: 151/199) patients experienced a first macrovascular or microvascular event and 95 patients (PEP/non-PEP: 34/61) died from any cause. After adjustment for confounding variables, patients allocated to the PEP had lower incidence rates of all-cause mortality [hazard ratio (HR): 0.589, 95 % confidence interval (CI) 0.380-0.915, P = 0.018] and first macrovascular or microvascular disease events (HR: 0.782, 95 % CI 0.632-0.968, P = 0.024) than those who did not take part in the PEP. These findings underline the importance of involving patients in their management to improve outcome in type 2 diabetes.
Macrovascular and microvascular disease in obese patients with type 2 diabetes attending structured diabetes education program: a population-based propensity-matched cohort analysis of Patient Empowerment Programme (PEP)

Wong CK, Wong WC, Wan EY et al.

Polypill benefits modified by cardiovascular risk

Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy, lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular exercise, weight loss, smoking cessation) is the cornerstone of cardiovascular disease prevention. Fixed-dose combination treatments, or polypills, have been proposed as a means of optimising adherence and have been shown to reduce cardiovascular risk. Questions remain, however, as to whether the benefit varies according to the level of risk in the patient population. This question was investigated in a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but with an estimated five-year risk for cardiovascular disease ?7.5%. During follow-up, patients in the polypill group had low-density lipoprotein cholesterol (LDL-C) levels which were lower on average by 0.9 mmol/l (95% confidence interval (CI) 0.8-1.0) than those on placebo. Individuals with elevated LDL-C at baseline (>3.6 mmol/l) derived greater benefit from treatment with the polypill than those with a lower baseline LDL-C (placebo-corrected, -1.1 versus -0.6 mmol/l, respectively). Additionally, individuals with elevated systolic blood pressure at baseline (>135 mm Hg) had a greater absolute blood pressure reduction than those with a lower systolic blood pressure (placebo-corrected, -12 versus -7 mm Hg, respectively). Overall, the mean cardiovascular relative risk reduction associated with polypill treatment was 48% (95% CI 43-52%). Both baseline LDL-C and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. In conclusion, these findings indicate that patients with only mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill.
Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease.

Lafeber M, Webster R, Visseren FL et al.

2015

Statin intolerance: a contributor to residual cardiovascular risk?

This analysis investigated real-world lipid lowering treatment based on the IMS LifeLink PharMetrics Plus commercial claims database. Patients who were initiated on statin ± ezetimibe were classified according to history of cardiovascular events (n=41,934) or coronary heart disease risk equivalent (n=170,344). The primary outcomes were index statin intensity, treatment modifications, possible associated statin/nonstatin intolerance and/or ineffectiveness issues (based on treatment modification), and time-to-treatment modifications. Among all patients, about 1 in 4 (25% to 26%) had possible statin intolerance and/or ineffectiveness issues, and up to 1 in 4 (21% to 24%) permanently discontinued lipid lowering treatment during follow-up. These findings implicate statin tolerability issues as common contributors to residual cardiovascular risk. This is highly relevant when considering the cost of cardiovascular disease, estimated to account for $290 billion of annual health-care expenditure in the USA and Euro 1.25 billion in the European Union.
A US Claims-Based analysis of real-world lipid-lowering treatment patterns in patients with high cardiovascular disease risk or a previous coronary event.

Quek RG, Fox KM, Wang L et al.

Novel genetic variants associated with lipids identified in Asian cohorts

The first Asian exome-wide association analysis on blood lipid levels has identified three novel lipid-associated loci in the genes, PNPLA3, PKD1L3 and TEAD2. This study genotyped 145,276 single nucleotide polymorphisms (SNPs) from 12,685 individuals from two Chinese cohorts, the University of Hong Kong Theme-based Research Scheme (N=5,233) and Peking University Health Science Center and the University of Michigan Medical School study of Myocardial Infarction (N=7,452). Single-variant and gene-based association analyses were carried out for four blood lipid levels: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglycerides. The analysis identified 19 loci associated with lipids at exome-wide significance (P<2.69 x 10-7), including three Asian-specific coding variants in in CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp. Missense variants at two novel loci (PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser) were shown to influence plasma levels of triglycerides and LDL-C, respectively, and another novel gene, TEAD2, was associated with HDL-C. Most of these novel variants were implicated with coronary artery disease. These findings highlight the need to take account of genetic differences in lipid heritability in different populations which may influence blood lipids, and hence contribute to differences in susceptibility to cardiovascular disease. Such studies may offer insights into novel biological pathways for lipid metabolism, and potentially, novel therapeutic targets.
Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese.

Tang CS, Zhang H, Cheung CY et al

Medias role in statin adherence and impact on cardiovascular risk reduction

Negative media publicity about statins has been thought to affect patient compliance with therapy. This Danish study provides support for this proposal and also shows a detrimental impact on risk for cardiovascular events. Data from 674,900 adults aged at least 40 years who started statin treatment between 1995-2010 and were followed until 31 December 2011, were evaluated. As the proportion of people on statins increased (from <1% in 1995 to 11% in 2010), early statin discontinuation trebled (from 6% in 1995 to 18% in 2010). Early statin discontinuation was associated with negative statin-related news stories (odds ratio 1.04, 95% CI 1.02-1.07); in contrast, positive news reports had a favourable effect, reducing discontinuation by 27% (odds ratio 0.73, 95% CI 0.72-0.74). Evidence that early statin discontinuation was also associated with increased risk of myocardial infarction (odds ratio 1.26, 95% CI 1.21-1.30) and death from cardiovascular disease (odds ratio 1.18, 95% CI 1.14-1.23) emphasises the need to take preventive action to optimise statin compliance and cardiovascular risk reduction.
Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study.

Nielsen SF, Nordestgaard BG

New review focuses on management of residual risk after statin therapy

While lowering low-density lipoprotein cholesterol (LDL-C) with a statin is the cornerstone of lipid-modifying intervention to prevent cardiovascular disease, it is well recognised that a substantial residual risk of cardiovascular events persists. This review highlights evidence for other lipid abnormalities, including triglycerides, apolipoproteins and lipoprotein(a) (Lp(a)), as contributors to lipid-related residual risk. The evidence for and relative advantages and disadvantages of different therapeutic approaches targeting non-LDL abnormalities is discussed. The review also highlights a role for ezetimibe and PCSK9 inhibitors for further lowering LDL-C to reduce cardiovascular risk.
Management of residual risk after statin therapy.

Reith C, Armitage J

Proteomic analysis highlights differences in apolipoprotein CIII association with triglycerides

Apolipoprotein C-III (apoC-III) plays a key role in regulation of triglyceride metabolism, and is therefore a potential target for therapeutic intervention. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. This study investigated the association of these different apoC-III proteoforms in 204 non-diabetic subjects. The ratios of apoC-III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in subjects who were overweight (n = 33) or obese (n = 155), compared with those with healthy weight (n=16). Moreover, fasting triglycerides were significantly correlated (p<0.001) with the ratio of apoC-III0a/apoC-III2, apoC-III0b / apoC-III2 and apoC-III1 / apoC-III2, implying that the association of apoC-III proteoforms with triglycerides appeared to be driven by apoC-III0a, apoC-III0b and apoC-III1 levels but not apoC-III2. In conclusion, the authors propose that proteomic analysis of apoC-III may provide insights into the biology of triglyceride metabolism in obesity.
The association of human apolipoprotein C-III sialylation proteoforms with plasma triglycerides.

Yassine HN, Trenchevska O, Ramrakhiani A et al.

Remnant cholesterol linked with premature MI

Previous reports have identified that remnant cholesterol, the cholesterol present in triglyceride-rich lipoproteins, is associated with elevated cardiovascular disease risk. This study adds new evidence showing that remnant cholesterol is a risk marker in young individuals with acute myocardial infarction (AMI). This prospective, multicentre, case-control study included 102 consecutive AMI survivors (?40 years) and 200 controls, matched for age, gender and centre. Overall, individuals with AMI had remnant cholesterol levels that were 1.7-fold higher compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL, p <0.001). Each 1 standard deviation increase in remnant cholesterol was associated with nearly 4-fold increase in AMI risk (odds ratio 3.87; 95% confidence interval 2.26-6.64; P <0.001), independent of other lipid levels. These data reinforce the importance of remnant cholesterol as a marker of coronary risk in this patient population.
Premature myocardial infarction is strongly associated with increased levels of remnant cholesterol.

Goliasch G, Wiesbauer F, Blessberger H et al.

Genetic variants of peroxisome proliferator-activated receptor ? linked with susceptibility to diabetic retinopathy

Diabetic retinopathy, one of the key reasons for loss of vision, is associated with substantial morbidity, disability and cost. Yet despite extensive research, the exact mechanism(s) responsible have yet to be fully elucidated. A pathogenic role of diabetes-induced peroxisome proliferator-activated receptor alpha (PPAR-alpha) down-regulation in microvascular dysfunction was previously reported (1). This study implicates PPAR-alpha with diabetic retinopathy in a cohort of Chinese type 2 diabetes patients. The study included 812 type 2 diabetes patients (373 men, 439 women, mean age 53.3±14.0 years), of whom 402 had diabetic retinopathy. The authors looked at the association between three single nucleotide polymorphisms previously shown to be associated with PPAR-alpha: rs4253778, rs135539 and rs1800206. Homozygous carriers of the variant rs1800206 had a 22% decreased risk of diabetic retinopathy compared with those with wild-type homozygotes (odds ratio 0.78, 95% confidence interval [CI] 0.66-0.94). There was also evidence of a potential genetic interaction between rs1800206 and the Leu162 allele, associated with the presence of abdominal obesity. Carriers with abdominal obesity had the lowest risk of diabetic retinopathy (odds ratio 0.39, 95% CI 0.30-0.74), after adjustment. In conclusion, this study indicates potential interaction between genetic determinants of PPAR-alpha, abdominal obesity and diabetic retinopathy in this population cohort.
1. Hu Y, Chen Y, Ding L et al. Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction. Proc Natl Acad Sci U S A. 2013;110:15401-6.
The association of peroxisome proliferator-activated receptor alpha with diabetic retinopathy, and additional gene-obesity interaction in Chinese type 2 diabetes mellitus patients.

Qi S, Wang C, Zhang Y et al

SPEAD-A: Alogliptin slows progression of atherosclerosis in type 2 diabetes

Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that decreases plasma glucose and has also been shown to improve postprandial triglycerides and triglyceride-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. While in the EXAMINE study (1), cardiovascular event rates were not higher with alogliptin than with placebo in type 2 diabetes patients with recent acute coronary syndrome, experimental studies suggested a beneficial effect on atherosclerosis progression in animal models. These findings provided a rationale for further clinical investigation in SPEAD-A (Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis). SPEAD-A was a prospective, randomized, open-label, blinded-end point study in 341 (mean age 64.4 years, 83% male) patients with type 2 diabetes but without history of cardiovascular disease. Patients were randomly allocated to treatment with alogliptin (n=172) or conventional management (n=169). The primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery, measured by carotid arterial echography, over 24 months. Compared with conventional management, alogliptin was associated with significant attenuation of atherosclerosis progression, as assessed by improvement in mean common IMT (?0.026 mm [standard error, SE 0.009] vs. 0.005 mm [SE 0.009] with conventional management, p = 0.022) and maximum IMT of the right and left carotid arteries ( ?0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], p = 0.025, and ?0.079 mm [SE 0.018] vs. ?0.015 mm [SE 0.018], p= 0.013, respectively). Based on these findings, the authors propose a large-scale prospective trial to evaluate the utility of DPP-4 inhibitors for primary prevention of cardiovascular disease in type 2 diabetes.
1. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327-1335
Alogliptin, a Dipeptidyl Peptidase-4 Inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A)

Mita T, Katakami N, Yoshii H et al.

ASPIRE-S study: action needed to improve prevention after ischaemic stroke

Results from the ASPIRE-S (Action on Secondary Prevention Interventions and Rehabilitation in Stroke) study highlight the need to improve implementation of guideline-recommended preventive measures in patients with ischaemic stroke. This study included 6 months’ follow-up of 256 patients with ischaemic stroke (mean age 69 years, range 22-95 years). Despite the need for comprehensive preventive strategies, 68% of patients were overweight (BMI >25 kg/m2), and 16% were still smoking. While there was a high prevalence of lipid-lowering therapy (95%) and anti-hypertensive treatment (75%), about one in four patients had low-density-lipoprotein cholesterol levels >2.5 mmol/L, and nearly two-thirds (63%) had a blood pressure >140/90 mmHg. Almost all patients (97%) were receiving anti-platelet and/or anticoagulant therapy. In conclusion, the findings from this prospective study show that despite the widespread prescription of secondary preventive therapy, most patients with a previous ischaemic stroke do not attain current targets for blood pressure and/or cholesterol.
Secondary prevention after ischaemic stroke: the ASPIRE-S study.

Brewer L, Mellon L, Hall P et al.

TG/HDL cut-off for cardiovascular risk differs with ethnicity

The atherogenic index, the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) is a prognostic marker for cardiovascular risk, especially among patients with evidence of cardiometabolic disease. However, it is not clear whether cut-off values for this index shown by European populations also apply to different ethnic groups. Data from 5,431 subjects (mean age 50.7 ± 11.6 years) enrolled in the Isfahan Cohort Study (ICS), an ongoing, longitudinal, population-based study in urban and rural areas of three districts in central Iran, was used to investigate this issue. A threshold TG/HDL-C ratio of 3.68 was used to screen for cardiovascular risk, with subjects categorised as either “low” or “high” risk at baseline. A slightly higher number of high-risk individuals were identified using European versus ICS cut-off points (63.7% versus 49.5%), although the adjusted hazard ratio for cardiovascular events was slightly higher in high-risk individuals identified by the ICS cut-off (1.58, 95% CI 1.36–1.84 versus 1.44, 95% CI 1.22–1.71 for European cut-off). These data indicate that a TG/HDL-C index of ?3.68 is appropriate for predicting cardiovascular events in this population.
Comparison between European and Iranian cutoff points of triglyceride/high-density lipoprotein cholesterol concentrations in predicting cardiovascular disease outcomes.

Gharipour M, Sadeghi M, Dianatkhah M et al.

Study suggests genetic connection between dyslipidaemia and type 2 diabetes

This experimental study suggests that shared genetic connections between dyslipidaemia and dysglycaemia may help to explain why both conditions commonly co-exist. The apolipoprotein E-deficient (Apoe?/?) mouse, cross-bred for BALB and SM, two strains that exhibit distinct differences in high-density lipoprotein (HDL), non-HDL cholesterol, and type 2 diabetes-related traits was used as the model of dyslipidaemia. Quantitative trait locus analysis was used to evaluate potential connections between 144 genetic markers across the genome. The report identified four loci implicated in control of fasting glucose levels, four loci for HDL cholesterol levels, nine loci for non-HDL cholesterol levels, and three loci for triglyceride levels. Importantly, there was evidence of genetic connections between dyslipidaemia (HDL and non-HDL cholesterol) and type 2 diabetes (fasting glucose) as indicated by trait analysis. A significant correlation between fasting glucose and triglyceride levels was also observed. These intriguing findings suggest that dyslipidaemia plays a causal role in the development of type 2 diabetes, but does not, however, prove causality.
Genetic linkage of hyperglycemia and dyslipidemia in an intercross between BALB/cJ and SM/J Apoe-deficient mouse strains.

Wang Q, Grainger AT, Manichaikul A et al.

Evacetrapib: insights into effects on HDL

In last month’s post it was reported that the clinical development programme with the cholesteryl ester transfer protein (CETP) inhibitor, evacetrapib, had been terminated on the basis of efficacy considerations. With a report confirming that the REVEAL trial with the CETP inhibitor anacetrapib is still ongoing, questions have been raised as to whether there are mechanistic differences between these molecules. However, this month comes news that evacetrapib, either as monotherapy and combined with statins, increased macrophage cholesterol efflux capacity, including ABCA1-specific activity, as well as pre–beta-1 high-density lipoprotein (HDL), compared with placebo. This report analysed data from a phase II trial in 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels based on the National Cholesterol Education Program Adult Treatment Panel III criteria, and triglyceride levels <400 mg/dl. As monotherapy, evacetrapib resulted in a significant, dose-dependent increase in total efflux capacity, by 18% with 30 mg to 34% with the 500 mg dose. There was also a significant increase in ABCA1-specific efflux, although this effect was not dose-dependent. When combined with a statin, evacetrapib also increased cholesterol efflux capacity, although the effect was lesser (by 21% versus statin monotherapy, compared with 31% versus placebo with monotherapy at the same evacetrapib dose). A similar effect was observed for ABCA1-specific efflux activity (15% for evacetrapib plus statin versus 26% for evacetrapib monotherapy, at the 100 mg dose). Pre-beta HDL 1 was also increased by evacetrapib, albeit to a lesser extent in combination with a statin. The authors suggest that these findings imply that this CETP inhibitor has effects on HDL function beyond effects on raising plasma HDL-C levels, although further study is clearly warranted.
Cholesterol efflux capacity and pre-Beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib.

Nicholls SJ, Ruotolo G, Brewer HB et al.

Frequent short bursts of activity improve postprandial triglycerides

In postmenopausal women, frequent bouts of physical activity to interrupt sitting time reduces postprandial triglycerides. Fifteen subjects completed the trial, involving a randomly allocated order of 1) prolonged sitting (for 8 hours), 2) regular walking (either twenty 90-second bouts over 8 hours or one 30 minute bout from 09:00), and 3) prolonged sitting preceded by continuous walking. The incremental area under the curve for plasma triglycerides was 15% and 14% lower after regular walking versus prolonged sitting, or versus prolonged sitting after continuous walking (4.73±2.50 vs. 5.52±2.95 vs. 5.50±2.59 mmol/L, respectively p=0.023). These findings add to evidence for the importance of frequent physical activity to counter deleterious effects of prolonged sedentary behaviour.
Interrupting sitting time with regular walks attenuates postprandial triglycerides.

Miyashita M, Edamoto K, Kidokoro T et al

Cochrane review supports calls for a definitive fibrate outcomes study

This meta-analysis including more than 16,000 patients showed a protective effect with fibrate therapy in the secondary prevention setting, especially for preventing recurrent myocardial infarction (MI). However, the report also makes the case for a definitive outcomes study in patients receiving best evidence-based medicine, including statins. The meta-analysis included 16,112 patients with a history of cardiovascular disease enrolled in 13 randomised controlled trials. Compared with placebo, fibrate treatment was associated with a protective effect for the primary composite outcome of non-fatal stroke, non-fatal MI and vascular death (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.83 to 0.94), with a moderate benefit in preventing MI (RR 0.86, 95% CI 0.80 to 0.93). There was no significant effect on all-cause or vascular death, or stroke. Even with exclusion of data from the clofibrate trials, the benefit of fibrates in preventing MI persisted (RR 0.85, 95% CI 0.76 to 0.94), although there was no effect on the primary outcome (RR 0.90, 95% CI 0.79 to 1.03). These findings support the need for a definitive trial to assess the effects of fibrate treatment in the secondary prevention setting against current standards of care including statins.
Fibrates for secondary prevention of cardiovascular disease and stroke.

Wang D, Liu B, Tao W et al.

Trial news: Outcomes study with RVX-208 (apabetalone)

The first patient has now been randomized in the Phase III outcomes trial with this agent: BETonMACE. The trial will recruit type 2 diabetes patients at high-risk of coronary artery disease. The primary outcome is time to first occurrence of major adverse cardiovascular events (MACE), defined as a single composite endpoint of cardiovascular death, or non-fatal myocardial infarction or stroke. Patients on high-dose statin therapy (atorvastatin or rosuvastatin) will be randomised to 200 mg/day of apabetalone or placebo. Apabetalone is an orally active small molecule that interacts selectively with the second ligand domain found in bromodomain extra-terminal proteins (BET). This interaction inhibits acetylated lysine, present in histones, from binding to the same site thus altering chromatin structure and in turn activity of selected genes. RVX-208 has been previously shown to increase production of apolipoprotein A-I, the predominant protein in HDL.
Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk T2DM Subjects With CAD (BETonMACE)

AHA 2015 : EURIKA: Atherogenic dyslipidaemia prevalent despite high-intensity statin therapy

Evidence from EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice), showed that despite high-intensity statin treatment, about one in six patients (16.8%) with type 2 diabetes have atherogenic dyslipidaemia (the combination of elevated triglycerides and low high-density lipoprotein cholesterol [HDL-C], as defined by guidelines). While prevalence was lower in non-diabetic patients, still 7% at high global risk (SCORE ?5%) had atherogenic dyslipidaemia. Importantly, about one in three patients with type 2 diabetes (37%) and one in four without type 2 diabetes (22.4%) had elevated triglycerides (as defined by guidelines) despite high-intensity statin treatment. These data clearly highlight the unmet clinical need in these high cardiovascular risk patients.
Assessing the prevalence of atherogenic dyslipidemia in EURIKA patients.

Halcox JP, Roy C, Henriksson KM.

AHA 2015 : Focus on triglycerides

Two studies highlighted a link between elevated triglycerides, endothelial dysfunction and subclinical atherosclerosis. In this cross-sectional analysis from the FMD-Japan Registry (1) including 4,908 subjects (3,842 men and 1,066 women; mean age 48±12 years), flow-mediated dilatation (FMD), a marker of endothelial function, decreased with increasing triglycerides (from 7.0±3.5% in individuals with triglycerides ?63 mg/dL, 5.8±3.2% in those with triglycerides 132 to 179 mg/dl, and 5.5±3.0% in subjects with triglycerides ?180 mg/dL, p for trend<0.001). This association persisted even after adjustment for age, sex, and cardiovascular risk factors including low plasma concentration of high-density lipoprotein cholesterol. Furthermore, cohort analysis from the ELSA-Brasil Study (2) showed that fasting triglycerides was an independent predictor of subclinical atherosclerosis. This report evaluated data for coronary artery calcium from 2,911 subjects without prior history of cardiovascular disease and who were not receiving lipid-lowering therapy (mean age 50.3±8.5 years, 54% women). After adjustment for cardiovascular risk factors, log transformed triglycerides and the triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio were each significantly associated with coronary artery calcium (p<0.05), although HDL-C was not. Each standard deviation increase in log transformed triglycerides increased the likelihood of coronary artery calcium >0 by 17%, p=0.005. Taken together, these data support the rationale of targeting elevated triglycerides to reduce the risk of atherosclerosis progression and cardiovascular events.
1. Kajikawa M, Higashi Y, Maruhashi T et al. Increased triglyceride levels are associated with endothelial dysfunction: FMD-Japan Registry. Circulation 2015; 132: 10041.
2. Bittencourt MS, Santos RD, Staniak H et al. Fasting triglycerides are independently associated with subclinical atherosclerosis: The ELSA-Brasil Study. Circulation 2015;132:A13139.
Increased triglyceride levels are associated with endothelial dysfunction: FMD-Japan Registry.

Kajikawa M, Higashi Y, Maruhashi T et al.

AHA 2015 : ACCORDION: follow-up of ACCORD brings new data

ACCORDION, long-term passive follow-up of 4,644 statin-treated patients with type 2 diabetes from the ACCORD (Action to Control Cardiovascular Risk in Diabetes), provides further support for add-on fenofibrate therapy in patients with residual atherogenic dyslipidaemia (the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol) on simvastatin monotherapy. However, as in the main ACCORD study, there was no benefit in the overall study population. Over a 9-year follow-up period (from the start of ACCORD to the end of ACCORDION), patients originally allocated to fenofibrate + simvastatin had a nonsignificant reduction in the primary endpoint of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death (hazard ratio 0.93, 95% CI 0.83-1.05 95%CI, p=0.25). However, in the subgroup with atherogenic dyslipidaemia at baseline, there was a 37% reduction in this endpoint (hazard ratio 0.73, 95% CI 0.56-0.95) versus no effect in those without this lipid profile (hazard ratio 0.99, 95% CI 0.86-1.13) (interaction p=0.048). These findings reinforce the case for an outcomes trial to test the hypothesis of specifically targeting atherogenic dyslipidaemia in high cardiovascular risk individuals. Importantly, such a trial should also include sufficient numbers of women to fully evaluate the effects of therapy in this patient group.
The Effect of Combined Statin/Fibrate Therapy on Cardiovascular Disease is Influenced by Sex and Dyslipidemia: ACCORDION-Lipid Long-Term Follow-up.

Elam MB, Lovato LC, Ginsberg HN et al on behalf of the ACCORD/ACCORDION Study Group.

Innovative approaches to improving lifestyle adherence in secondary prevention

Lifestyle intervention is the fundamental cornerstone of cardiovascular disease (CVD) prevention. However, ensuring adherence is usually problematic, even in individuals with established CVD. Using a text messaging service may improve adherence, and as a result control of cardiovascular risk factors, including low-density lipoprotein cholesterol (LDL-C), according to this report from the Tobacco, Exercise and Diet Messages (TEXT ME) trial. This was a parallel-group, single-blind, randomised study including 710 patients (mean age 58 years; 82% men; 53% current smokers) with proven coronary heart disease. Patients were randomly allocated to a text messaging service providing advice, motivational reminders, and support to change lifestyle (4 text messages per week for 6 months, n = 352) in addition to usual care, or usual care alone (n=358). At 6 months, levels of LDL-C were significantly lower in the intervention group (by 5 mg/dL, p=0.04). There were also reductions in systolic blood pressure (by 7.6 mmHg, p<0.001), body mass index (by 1.3 kg/m2, p<0.001) and smoking (by 39%, p=0.003), as well as increased physical activity (p=0.003) compared with the control. However, questions remain regarding the duration of these effects, and whether there is any corresponding benefit on clinical outcomes.
Effect of lifestyle-focused text messaging on risk factor modification in patients with coronary heart disease: a randomized clinical trial.

Chow CK, Redfern J, Hillis GS et al.

High-dose statin therapy ameliorates the impact of elevated triglycerides

Treating high cardiovascular risk patients to guideline-recommended low-density lipoprotein cholesterol (LDL-C) goal attenuated the risk of major cardiovascular events associated with high triglycerides, hypertension and elevated fasting glucose, according to this analysis from the Treating to New Targets (TNT) study. The TNT study included patients with clinical stable CHD who were randomised to double-blind therapy with atorvastatin 10 mg/day (n=5,006) or 80 mg/day (n=4,995) and followed-up for a median of 4.9 years. In patients on atorvastatin 10 mg/day (on-treatment LDL-C 2.6 mmol/L), the presence of each component of the metabolic syndrome significantly increased the risk of major cardiovascular events (high body mass index ?28 kg/m2, p=0.014; elevated triglycerides ?1.7 mmol/L, p=0.006; low HDL-C [1.0 mmol/L in men and <1.3 mmol/L in women], p=0.0006; blood pressure ?130/85 mmHg, p<0.0001; and fasting glucose ?5.6 mmol/L, p<0.0001). However, further lowering of LDL-C with atorvastatin 80 mg/day (on-treatment LDL-C 2.0 mmol/L) attenuated the predictive power of elevated triglycerides and fasting glucose, and to a lesser extent, hypertension. It is pertinent that a majority of patients in the TNT study had these characteristics: over 75% were hypertensive, 60% had elevated triglycerides and about 50% of patients had elevated fasting glucose or high body mass index. Although the impact of elevated triglycerides was reduced, the presence of this component was still associated with a 9% major cardiovascular event rate over the follow-up period.
Effect of high-dose atorvastatin on the cardiovascular risk associated with individual components of metabolic syndrome: A subanalysis of the Treating to New Targets (TNT) study.

Deedwania PC, Shepherd J, Breazna A, DeMicco DA.

Triglycerides associate with carotid artery intima-media thickness

Common carotid artery intima-media thickness (CCA-IMT), an established marker for atherosclerosis, was associated with fasting triglycerides in ischaemic stroke patients; however, there was no association with nonfasting triglycerides. In total, 158 ischaemic stroke patients (34% female; mean age 63 years) who were enrolled in the Berlin "Cream and Sugar" study, were included. A combined oral glucose and triglyceride tolerance test was performed 3-7 days after the incident ischaemic stroke, and patients were classified on the basis of time to peak triglycerides post-fat challenge. Multiple regression analysis, adjusting for modifiable risk factors, showed that older age, more severe strokes, and higher levels of fasting triglycerides were significantly and independently associated with higher mean CCA-IMT.
Triglycerides and carotid intima-media thickness in ischemic stroke patients.

Batluk J, Leonards CO, Grittner U et al.

Triglyceride/HDL ratio a predictor of non-alcoholic fatty liver disease?

The triglyceride (TG): high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) is an index of atherogenic dyslipidaemia, as well as a surrogate for insulin resistance. A new report also shows that the TG/HDL-C ratio is strongly associated with increased risk of incident fatty liver disease. This observational cohort study included 4,518 healthy Japanese subjects (2,637 men and 1,881 women) who underwent yearly health-check-ups. Fatty liver was diagnosed using ultrasonography. Over a 10-year period, 38.8% men and 17.2% of women developed fatty liver. The odds ratio for the association of TG/HDL-C with incident fatty liver was 1.59 (95% confidence interval [CI] 1.42-1.79, p<0.0001) in men and 2.50 (95% CI 1.80-3.51, p <0.0001) in women. The optimal cut-point was a TG/HDL-C >0.88 in men and >0.64 in women. Given that the TG/HDL-C ratio is readily measured in routine clinical practice, identification of individuals at risk of incident fatty liver disease and implementation of lifestyle intervention can have important implications for public health.
Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population based cohort study.

Fukuda Y, Hashimoto Y, Hamaguchi M et al.

PCSK9 modulates the function of CD36 and triglyceride metabolism

Previous studies implicate PCSK9 (proprotein convertase subtilisin/kexin type 9) in triglyceride metabolism. Findings from a mechanistic in vitro study suggest that PCSK9-mediated CD36 degradation may limit fatty acid uptake and triglyceride accumulation in tissues, such as the liver. CD36, a member of the class B scavenger receptor family of cell surface proteins, has a key role in fatty acid transport and metabolism, and may also be involved in glucose intolerance and atherosclerosis. In this report, overexpression or recombinant PCSK9 induced CD36 degradation, and reduced uptake of the palmitate analogue Bodipy FL C16 in 3T3-L1 adipocytes and oxidized low-density lipoprotein in hepatic HepG2 cells. Small interference RNA knockdown of endogenous PCSK9 in hepatic cells increased CD36 protein more than 3-fold. Similar increases were observed in the liver and visceral adipose tissue of PCSK9 deficient mice, and were correlated with increased uptake of fatty acid and accumulation of triglycerides. Taken together, these findings implicate a role for PCSK9 beyond low-density lipoprotein cholesterol, specifically in triglyceride metabolism.
PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver.

Demers A, Samami S, Lauzier B et al.

** STOP PRESS**

ACCELERATE, the Phase III outcomes trial with the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, has been terminated on the recommendation of the Independent Data Monitoring Committee due to insufficient efficacy. This decision was based on data from periodic data reviews, which suggested there was a low probability that the study would achieve its primary endpoint. The study is not being stopped for safety findings. Lilly will discontinue development of evacetrapib for the treatment of high-risk atherosclerotic cardiovascular disease and will now conclude other studies in the programme. Source: https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130
 
This leaves the REVEAL trial with the CETP inhibitor anacetrapib as the sole ongoing outcomes trial in the field of CETP inhibition. For further information: http://www.ctsu.ox.ac.uk/reveal/

HDL cholesterol associated with inflammation in ACS

This report suggests a link between low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and inflammatory biomarker levels in patients with acute coronary syndrome (ACS). This cross-sectional study included 6,134 patients with ACS, with very low (<30 mg/dL), low (30–39.9 mg/dL), or normal HDL-C (?40 mg/dL) plasma concentration. Overall, 18.5% of patients had very low HDL-C levels; these patients also had higher levels of high sensitivity-C-reactive protein (hs-CRP) compared with those with low or normal HDL-C levels (median 17.8 [interquartile range 7.2–54.5] versus 12.6 [5.6–33.9] versus 12.0 [5.4–36.9] mg/L, respectively, p <0.001). In addition, patients with the lowest HDL-C plasma concentration also had the lowest albumin levels (median 3.6 [3.3–4.0] versus 3.8 [3.5–4.0] versus 3.8 [3.5–4.1] g/dL, respectively, p <0.001). Multivariate analysis showed that both low albumin (?3.5 g/dL) and elevated hs-CRP (?10 mg/L) were independent predictors of very low HDL-C plasma levels in patients with ACS.
Levels of High-density Lipoprotein Cholesterol are Associated with Biomarkers of Inflammation in Patients with Acute Coronary Syndrome

González-Pacheco H, Amezcua-Guerra LM, Vazquez-Rangel A et al.

Accumulation of small chylomicron particles in moderate hypertriglyceridaemia

Accumulation of circulating small size chylomicron particles may partly explain the increased cardiovascular risk of individuals with hypertriglyceridaemia, according to this study. The concentration of apolipoprotein (apo) B48, a measure of chylomicron particle number, in different density lipoprotein fractions was compared between normocholesterolaemic subjects with hypertriglyceridaemia (?1.7 mmol/L, n=12) and those without (n=12), matched for age and gender. The distribution of chylomicron particles was assessed by determining the fasting concentration of apoB48 in serum lipoprotein fractions with Svedberg flotation rates of (Sf) >400, Sf 20-400 and Sf <20. ApoB48 concentration in subjects with hypertriglyceridaemia was almost twice that observed in controls (8.7 ± 1.0 ?g/mL vs 5.0 ± 0.6 ?g/mL, p=0.016), with >80% of the increase residing in the small, dense lipoprotein fraction (Sf<20 fraction). Significantly greater concentrations of apoB48 were also observed in the less dense fractions (p<0.001). These findings indicate that increased atherogenic risk in normocholesterolemic, moderately hypertriglyceridaemic subjects is due to greater apoB48 concentration in the small, dense lipoprotein fraction.
Hypertriglyceridemic subjects exhibit an accumulation of small dense chylomicron particles in the fasting state

Irawati D, Mamo JCL, Soares MJ et al

Targeting lipoprotein(a) to reduce aortic valve stenosis

Elevated lipoprotein(a) (Lp[a]), a potential contributor to residual cardiovascular risk, is also associated with aortic stenosis. This study sought to provide insights into how Lp(a) mediates progression of aortic stenosis. The study measured oxidised phospholipids, key mediators of calcification in valvular cells, on apolipoprotein B100 (apoB100), as well as Lp(a) in 220 patients with mild-to-moderate aortic stenosis. The primary endpoint was the progression rate of aortic stenosis, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography. The secondary endpoint was the need for aortic valve replacement and cardiac death. During a mean 3.5 years of follow-up, patients in the top tertiles of Lp(a) and oxidised phospholipid-apoB100 showed more rapid progression of aortic stenosis than those in the lowest tertile (p=0.005 and p=0.01, respectively). After multivariable adjustment, elevated Lp(a) or oxidised phospholipid-apoB100 levels remained independent predictors of faster aortic stenosis progression. In conclusion, these findings support the hypothesis that Lp(a) mediates progression of aortic stenosis via its association with oxidised phospholipids. Randomized trials of treatments with the potential for lowering Lp(a) and oxidised apoB100 in aortic stenosis are merited.
Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis.

Capoulade R, Chan KL, Yeang C et al.

PCSK9 inhibition: potential impact on triglycerides?

While pro-protein convertase subtilisin-kexin 9 (PCSK9) inhibition is effective in lowering low-density lipoprotein cholesterol levels, the potential impact of this treatment on the metabolism of triglyceride-rich lipoproteins (TRL) is attracting increasing attention. This timely review summarises current evidence supporting a link between PCSK9 and TRL. This includes evidence of a correlation between plasma PCSK9 and triglycerides (TG) levels, as well as between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism. In addition, TG-lowering treatments such as fibrates have been shown to lower plasma PCSK9 levels. There is also evidence of effects of PCSK9 on postprandial lipaemia, adipose tissue biology, apolipoprotein B production in the liver and intestine, as well as on receptors other than low-density lipoprotein receptor (LDLR) that are involved in TRL metabolism. Finally, subgroup analyses have shown TG-lowering effects with-PCSK9 monoclonal antibody therapy which warrant further evaluation. These emerging data highlight the need for further investigation of the underlying mechanisms of these effects.
PCSK9 and triglyceride-rich lipoprotein metabolism.

Druce I, Abujrad H, Ooi TC.

PREDIMED: Mediterranean diet protects against diabetic microvascular complications

A Mediterranean diet supplemented with extra virgin olive oil may protect against the development of diabetic retinopathy, according to this report from the PREvencion con DIeta MEDiterranea (PREDIMED) study group. The PREDIMED Investigators conducted a post hoc analysis of 3,614 type 2 diabetes subjects (mean age 67 years, 47% men, 61% with dyslipidaemia) who were free of microvascular complications at entry. Subjects were randomly allocated to Mediterranean diet supplemented with extra virgin olive oil or nuts, or a low-fat control diet. Over a median follow-up of 6.0 years, 74 subjects developed retinopathy (22 in the Mediterranean diet + olive oil group, 20 in the Mediterraenean diet + nuts group and 32 in the control group) and 168 developed nephropathy (64, 51 and 53, respectively). Compared with the control diet, subjects allocated either Mediterranean diet regimen had reduction in the risk of developing retinopathy, by 44% (hazard ratio 0.56, 95% CI, 0.32–0.97) for the group also receiving olive oil, and by 37% (hazard ratio 0.63 (0.35–1.11, not statistically significant) for the group also receiving nuts. Furthermore, the protective effect of the Mediterranean diet plus olive oil was even greater in subjects who were highly adherent to the diet (66% relative reduction, hazard ratio 0.34, 95% CI, 0.13–0.89, p=0.001 for trend) compared with subjects with the lowest adherence. There were no differences between groups observed for new-onset nephropathy. In conclusion, this post hoc analysis of the PREDIMED study suggests that dietary intervention based on a Mediterranean diet supplemented with extra virgin olive oil protects against diabetic retinopathy but not diabetic nephropathy in elderly subjects with type 2 diabetes.
Mediterranean diet, retinopathy, nephropathy, and microvascular diabetes complications: A post hoc analysis of a randomized trial.

Diaz-Lopez A, Babio N, Martinez-Gonzalez MA et al.

Atherogenic dyslipidaemia more prevalent in type 2 diabetes ‘Night owls’

Patients with type 2 diabetes and an evening chronotype (so-called ‘night owls’) have a higher prevalence of atherogenic dyslipidaemia and poorer glycaemic control, but a markedly lower prevalence of cerebrovascular disease. In this study, 454 patients with type 2 diabetes (mean age 66 years; mean diabetes duration 16 years), were categorised by chronotype based on self-reported mid-sleep time (i.e. the midpoint between sleep onset and wake time) on weekends. Patients with an evening chronotype had significantly worse metabolic control than morning chronotypes, as characterised by HbA1c (mean [SD] 59[10] vs. 57[10] mmol/mol, p 0.0388), and an increased prevalence of atherogenic dyslipidaemia (56% vs. 42%, p 0.0028). The ratio of log[TG/HDL-C] was also higher in evening compared with morning chronotypes (mean [SD] 0.50[0.34] vs. 0.43[0.34], p 0.0335). However, the prevalence of transient ischaemic attack/stroke was higher in morning than evening chronotypes (11% vs. 3%, p 0.0066). There were no significant differences between the two groups with respect to other characteristics.
Evening chronotype in T2DM linked to atherogenic dyslipidemia and lower prevalence of cerebrovascular disease.

Hermans MP, Camara S, Ahn SA, Rousseau MF

Abstract 702-P.

**News from American Diabetes Association's Scientific Sessions, June 5 - 9, 2015, Boston, Massachusetts**

Data from the European Study on Cardiovascular Risk Prevention and Management in Daily Practice (EURIKA, NCT00882336) highlighted the prevalence of atherogenic dyslipidaemia (elevated triglycerides [TG] with/without low high-density lipoprotein cholesterol [HDL-C]), especially in diabetic patients on a statin. EURIKA was a cross-sectional study conducted in 12 European countries which recruited 7,641 patients aged ? 50 years (48% male, mean age 63.2 years), without clinical cardiovascular disease (CVD) but with at least one CVD risk factor. Elevated TG was defined as ?200 mg/dL (2.26 mmol/L) and low HDL-C was defined as <40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women. In the overall population, the prevalence of elevated TG, low HDL-C and both were 20.8%, 22.1% and 9.9%, respectively. Less than 60% of diabetes patients were receiving lipid-modifying therapy. In patients with diabetes who were on a statin, 27.9% had elevated TG, 29.8% had low HDL-C, and 14.6% had both. These data highlight the unmet clinical need for improved management of atherogenic dyslipidaemia in primary prevention patients, especially those with diabetes.
Treatment of patients with elevated triglycerides and low HDL-C in Europe: Results from EURIKA.

Halcox JP, Pasquet B, Hendriksson KM

Abstract 695-P

Dyslipidaemia and diabetic macular oedema: is there more than meets the eye?

The link between lipid levels and diabetic macular oedema (DME) warrants further investigation, according to this systematic review and meta-analysis. The authors identified 21 studies reporting on the relationship between blood lipid levels and DME (5 cross-sectional, 5 cohort, 7 case-control, and 4 randomised controlled studies). Meta-analysis of case-control studies showed that mean total serum cholesterol (p<0.001), low-density lipoprotein cholesterol (p<0.05), and serum triglycerides (p<0.05) were significantly higher in patients with DME than in those without DME. However, meta-analysis of prospective randomised controlled trials did not show significant increased risk of worsening of hard exudates and severity of DME in patients treated with lipid-modifying agents compared with placebo. Given the significant public health relevance, further investigation of these discrepancies is warranted.
Dyslipidemia and diabetic macular edema: a systematic review and meta-analysis

Das R, Kerr R, Chakravarthy U, Hogg RE

Low HDL-C plus elevated CRP levels predict worse outcome following PCI

Coronary artery disease (CAD) is an inflammatory state which has been shown to adversely affect the biological function of high-density lipoproteins (HDL). This study investigated the interaction between HDL cholesterol (HDL-C) and C-reactive protein (CRP) in CAD patients undergoing first percutaneous coronary intervention (PCI). Of 3,507 consecutive patients undergoing PCI, 1,682 patients (48%) had been treated with statin at this time. This group were stratified by HDL-C levels (cutoffs of 40 (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, respectively) and a CRP cutoff of 2 mg/dL into four groups: 1) high HDL-C/low CRP, 2) high HDL-C/high CRP, 3) low HDL-C/low CRP, and 4) low HDL-C/high CRP. Over a median follow-up of 1,985 days, 197 (11.7%) patients died due to cardiac death (n=58), carcinoma (n=61), stroke (n=10) and other causes (n=69). Multivariate Cox hazard regression analyses showed that the group with low HDL-C and high CRP had a significantly higher rate of all-cause death even after adjustment for other covariates (hazard ratio 2.38, 1.59-3.61, p<0.0001). The authors highlight the combination of low HDL-C and elevated CRP as predictive of worse long-term outcome after PCI in statin-treated CAD patients.
Impact of combined C-Reactive Protein and High-Density Lipoprotein Cholesterol levels on long-term outcomes in patients with coronary artery disease after a first percutaneous coronary intervention.

Ogita M, Miyauchi K, Tsuboi S et al

New meta-analysis shows PCSK9 monoclonal therapies are safe and effective

In this meta-analysis of more than 12,200 patients in 25 randomised controlled trials, the PCSK9 inhibitors evolocumab and alirocumab were shown to be well tolerated, lowering low-density lipoprotein (LDL) cholesterol by 50-55%. Evolocumab has now been approved for use in Europe; alirocumab is approved by the US Food and Drug Administration (FDA) and has also received a favourable response from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMA). Alirocumab was associated with an increased rate of injection-site reactions (relative risk [RR] 1.48, 95 % CI: 1.05 to 2.09, p = 0.02); and evolocumab was associated with reduced rates of abnormal liver function (RR 0.43, 95 % CI: 0.20 to 0.93, p = 0.03) compared with placebo. Both evolocumab and alirocumab significantly reduced LDL cholesterol (by 54.6%, 95% CI 58.7 to 50.5% for evolocumab, 52.6%, 95% CI: -58.2 to -47.0% for alirocumab) versus placebo, and increased high-density lipoprotein cholesterol (by 6-8%) These findings reaffirm the efficacy and safety profiles of these novel therapies previously observed in individual studies.
Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials.

Zhang XL, Zhu QQ, Zhu L et al

Resistin: a novel marker of residual vascular risk in statin-treated patients

According to this report from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE-IT TIMI) 22 group, the adipokine resistin is a marker of residual cardiovascular risk in patients hospitalised with a recurrent acute coronary syndrome. This nested case-control cohort of statin-treated patients in the PROVE-IT TIMI 22 study measured plasma levels of resistin and leptin in 176 cases with coronary death, myocardial infarction, or unstable angina pectoris during follow-up, matched 1:1 to 176 controls. In logistic regression analysis adjusted for additional risk factors including high-sensitivity C-reactive protein and history of diabetes, on-statin resistin levels were associated with recurrent coronary events (tertile 3 vs 1 adjusted odds ratio 2.08; 95% confidence interval 1.04 to 4.19). There was, however, no association between circulating leptin levels and recurrent coronary events. These findings suggest potential for other biomarkers, beyond lipids, in residual vascular risk.
On-statin resistin, leptin, and risk of recurrent coronary events after hospitalization for an acute coronary syndrome (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Study)

Khera AV, Qamar A, Murphy SA et al.

**Hot off the Press: NLA guidelines on dyslipidaemia: Special groups and residual risk**

Part 2 of the National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia are due to published later this year. These recommendations will focus on special patient populations, including Hispanics, South Asians, African Americans, older patients, and children and adolescents. In addition, there will be specific recommendations for residual risk, as well as unique issues in women's health.

For further information: https://www.lipid.org/recommendations

Peroxisome proliferator-activated receptor-alpha increases cholesterol efflux capacity in metabolic syndrome

Cholesterol efflux is a marker of high-density lipoprotein (HDL) function. In this study, the potent and selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, LY518674, was shown to increase cholesterol efflux capacity in metabolic syndrome patients. Subjects with metabolic syndrome were randomised to either LY518674 100 ug daily (n = 13) or placebo (n = 15) for 8 weeks. Cholesterol efflux capacity was measured in an ex vivo assay using apolipoprotein-B depleted plasma. After 8 weeks, LY518674 resulted in a 15.7% increase from baseline in efflux capacity compared with placebo (p=0.01). The change in apolipoprotein A-I production rate was strongly associated with the change in cholesterol efflux capacity (p= 0.01). These findings reinforce the relevance of PPAR alpha stimulation to HDL functionality.
Potent peroxisome proliferator-activated receptor-alpha agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome.

Khera AV, Millar JS, Ruotolo G et al.

Does increased uptake of atherogenic lipoproteins from interstitial fluid in type 2 diabetes explain accelerated atherosclerosis?

This study sought to investigate the underlying rationale for the accelerated atherosclerosis that is characteristic of type 2 diabetes. The authors hypothesised that the interstitial fluid (IF)-to-serum gradient ratio for apolipoprotein (apo)B-containing atherogenic lipoproteins may be greater in type 2 diabetes than in healthy controls, reflecting increased leakage of lipoproteins across the vascular wall. However, evaluation of lipoprotein profiles in serum and IF from 35 patients with type 2 diabetes and 35 healthy controls showed that this was not the case. Instead, the IF-to-serum gradients for very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) cholesterol, and apoB were all reduced in patients with type 2 diabetes compared to healthy controls. The authors suggest that increased uptake of atherogenic lipoproteins from the IF may lead to an increased load of cholesterol to peripheral tissues, which in turn would contribute to the markedly higher propensity to develop atherosclerosis in type 2 diabetes.
Levels of atherogenic lipoproteins are unexpectedly reduced in interstitial fluid from type 2 diabetes patients.

Apro J, Parini P, Broijersen A et al.

No increased risk of diabetes with PCSK9 loss-of-function variant

Whether PCSK9 inhibitors (the most advanced awaiting regulatory approval), have any effect on glucose homeostasis has long been debated, following conflicting data in mouse models. However, results from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study show no increased risk of incident type 2 diabetes in individuals carrying the PCKS9 p.R46L loss-of-function variant. This analysis included data from 4,630 French subjects in the DESIR study and 1,342 French subjects with type 2 diabetes. Not surprisingly, carriage of p.R46L was associated with lower total cholesterol (-0.394 mmol/l), low-density lipoprotein cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, there was no association between carriage of p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin and glycated haemoglobin), and risk of incident type 2 diabetes. These findings provide reassurance regarding the safety of PCSK9 inhibitors as regards glucose homeostasis.
The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis.

Bonnefond A, Yengo L, Le May C et al.

Cardiac autonomic neuropathy evident in early type 2 diabetes

This report from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) shows that cardiac autonomic neuropathy (CAN) can be detected very early in newly diagnosed type 2 diabetes, emphasising the importance of early testing for cardiovascular autonomic function. The study included data from a cohort of 557 patients with newly diagnosed type 2 diabetes (mean age 58.3 years, glycated haemoglobin 6.9%). Early and confirmed neuropathy were assessed using a standardised methodology. Early CAN was detected in 15.3% of patients (15.9% in men and 14.5% in women); confirmed CAN was present in 1.8% of all patients. Clinicians should therefore be aware of the possibility of autonomic dysfunction soon after diagnosis in type 2 diabetes, and test and treat accordingly.
The prevalence of cardiovascular autonomic neuropathy in a cohort of patients with newly diagnosed type 2 diabetes: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

Zoppini G, Cacciatori V, Raimondo D et al.

News from ANCHOR: icosapent ethyl reduced atherogenic lipoprotein particle concentration in statin-treated patients with elevated triglycerides

ANCHOR study evaluated icosapent ethyl, a high-purity prescription form of eicosapentaenoic acid ethyl ester, in statin-treated patients at high risk for cardiovascular disease with persistently high triglycerides (?200 and <500 mg/dL) and well controlled low-density lipoprotein cholesterol levels. This exploratory analysis evaluated the effect of treatment on lipoprotein particle concentration and size, as assessed using nuclear magnetic resonance spectroscopy. Data from 216 patients in the icosapent ethyl 4 g/day group and from 211 patients on placebo were analysed. Compared with placebo, treatment with icosapent ethyl significantly reduced key atherogenic lipoprotein particle concentrations, including very-low-density lipoprotein particles (by 12.2%, p=0.0002), small low-density lipoprotein particles (by 13.5%, p<0.0001) and total high-density lipoprotein (HDL) particles (by 7.4%, p<0.0001), and also increased LDL particle size. To determine whether these potentially beneficial effects translate into reduction in cardiovascular events, the results of the REDUCE-IT study (Reduction of Cardiovascular Events with EPA-Intervention Trial) are awaited.
Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study).

Ballantyne CM, Braeckman RA, Bays HEet al.

Elevated triglycerides and cardiovascular risk in Korea

In this large prospective observational study, elevated triglycerides were independently associated with an increased risk for cardiovascular disease. The study included 76,434 participants who had undergone a regular health check between January 2007 and June 2011. Higher triglycerides were associated with ?50% increase in risk for major cardiovascular disease events (odds ratio: 1.52, 95% CI: 1.27-1.82) and overall cardiovascular disease events (odds ratio 1.49, 95% CI: 1.37-1.63). These findings remained significant after adjustment for multiple risk factors including HDL-cholesterol. These findings add to the evidence-base supporting elevated triglycerides as a cardiovascular risk factor.
Serum triglyceride levels and cardiovascular disease events in Koreans.

Kim EH, Lee JB, Kim SH et al.

Insights into the renoprotective effects of fenofibrate

Attenuation of endothelial function may underlie the renoprotective effects of fenofibrate, according to results in an animal model of diabetic nephropathy. Diabetic rats were treated with fenofibrate (100 mg/kg/day) for 12 weeks. At the end of treatment, there was improvement in renal function, as shown by reduction in urinary albumin excretion and serum levels of creatinine and urea, as well as an increase in creatinine clearance compared with controls. Mechanistically, fenofibrate led to increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 (LKB1), indicative of improved endothelial function. These findings merit further investigation of the underlying effects of fenofibrate on renal function.
Renoprotective effects of fenofibrate via modulation of LKB1/AMPK mRNA expression and endothelial dysfunction in a rat model of diabetic nephropathy.

Al-Rasheed NM, Al-Rasheed NM, Attia HAet al.

Adiponectin implicated in diabetic retinopathy

Findings from this cross-sectional, family-based observational cohort study suggest a role for adiponectin in the underlying pathogenesis of diabetic retinopathy. The study included 507 Latino subjects with type 2 diabetes, with diabetes for at least 10 years or more and/or with diabetic retinopathy. Serum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment (HOMA). Diabetic retinopathy was assessed by digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale. Fasting adiponectin concentrations were elevated in patients with diabetic retinopathy compared with those without (12.9±0.5 ug/ml vs. 10.5±0.5 ug/ml, p=0.0004). This effect remained significant after multiple covariate adjustment (age, gender, body mass index, HbA1c, diabetes duration, statin use, blood pressure, and renal function, p=0.013 - 0.018). Adiponectin was also positively correlated with the severity of diabetic retinopathy in patients with non-proliferative disease (p<0.0003). Further research is indicated to investigate whether adiponectin is a marker or biological mediator of diabetic retinopathy.
Adiponectin, Insulin Sensitivity and Diabetic Retinopathy in Latinos with Type 2 Diabetes.

Kuo JZ, Guo X, Klein R et al.

Time to re-evaluate the role of HDL in cardiovascular risk?

Extensive epidemiologic data support low high-density lipoprotein cholesterol (HDL-C) as a risk factor for cardiovascular disease. However, to date clinical trials evaluating HDL-targeted therapy have been largely negative, and in the case of niacin (nicotinic acid), associated with harm. Given these discrepancies, together with growing realisation that the HDL particle population is heterogeneous in terms of size, structure, composition and functionality, there has been a view that the functional activity of HDL particles may be more relevant than HDL-C level. This report from the University of Pennsylvania helps to clarify this. This nested case-control sample from the prospective EPIC-Norfolk study showed that cholesterol efflux capacity, a potentially atheroprotective function of HDL, was significantly and inversely associated with incident coronary heart disease events, independent of several established cardiovascular risk factors and even after adjusting for HDL-C or apolipoprotein A-I concentrations. However, the researchers advise caution in the interpretation of causality, until Mendelian randomisation studies have been conducted to investigate this potential association.
Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study.

Saleheen D, Scott R, Javad S et al.

Aging and population growth key drivers for CVD rates

New analyses from the Global Burden of Disease Study 2013 report that aging and population growth are primarily responsible for increasing global cardiovascular death rates, despite an overall decrease in age-specific death rates in most regions. In 2013, more than 17 million people from 188 countries died from cardiovascular disease.
 
This report shows that over the period 1990-2013, worldwide there was a 41% increase in cardiovascular disease mortality. This was driven both by a 55% increase in mortality due to the aging of populations, together with a 25% increase due to population growth. Only in Central and Western Europe did gains in cardiovascular health offset these demographic sufficiently to cause a decline in the number of cardiovascular deaths.
These data highlight the need for health system planning to understand the absolute burden of disease, also taking account of the effect of population aging.
Demographic and epidemiologic drivers of global cardiovascular mortality.

Roth GA, Forouzanfar MH, Moran AE et al

TG/HDL-C ratio: an important prognostic indicator of risk

Recent studies have highlighted the relevance of this parameter, the ratio of triglycerides/high-density lipoprotein cholesterol (TG/HDL-C), to risk prediction.
 
The TG/HDL-C ratio is an indirect measure of insulin resistance/hyperinsulinemia and an independent predictor of cardiovascular risk. Moreover, in patients with chronic kidney disease (CKD), the TG/HDL-C ratio was also a predictor of poor cardiovascular outcome. In a longitudinal, observational, retrospective study in 197 patients (CKD Stages 1 to 5), there were 11 cardiovascular (CV) deaths and 43 nonfatal CV events over a mean follow-up period of 30 months.1 The TG/HDL-C ratio was a significant independent determinant of CV outcomes (hazard ratio 1.36, 95% CI 1.11-1.67, p = 0.003). Furthermore, the TG/HDL-C ratio was also an independent determinant of flow-mediated vasodilatation of the brachial artery (assessed by high-resolution ultrasonography), a marker of endothelial dysfunction (p = 0.02). Based on these findings, the authors argue for consideration of the TG/HDL-C ratio as a novel predictor of CVD risk in subjects with CKD.
 
Furthermore, there is also evidence that the TG/HDL-C ratio may be a better discriminator of cardiometabolic risk than non-HDL-C in obese children. In a retrospective, cross-sectional study in 5,505 children (aged 5-18 years), 78% were shown to be obese.2 When categorised according to the 75th percentile of non-HDL-C (?130 mg/dl) or TG/HDL-C ratio (?2.2), the odds ratios for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increase in carotid intima-media thickness and left ventricular hypertrophy were higher in children with a high TG/HDL-C ratio compared with children with high levels of non-HDL-C.
The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease.

Sonmez A, Yilmaz MI, Saglam M et al.

TG/HDL-C ratio: an important prognostic indicator of risk

Recent studies have highlighted the relevance of this parameter, the ratio of triglycerides/high-density lipoprotein cholesterol (TG/HDL-C), to risk prediction.
 
The TG/HDL-C ratio is an indirect measure of insulin resistance/hyperinsulinemia and an independent predictor of cardiovascular risk. Moreover, in patients with chronic kidney disease (CKD), the TG/HDL-C ratio was also a predictor of poor cardiovascular outcome. In a longitudinal, observational, retrospective study in 197 patients (CKD Stages 1 to 5), there were 11 cardiovascular (CV) deaths and 43 nonfatal CV events over a mean follow-up period of 30 months.1 The TG/HDL-C ratio was a significant independent determinant of CV outcomes (hazard ratio 1.36, 95% CI 1.11-1.67, p = 0.003). Furthermore, the TG/HDL-C ratio was also an independent determinant of flow-mediated vasodilatation of the brachial artery (assessed by high-resolution ultrasonography), a marker of endothelial dysfunction (p = 0.02). Based on these findings, the authors argue for consideration of the TG/HDL-C ratio as a novel predictor of CVD risk in subjects with CKD.
 
Furthermore, there is also evidence that the TG/HDL-C ratio may be a better discriminator of cardiometabolic risk than non-HDL-C in obese children. In a retrospective, cross-sectional study in 5,505 children (aged 5-18 years), 78% were shown to be obese.2 When categorised according to the 75th percentile of non-HDL-C (?130 mg/dl) or TG/HDL-C ratio (?2.2), the odds ratios for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increase in carotid intima-media thickness and left ventricular hypertrophy were higher in children with a high TG/HDL-C ratio compared with children with high levels of non-HDL-C.
 
Sonmez A, Yilmaz MI, Saglam M et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids in Health and Disease 2015;14:29.
Comparison of non-HDL-cholesterol versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: The CARITALY study.

Di Bonito P, Valerio G, Grugni G et al.

Is HDL-C a predictor of lower extremity amputation in diabetes?

HDL-C may be implicated as a novel predictor of lower-extremity amputation risk in diabetes patients with foot ulcers, according to this observational study in 163 Japanese patients with diabetic foot ulcers. The primary endpoint was a composite of the worst of the following outcomes for each individual; (1) minor amputation (below the ankle), (2) major amputation (above the ankle), and (3) wound-related death.
 
Over a median follow-up period of 5.1 months, this endpoint was observed in 67 patients (41%): 43 had minor amputations, 16 had major amputations, and 8 had wound-related deaths. Univariate Cox proportional hazard model analysis showed that a lower HDL-C concentration was associated with increased incident primary outcome (hazard ratio 0.16, 95% CI 0.08-0.32, p < 0.001). Multivariate Cox proportional hazard model analysis (hazard ratio 0.30, 95% CI 0.14-0.63, p = 0.002). and categorical variable analysis (HDL-C ?1.03 mmol/L or <1.03 mmol/L) also identified low HDL-C as a predictor of incident lower-extremity amputation.
HDL cholesterol as a predictor for the incidence of lower extremity amputation and wound-related death in patients with diabetic foot ulcers.

Ikura K, Hanai K, Shinjyo T, Uchigata Y.

More insights into PCSK9 inhibitor therapy and cardiovascular outcomes

A new systematic review and meta-analysis provides further insight suggestive of clinical benefits with monoclonal antibody therapy targeting PCSK9 (proprotein convertase subtilisin/kexin type 9). This analysis included data from 10,159 patients included in 24 Phase II and III randomised controlled trials.
 
Not surprisingly, treatment with PCSK9 antibody therapy reduced low-density lipoprotein cholesterol to a significantly greater extent than in patients who did not receive this treatment (by 47%, p <0.001). Additionally, PCSK9 inhibitor treatment was associated with reduction in all-cause mortality by 55% (odds ratio 0.45, 95% CI 0.23 to 0.86, p = 0.015); and cardiovascular mortality by 50% (odds ratio 0.50, 05% CI 0.23 to 1.10, p = 0.084). Treatment was well tolerated with no increase in serious adverse events.
 
While acknowledging that the analysis was based on limited endpoints and study-level rather than patient-level data, the findings do suggest promise with this mode of lipid-modifying therapy for reducing residual cardiovascular risk.
Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis

Navarese EP, Ko?odziejczak M, Schulze V et al.

Lowering triglycerides to modify cardiovascular risk: new review

A new review discusses the potential of specific therapeutic strategies that directly target hypertriglyceridaemia to reduce vascular risk. A growing evidence-base, including cohort studies and meta-analyses, supports an association between increases in fasting and nonfasting triglycerides levels and cardiovascular risk. Furthermore, genomic and biomarker studies show that the metabolism of triglyceride-rich lipoproteins plays an important role in atherosclerosis. These data support resurgence in the use of omega-3 fatty acids for therapeutic lowering of triglycerides levels, including in patients with moderately elevated levels. Specifically, the review discusses data for icosapent, containing only eicasopentaenoic acid (EPA). Definitive evidence is awaited from the ongoing outcomes study, REDUCE-IT.
Lowering triglycerides to modify cardiovascular risk: will icosapent deliver

Scherer DJ, Nicholls SJ.

Diabetes and cardiovascular disease in China

Evidence from the Da Qing study highlights diabetes as a major cause of cardiovascular disease, predominantly stroke, in China. This report included data from 630 people with newly-diagnosed diabetes (NDD) and 519 with normal glucose tolerance (NGT) who were included in the study in 1986. Over a 23 year follow-up period, 338 (57%) of those with NDD and 100 (20%) with NGT died. CVD was the cause of death in nearly half of those with diabetes (48% in men and 50% in women), the majority due to stroke (52% in men and 42% in women). Furthermore, the age-standardised incidence of all-cause mortality was 3-fold higher in subjects with NDD compared with those with NGT (incidence per 1,000 person-years: 36.9, 95% CI 31.5-42.3 versus 13.3, 95% 10.2-16.5 in men; and 27.1, 95% CI 22.9-31.4 vs. 9.2, 95% CI 7.8-10.6 in women, both p < 0.0001). These data highlight an urgent need for action to address escalating rates of diabetes and cardiovascular disease in China.
Cardiovascular and All-Cause Mortality Over a 23-Year Period Among Chinese With Newly Diagnosed Diabetes in the Da Qing IGT and Diabetes Study.

An Y, Zhang P, Wang J et al.

Jackson Heart Study: metabolic syndrome, diabetes and subclinical atherosclerosis in African Americans

While the presence of subclinical disease measures has been directly associated with the development of cardiovascular disease in whites, there are less data for African Americans. This analysis from the Jackson Heart Study showed a moderately high prevalence of subclinical disease in this group, which in turn translated to higher cardiovascular risk, especially with concomitant metabolic syndrome and diabetes.
 
The analysis included 4,416 subjects (mean age 54 years; 64% women) who attended the first examination of the Jackson Heart Study. In total, 1,155 (26%) subjects had subclinical disease, defined as the presence of peripheral arterial disease, left ventricular hypertrophy (LVH), microalbuminuria, high coronary artery calcium (CAC) score, and/or low left ventricular ejection fraction. Cross-sectional multivariable-adjusted logistic regression analysis showed that subjects with metabolic syndrome or diabetes were at high risk of subclinical disease compared with those without these conditions (odds ratios 1.55 [95% CI 1.30–1.85] and 2.86 [95% CI 2.32–3.53], respectively). Furthermore, having either condition significantly increased the hazard of incident cardiovascular disease, independent of the presence of subclinical disease (P < 0.001).
Relations Between Subclinical Disease Markers and Type 2 Diabetes, Metabolic Syndrome, and Incident Cardiovascular Disease: The Jackson Heart Study.

Xanthakis V, Sung JH, Samdarshi TE et al.

Presence of diabetic retinopathy may increase risk of future CV events

There has been support for the concept that the presence of microvascular complications is predictive of an increased risk of cardiovascular events. This study tested this concept in patients with type 2 diabetes and diabetic retinopathy (DR) compared with those without DR. A total of 312 people with diabetes (mean age 57 years, 51% male) were included in the study, of whom 153 (49%) had DR. All participants underwent carotid ultrasound imaging to assess carotid intima-media thickness and the presence of carotid plaques. A higher percentage of patients with DR had carotid plaques than those without DR (68% vs 52%, p=0.0045). Patients with DR also had a higher prevalence of ?2 carotid plaques (44.4% vs 21.4%, p<0.0001). However there were no differences in the cIMT measured at different carotid regions between the two groups. Using multivariate logistic regression (with adjustment for major risk factors for atherosclerosis), DR was independently associated with mean-internal cIMT (p = 0.0176), the presence of carotid plaques (p = 0.0366) and carotid plaque burden (?2 plaques; p < 0.0001).
 
DR in patients with type 2 diabetes is associated with a higher atherosclerotic burden in the carotid arteries than seen in patients with type 2 diabetes and no DR. As patients with increased atherosclerotic burden have a higher risk of cardiovascular events, the authors recommended that patients with type 2 diabetes and DR should be considered for carotid ultrasound imaging to ensure a more individualised and careful cardiovascular assessment.
Type 2 diabetes-associated carotid plaque burden is increased in patients with retinopathy compared to those without retinopathy.

Alonso N, Traveset A, Rubinat E et al.

Much to be done to improve awareness and control of dyslipidaemia in China

A new study from China highlights differences in the awareness, treatment and control of hypertension and dyslipidaemia in previously-diagnosed and newly-diagnosed subjects with diabetes. In total, 98,658 adults aged at least 18 years were identified from the China Noncommunicable Disease Surveillance 2010 study. Glycaemia was defined according to the 2010 American Diabetes Association criteria; hypertension was diagnosed according to the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; and dyslipidaemia was diagnosed according to the 2004 National Cholesterol Education Program Adult Treatment Panel III. The prevalence of dyslipidaemia increased from 47% in subjects with normal glucose levels to 63% in subjects with newly-diagnosed diabetes and 70% in those with previously-diagnosed diabetes. Compared with subjects with newly-diagnosed diabetes, those with previously diagnosed diabetes were more likely to aware of dyslipidaemia (34% versus 13%), and were receiving pharmacotherapy (19% versus 5%). Among subjects with previously diagnosed diabetes, low-density lipoprotein cholesterol levels were controlled in 87%; however, management of triglycerides and high-density lipoprotein levels lagged behind (50% and 27% had controlled levels). These findings show that detection and control of dyslipidaemia remains far from optimal in Chinese adults.
Treatment and control of cardiometabolic disorders in Chinese adults with diabetes: a national representative population study.

Wang T, Xu Y, Xu M et al. Awareness

Elevated serum remnant-like cholesterol linked to coronary plaque development

Increasingly, evidence supports elevated remnant cholesterol, for which serum triglycerides are a marker, with residual cardiovascular disease risk in patients with well controlled levels of low-density lipoprotein cholesterol (LDL-C). New data suggest that remnant cholesterol may contribute to formation of coronary plaque.
 
In this study, 40 Japanese men with stable angina (mean 71 years, mean baseline LDL-C 107 mg/dL or 2.8 mmol/L) underwent intravascular ultrasound and coronary angiography to evaluate the severity of coronary artery disease, and plaque morphology and composition. Blood samples were taken to measure serum levels of adiponectin, omentin-1 and serum remnant cholesterol. The cross-sectional area at the most stenotic site of the plaque of target lesions correlated strongly with body mass index (r5=0.53, p<0.001) and negatively with serum adiponectin levels (r5=-0.34, p=0.03). Serum remnant cholesterol was the strongest positive factor for necrotic tissue and a negative determinant for fibrotic tissue in the plaques. Furthermore, the remnant cholesterol/triglyceride ratio was significantly correlated with the proportion of lipid in plaques, whereas serum LDL-C or high-density lipoprotein cholesterol levels were not. In conclusion, this study supports the concept that increased serum remnant-like cholesterol levels may contribute to the development of coronary plaques in patients with stable angina with well controlled LDL-C levels on statin therapy. Measurement of remnant cholesterol may aid evaluation of residual cardiovascular risk in this setting.
Impact of remnant lipoprotein on coronary plaque components.

Matsuo N, Matsuoka T, Onishi S et al.

Genetic variants of APOA5 predispose to atherogenic dyslipidaemia and subclinical atherosclerosis

Elevated triglycerides are a marker of elevated remnant cholesterol and a component of atherogenic dyslipidaemia. Atherogenic dyslipidaemia is a key driver of atherosclerosis especially in individuals with cardiometabolic disease. It has been proposed that variation at the APOA5 gene locus, encoding apoAV, a key regulator of triglyceride levels, modulates lipoprotein subclass distributions toward a more atherogenic pattern in dyslipidaemic patients.
 
In this study of 422 treatment-naïve subjects, two APOA5 variants, rs662799 (-1131T>C) and rs3135506 (S19W), were genotyped. Circulating lipoproteins were determined by nuclear magnetic resonance, and intima-media thickness (IMT) was evaluated using B-mode ultrasonography. Carriers of the rs662799 and rs3135506 variants had a proatherogenic lipid profile based on remnant (very low-density lipoprotein [VLDL] and intermediate density lipoprotein [IDL] subclasses), resulting in an increase in large VLDL (+133%, p < 0.001) and small LDL (+34%, p = 0.014). This atherogenic subclass distribution was significantly associated with increased carotid IMT, especially in patients with increased body mass index (?25 kg/m2). These findings add to the evidence supporting a link between remnant cholesterol, atherogenic lipoprotein profile and IMT-defined subclinical atherosclerosis.
APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis.

Guardiola M, Cofán M, de Castro-Oros I et al.

Diabetic retinopathy signs related to an increased risk of ESRD

In a multi-ethnic Asian population, diabetic retinopathy was associated with prevalent and incident end-stage renal disease (ESRD). Data from 5,763 subjects (aged at least40 years) from the Singapore Malay Eye Study and the Singapore Prospective Study) were evaluated. Retinopathy was graded using the modified Airlie House classification system. Retinal vascular parameters were measured using computer-assisted programs to quantify the retinal vessel widths (arteriolar and venular caliber) and retinal vascular network (fractal dimension). Data on ESRD was obtained by record linkage with the ESRD cases registered by National Registry of Diseases Office, Singapore. Retinopathy was associated with prevalent ESRD (odds ratio [OR], 3.21, 95% confidence interval [CI]: 1.28–8.05) and incident ESRD (hazard ratio [HR], 2.51, 95%CI:1.14–5.54). This association was largely seen in subjects with diabetes and not in those without diabetes. However, other microvascular changes in the retina were not associated with ESRD.
Retinal microvascular abnormalities and risk of renal failure in Asian populations.

Yip WF, Sabanayagam C, Teo BW et al.

Atherogenic index: simple measure for assessing the risk of type 2 diabetes

Atherogenic dyslipidaemia, the combination of elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) is an important driver of cardiovascular risk in type 2 diabetes. This meta-analysis of 15 studies, with a total sample size of 4,010, showed a positive association between the Atherogenic Index, defined as log(TG/HDL-C) and type 2 diabetes. Indeed, the standardised mean difference (SMD) for the AIP was 1.78 (95% confidence interval (CI): 1.04-2.52), which was higher than for other parameters, including triglycerides (0.93, 95% CI: 0.78-1.09) and low-density lipoprotein cholesterol (LDL-C) ( 0.44, 95% CI: 0.11-0.77). Taken together, these results suggest AIP may be more closely associated with the risk of type 2 diabetes than other lipid parameters.
Meta-analysis of Atherogenic Index of Plasma and other lipid parameters in relation to risk of type 2 diabetes mellitus.

Zhu XW, Deng FY, Lei SF.

Fibroblast growth factor 21: a contributor to residual cardiovascular risk?

A new report from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, implicates fibroblast growth factor 21 (FGF21) levels in cardiovascular risk in patients with type 2 diabetes. FGF21 has already been shown to be elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. The investigators evaluated baseline plasma FGF21 levels in 9,697 individuals with type 2 diabetes in the FIELD study. The primary outcome was total cardiovascular disease (CVD) events. In analyses adjusted for confounding factors, higher baseline FGF21 levels were associated with higher risk for total CVD events (hazard ratio [HR] and 95% confidence interval [CI] 1.28, 1.10, to 1.50). Moreover, addition of FGF21 levels to a model including established CVD risk factors for predicting total CVD events led to significant improvement in discrimination and net reclassification of CVD risk. Taken together, these data add to emerging evidence for FGF21 as a contributor to cardiovascular risk in type 2 diabetes patients.
The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study.

Ong KL, Januszewski AS, O'Connell R et al.

EUROASPIRE IV: attainment of lipid targets still falls short

Latest findings from EUROASPIRE survey, a cross-sectional study of secondary prevention patients from 24 countries in Europe shows that achievement of guideline-recommended lipid goals is still far from optimal. This latest report from EURASPIRE include 7,998 patients (24.4% females) aged <80 years with coronary disease, who had coronary artery bypass graft, percutaneous coronary intervention or an acute coronary syndrome. Of the 74% of patients with dyslipidaemia, only 17% of women and 22% of men achieved the recommended low-density lipoprotein cholesterol goal of <1.8 mmol/L (70 mg/dL). This was despite 86.6% of patients receiving lipid-lowering therapy, principally statins. Moreover, there was also room for improvement with management of blood pressure, glycaemia, stopping smoking and lifestyle intervention. Nearly 50% of patients smoking at the time of the event were still smoking, 60% reported no or little physical activity, 38% of patients were obese (body mass index ?30 kg/m2), 43% had blood pressure ?140/90 mmHg and 27% had diabetes. Despite prescription of cardioprotective medication in >75% patients (anti-platelets 94%; beta-blockers 83%; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75%; and statins 86%), most coronary patients did not achieve guideline standards for secondary prevention. Clearly, much remains to be done in terms of achieving healthier lifestyles, better risk factor control and adherence with cardioprotective medication in these patients.
EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.

Kotseva K, Wood D, De Bacquer D et al.

Triglyceride-rich lipoproteins and their remnants; a key driver of dyslipidaemia in type 2 diabetes;

This review in Atherosclerosis brings together new evidence that conclusively shows that the different components of diabetic dyslipidaemia are not isolated abnormalities but closely linked metabolically. Of note, the underlying disturbances are hepatic overproduction and delayed clearance of triglyceride-rich lipoproteins. Recent findings clearly show that triglyceride-rich lipoproteins and their remnants are atherogenic. Thus, understanding of the pathophysiology of dyslipoproteinaemia in humans reinforces the importance of targeting triglyceride rich lipoproteins for the prevention and treatment of dyslipidaemia.
New insights into the pathophysiology of dyslipidemia in type 2 diabetes.

Taskinen MR, Borén J.

PCSK9 associated with atherogenic dyslipidaemia

PCSK9 plays a key role in cholesterol homeostasis by regulating the availability of low-density lipoprotein (LDL) receptors and in turn catabolism of LDL, thus influencing circulating levels of plasma LDL cholesterol. Moreover, there is also evidence that PCSK9 influences the metabolism of other lipoproteins including very low-density lipoprotein (VLDL), with high levels of PCSK9 shown to down-regulate VLDL receptor expression.1 This study investigated the relationship between PCSK9 and the lipoprotein profile using nuclear magnetic resonance (NMR) in 267 patients with diabetes and metabolic syndrome who were not receiving any lipid-lowering therapy. Levels of plasma PCSK9 levels were significantly and positively correlated with circulating levels of triglycerides (r=0.136, p=0.033), total cholesterol (r=0.219, p<0.001), and apolipoprotein B (r=0.226, p=0.006) and with an atherogenic lipoprotein profile. There was a positive association between circulating PCSK9 levels and large VLDL particles (r=0.210, p=0.001), and their remnants, specifically, proatherogenic circulating remnant lipoprotein cholesterol levels (r=0.171, p=0.006). In conclusion, these data highlight that PCSK9 is not only associated with LDL homeostasis, but also atherogenic lipoproteins such as VLDL, and remnant lipoprotein levels.
1. Roubtsova A, Munkonda MN, Awan Z et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 2011;31:785-91.
Circulating PCSK9 levels are positively correlated with NMR-assessed atherogenic dyslipidemia in patients with high cardiovascular risk.

Guardiola M, Plana N, Ibarretxe D, Cabré A, González M, Ribalta J, Masana L

Novel apolipoprotein C-II mimetic peptide: future potential in targeting triglycerides?

This study reports data with a novel apoC-II mimetic peptide in an experimental mouse model (apolipoprotein E-knockout mice). This peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells, and activated lipolysis by lipoprotein lipase in vitro. Intravenous administration (30 mg/kg) to apolipoprotein E-knockout mice significantly reduced plasma cholesterol (by 38%) and triglycerides (by 85%), at 4 hours. The authors concluded that this novel peptide may offer future therapeutic potential for the management of elevated triglycerides.
A Novel apolipoprotein C-II mimetic peptide that activates lipoprotein lipase and decreases serum triglycerides in apolipoprotein E-knockout mice.

Amar MJ, Sakurai T, Sakurai-Ikuta A, Sviridov D, Freeman L, Ahsan L, Remaley AT.

2014

Impact of diabetic retinopathy in working age individuals

The cost and impact on daily life of diabetic retinopathy (DR) and diabetic macular oedema (DME) were highlighted by this US retrospective cohort study, using claims data (2001-2012) from the Human Capital Management Services Group Research Reference Database on annual direct/indirect health benefit costs and absences for employees aged ? 18 years, total data (n=466,251). Employees were divided into two groups, drivers (n=39,702) or nondrivers (n=426,549). Among nondrivers with diabetes, the presence of DME or DR significantly increased sick leave and short-term disability costs. Thus, this study using real-world data highlights the need for renewed emphasis on early detection and management of diabetes-related eye disease in working-age adults. Beyond mandatory management of blood glucose and blood pressure, data from two major prospective studies support a role for fenofibrate in the management of early DR. As recommended by the R3i, incorporation of fenofibrate into management algorithms may help to reduce costs and improve quality of life among patients with diabetes.(1)
 
1. Hermans MP, Fruchart JC, Davignon J et al. Residual microvascular risk in type 2 diabetes in 2014: Is it time for a re-think? A perspective from the Residual Risk Reduction Initiative (R3i). Journal of Diabetes & Metabolism 2014, 5:413.
United States comparative costs and absenteism of diabetic ophthalmic conditions.

Brook RA, Kleinman NL, Patel S, Smeeding JE, Beren IA, Turpcu A.

US Diabetes and obesity costs updated

Recent data from the U.S. show reduced life expectancy and increased lifetime healthcare expenditure in obese individuals with diabetes compared with those of normal weight. These data highlight the urgent need to tackle the escalating burden of cardiometabolic disease in the US and beyond. The analysis included data from the National Health Interview Survey (NHIS, 1997-2000), the Medical Expenditure Panel Survey (1997-2000), and the NHIS Linked Mortality Public-use Files, with mortality followed-up to 2006. Markov modelling with risk and cost estimates was used to compute life years and total lifetime healthcare expenditures by age, race, sex, and body mass index (BMI) classifications for patients with or without diabetes. The presence of diabetes not only decreased life expectancy by 3.3 to 18.7 years, but also increased lifetime healthcare expenditures by $8,946 to $159,380, depending on age-race-sex-BMI classification groups. In U.S. adults aged 50 years, white females with diabetes and BMI >40 kg/m2 had 17.9 remaining life years and lifetime health expenditures of $185,609. By comparison, females with diabetes and normal weight had 22.2 remaining life years and lifetime health expenditures of $183,704. These data reinforce evidence on the costs of obesity, in terms of decreased life expectancy and increased lifetime healthcare expenditure.
Life years lost and lifetime healthcare expenditures associated with diabetes in the U.S., National Health Interview Survey, 1997–2000.

Leung MM, Pollack LM, Colditz GA, Chang SH.

Does microvascular disease predict macrovascular disease?

A previous review by the Residual Risk Reduction Initiative highlighted a link between microvascular and macrovascular disease in type 2 diabetes.(1) This new study adds to the evidence, suggesting that retinal microvascular endothelial dysfunction is a marker for underlying coronary artery disease (CAD) in non-diabetic subjects.
 
The study investigated 197 subjects, 119 without CAD but at least 2 cardiovascular risk factors (non-CAD controls) and 78 with stable CAD, using retinal arteriolar and venular dilatation to flicker light, a nitric oxide dependent phenomenon, as a marker of retinal microvascular endothelial dysfunction. Fingertip pulse volume amplitude to calculate reactive hyperaemia index (RHI) and brachial artery flow-mediated dilatation (FMD) were measures of peripheral microvascular and conduit vessel endothelial function, respectively. There was attenuation of mean retinal arteriolar dilatation in subjects with CAD (1.51±1.51% vs 2.37±1.95% in non-CAD controls; p = 0.001). Even after adjustment for age, gender, cardiovascular risk factors and medication use, retinal arteriolar dilatation remained independently associated with CAD (odds ratio 1.60, 95% CI 1.14, 2.25; p = 0.007). In conclusion, this study provides further support of a link between microvascular and macrovascular disease.
 
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.
Usefulness of retinal microvascular endothelial dysfunction as a predictor of coronary artery disease.

Al-Fiadh AH, Wong TY, Kawasaki R, Clark DJ, Patel SK, Freeman M, Wilson A, Burrell LM, Farouque O.

CETP gene-diet interaction impacts atherogenic dyslipidaemia

A new report provides evidence of an interaction between cholesteryl ester transfer protein (CETP) genotype and diet on changes in blood lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides, i.e. atherogenic dyslipidaemia).
 
This study evaluated whether the common CETP rs3764261 genotype influenced lipid changes in response to weight-loss diets, specifically the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) and Dietary Intervention Randomized Controlled Trial (DIRECT) studies. In the POUNDS LOST study in 732 overweight/obese adults, those carrying the CETP-rs3764261 CC genotype and on a high-fat diet had larger increases in HDL-C (10.1% vs 4.5%, p=0.001) and decreases in triglycerides (24.0% vs 14.7%, p=0.007) than individuals on a low-fat diet at 6 months. These gene-diet interactions affecting changes in HDL-C and triglycerides were replicated in the DIRECT study. The authors concluded that individuals with the CETP rs3764261 CC genotype might derive greater benefit in targeting atherogenic dyslipidaemia with a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet.
CETP genotype and changes in lipid levels in response to weight-loss diet intervention: gene-diet interaction analysis in the POUNDS LOST and DIRECT randomized trials.

Qi Q, Durst R, Schwarzfuchs D, Leitersdorf E, Shpitzen S, Li Y, Wu H, Champagne CM, Hu FB, Stampfer MJ, Bray GA, Sacks FM, Shai I, Qi L.

Triglycerides in the news

Recent reviews highlight the case for triglycerides, more specifically triglyceride-rich lipoproteins (TRLs), in the development of cardiovascular risk.
 
Tenenbaum et al argue for re-consideration of the role of TRLs in cardiovascular disease, taking into account epidemiological, genetic and mechanistic data. This review also discusses mechanisms whereby TRLs stimulate atherogenesis, including excessive free fatty acid (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. As discussed by Khetarpal and Rader,2 genetic studies have provided convincing evidence that plasma levels of TRLs are causally related to the development of coronary artery disease (CAD), specifically implicating the key triglyceride-regulating enzyme lipoprotein lipase (LPL), in CAD risk. Beyond LPL, there is also strong evidence implicating the genes APOC3 and APOA5, encoding apolipoproteins (apo) C-III and apoA-V, respectively; data indicate that apoC-III promotes and apoA-V protects against CAD.
 
While the mainstay of management of hypertriglyceridaemia is lifestyle, genetic data also provide a rationale for the development of novel targeted therapies, such as an antisense APOC3 oligonucleotide, which offer the potential for reducing residual cardiovascular risk beyond that achieved with current therapy.
 
1. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk. New insights from human genetics. Arterioscler Thromb Vasc Biol 2015 [Epub ahead of print].
2. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2014 [Epub ahead of print]
Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia

Atherogenic dyslipidaemia: how to treat?

A new review highlights the importance of targeting atherogenic dyslipidaemia, the key feature linking metabolic syndrome and type 2 diabetes, which is insufficiently addressed by statin therapy. In particular, the review highlights the need for urgent action in regions characterised by a high prevalence of atherogenic dyslipidaemia, notably south Asia and the Middle East. Consistent with recommendations of the Residual Risk Reduction Initiative,(1) the authors advocate a role for fibrates and omega-3 polyunsaturated fatty acids that target atherogenic dyslipidaemia and elevated triglycerides, respectively, and thus offer the potential to reduce residual cardiovascular risk associated with this dyslipidaemia.
 
1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
Type 2 diabetes mellitus, metabolic syndrome, and mixed dyslipidemia: How similar, how different, and how to treat?

Halcox J, Misra A.

Genetic polymorphisms protect from development of atherogenic dyslipidaemia in HIV

HIV patients undergoing antiretroviral therapy are at increased risk of developing atherogenic dyslipidaemia, and thus predisposed to cardiovascular disease. This cross-sectional, observational outpatient study investigated whether variability in the genes influencing the metabolism of triglycerides, APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5 and VLDLR, may predispose to the development of atherogenic dyslipidaemia. The study enrolled 468 antiretroviral-treated HIV-infected patients, 173 with normal lipids and 148 with atherogenic dyslipidaemia, defined as triglycerides >1.7 mmol/L and high-density lipoprotein cholesterol [HDL-C] < 1.02 in men or 1.28 mmol/L in women. Genetic analyses showed that specific polymorphisms in LPL (rs328), CETP (rs708272) and HL (rs1800588) were more frequent in subjects with normal lipid levels than in those with atherogenic dyslipidaemia, with at least one of these polymorphisms detected in 90% of patients (versus 75% in patients with atherogenic dyslipidaemia, p=0.003). Indeed, in patients with the combination of these protective alleles, there was a trend towards higher HDL-C levels (mean 1.13 versus 1.24 mmol/L), lower triglycerides (2.23 versus 1.89 mmol/L) and lower remnant lipoprotein concentration (16.4 versus 13.0 mmol/L). Further study is needed to investigate genetic variability in susceptibility to atherogenic dyslipidaemia as a factor predisposing to protection against cardiovascular disease in HIV patients.
Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from atherogenic dyslipidemia in an allele-dose-dependent manner.

Echeverría P, Guardiola M, González M et al.

HDL cholesterol efflux and cardiovascular disease

While observational studies support a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) as a strong CV risk factor, it may not be the optimal surrogate for cardiovascular risk. Indeed, in recent major prospective clinical studies, such as dal-OUTCOMES,(1) targeting HDL-C did not result in reduction in cardiovascular disease outcomes. Given that HDL particles have been associated with multiple atheroprotective functions, it is likely that HDL-C level, a static measure, is inappropriate as a biomarker of HDL function and dynamics. Instead, there is growing support for measures of HDL functionality as improved biomarkers for cardiovascular risk. Attention has focused on cholesterol efflux from macrophages to HDL, a key step in reverse cholesterol transport, as one of the most important functions of HDL. Previous studies have shown an inverse association between cholesterol efflux capacity and prevalent coronary artery disease, which is independent of HDL-C level.(2)
The current study investigated the association between cholesterol efflux capacity and incident cardiovascular disease events in 2,924 subjects (median age 42 years, 43% male, 49% black and with median low-density lipoprotein cholesterol 104 mg/dL [2.7 mmol/L]) from the Dallas Heart Study free from clinical cardiovascular disease at baseline. Overall, 46% of women had HDL-C <50 mg/dL (1.3 mmol/L) and 35% of men had HDL-C <40 mg/dL (1.05 mmol/L). The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or death from cardiovascular causes. Over a median follow-up of 9.4 years, 132 subjects had a primary atherosclerotic cardiovascular disease event. There was a graded inverse association between HDL cholesterol efflux capacity and the primary end point, which persisted after adjustment for multiple traditional cardiovascular risk factors. Comparing the highest versus lowest quartiles, there was a 67% reduction in cardiovascular risk (hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Thus, this study adds to emerging data for the value of HDL cholesterol efflux capacity as a biomarker for cardiovascular risk. However, this measure is a research tool with further validation needed before this can be translated to routine clinical practice.
 
1. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
2. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.
HDL cholesterol efflux capacity and incident cardiovascular events.

Rohatgi A, Khera A, Berry JD et al.

Importance of triglycerides as a risk factor in middle-aged women

Decision tree analysis identified elevated triglycerides as the main risk factor for carotid atherosclerosis in middle-aged women.
Decision tree analysis is commonly used to identify a strategy most likely to reach a goal, and thus may be relevant in assessing the relative importance of different risk factors for carotid atherosclerosis, an intermediate clinical endpoint used as surrogate for cardiovascular disease. This study included 5,822 subjects aged 20-80 years, who underwent physical examination and routine laboratory testing (blood pressure, fasting plasma glucose, total cholesterol, triglycerides, high density lipoprotein-cholesterol and low density lipoprotein-cholesterol). Carotid intima-media thickness (CIMT) was measured by carotid ultrasonography. CIMT was defined as carotid atherosclerosis when CIMT was ?0.9 mm. Overall, the incidence of carotid atherosclerosis was 12.2% (14.1% in men and 9.2% in women). The most important modifiable risk factors in men aged 20-40 years was total cholesterol (>6.31 mmol/L), whereas in those aged 41–59 years, fasting plasma glucose (>5.79 mmol/L) was more important. In contrast, in women, fasting plasma glucose (>5.52 mmol/L) was key in younger subjects (20–40 years), but triglycerides (>1.51 mmol/L) most relevant in those 41–59 years of age. These findings suggest that cardiovascular prevention strategies should target modifiable risk factors according to their relevance in men and women.
Decision tree analysis of traditional risk factors of carotid atherosclerosis and a cutpoint-based prevention strategy.

Qin G, Luo L, Lv L et al.

Metabolic syndrome components linked with decreased glomerular filtration rate

In a large study from China, critical components of the metabolic syndrome, including low plasma concentration of high-density lipoprotein cholesterol (HDL-C), were risk factors for reduced glomerular filtration rate (GFR). This cross-sectional study included 75,468 urban workers (21,497 with the metabolic syndrome) who underwent annual health examinations between March 2010 and September 2012. The group with metabolic syndrome had a higher mean age (52.3 versus 47.4 years) and a greater percentage of men (66% versus 52%) compared with those without metabolic syndrome. The presence of the metabolic syndrome was associated with reduced GFR (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.13-1.83). In multivariate analyses, elevated blood pressure (OR 1.34, 95% CI 1.00-1.78), low HDL-C (OR 1.88, 95% CI 1.44-2.43), and elevated fasting blood glucose (OR 1.42, 95% CI 1.09-1.85) were each independently associated with the metabolic syndrome. Low HDL-C was associated with a 19.7% population-attributable risk for reduced GFR. The study adds to other findings, such as those from the ADVANCE study, showing a link between HDL-C and decreased renal function.(1,2)
 
1. Zoppini G, Targher G, Chonchol M et al. Higher HDL cholesterol levels are associated with lower incidence of chronic kidney disease in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 2009;19:580-6.
2. Morton J1, Zoungas S, Li Q et al. Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy: results of the ADVANCE study. Diabetes Care 2012;35:2201-6.
Association of metabolic syndrome with decreased glomerular filtration rate among 75,468 Chinese Adults: A cross-sectional study.

Song H, Wang X, Cai Q et al.

Nonfasting remnant cholesterol levels as mediator of obesity-related ischaemic heart disease risk

The increased risk of ischaemic heart disease in obesity is mediated partly by elevated levels of nonfasting remnant cholesterol, according to this Danish study.
The study used a Mendelian randomisation approach, a type of ‘natural randomised trial’, to delineate which variables prevalent with obesity are likely to be mediators of the risk of ischaemic heart disease associated with obesity. Data from ? 90,000 subjects from the Copenhagen General Population Study (n=69,535), the Copenhagen City Heart Study (n=10,099), and the Copenhagen Ischemic Heart Disease Study (n=5,050) were analysed. The potential association of lipoproteins, blood pressure, glucose, and/or C-reactive protein with ischaemic heart disease was initially examined in observational analyses, and thereafter in genetic analyses based on the presence of variants known to be associated with body mass index, and seven intermediate variables: nonfasting remnant cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL-C), systolic and diastolic blood pressure, glucose and C-reactive protein. The genetic data were not subject to confounding and reverse causation as were the observational data. Elevated levels of nonfasting remnant cholesterol and LDL-C, elevated blood pressure, and possibly elevated nonfasting glucose levels, were implicated as causal mediators of the increased risk of ischaemic heart disease due to obesity, whereas HDL-C and C reactive protein were not. In genetically determined obesity, LDL cholesterol, systolic blood pressure and remnant cholesterol contributed 8%, 7% and 7%, respectively, of the excess risk of ischaemic heart disease, whereas in observational data, the corresponding excess risks were 21%, 11%, and 20%, respectively. These data provide a rationale for prospective studies testing whether lowering of elevated remnant cholesterol, closely associated with elevated triglycerides, may reduce ischaemic heart disease risk.
Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease.

Varbo A, Benn M, Davey Smith G et al.

Spain: High prevalence of atherogenic dyslipidaemia in lipid clinics

One in 6 patients treated in lipid and vascular risk units has atherogenic dyslipidaemia, according to a report from EDICONDIS-ULISEA. This observational, retrospective study included patients aged ?18 years who were referred for dyslipidaemia and vascular risk to 43 lipid clinics in Spain. In total, 295 (17.9%) of 1,649 patients with a lipid profile at first visit had atherogenic dyslipidaemia. However, only a minority (44 or 16.1%) of these patients with atherogenic dyslipidaemia were successfully managed at subsequent follow-up. The authors concluded that management of atherogenic dyslipidaemia, characterised by elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), clearly needs to improve in Spain.
Atherogenic dyslipidemia: prevalence and management in lipid clinics.

Pedro-Botet J, Flores-Le Roux JA, Mostaza JM et al.

CEPHEUS Study: Lipid control far from optimal in Middle East

The CEPHEUS (Centralized Pan-Middle East Survey) evaluated the treatment of hypercholesterolemia in patients aged ?18 years of age in six Middle Eastern countries (November 2009 -July 2010). Lipid goals were those recommended by the joint Consensus Statement of the American Diabetes Association and American College of Cardiology. The study included 5,275 patients (mean age 56?±?13 years, 58% male and 69% at very high cardiovascular risk). In very high-risk patients, there was suboptimal management of LDL-C (only 25% achieved recommended targets), non-HDL-C (36%) and apolipoprotein B (38%); in patients with triglycerides ?2.2?mmol/L, LDL-C and apolipoprotein B goal attainment was even lower (16% and 15%, respectively). Thus, despite being on lipid-modifying therapy, patients at very high cardiovascular risk remain inadequately managed across this region.
Therapeutic lipid target achievements among high and highest risk patients: results from the CEPHEUS study in the Arabian Gulf.

Al-Rasadi K, Al-Zakwani I, Al Mahmeed W et al.

Chemokine ligand 2: a potential target in diabetic retinopathy?

Accumulating evidence indicates a role for retinal inflammation in the pathogenesis of diabetic retinopathy. Chronic inflammation in the diabetic retina leads to leukocyte activation, via the action of specific chemokines, adhesion to the vascular endothelium and extravasation into the retinal tissues. One of the most potent chemotactic factors for monocytes is CCL2, also known as monocyte chemoattractant protein (MCP-1). In this experimental study, expression of CCL2 was significantly up-regulated in the retinas of the streptozotocin-treated rats (a well established model of diabetes), as well as in human retinal endothelial cells treated with high glucose and glucose flux. Subsequent studies in Cx3cr1-GFP mice showed that intraocular injection of CCL2 increased retinal monocyte/macrophage infiltration; when these mice were made diabetic and CCL2 injected, there was increased infiltration of monocytes/macrophages in retinal tissues, as well as activation of retinal microglia. Cell culture impedance sensing studies showed that while purified CCL2 was unable to modify the integrity of the human retinal endothelial cell barrier, monocyte conditioned medium led to significant reduction in cell resistance, implying that CCL2 may take part in early immune cell recruitment leading to subsequent changes in the blood-retinal-barrier. Taken together, these findings suggest that chemokine CCL2 plays an indirect role in mediating the increase in retinal vascular permeability brought about by hyperglycaemia, and thus may represent a potential therapeutic target for reducing the residual risk of this complication in diabetic patients.
Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy.

Rangasamy S, McGuire PG, Franco Nitta C et al.

FATS-Observational Study: combination lipid therapy reduces atherosclerotic burden

Compared with statin monotherapy, the combination of statin plus niacin was associated with less progression of carotid intima-media thickness (CIMT) when given long-term in patients with coronary artery disease. Patients who completed the Familial Atherosclerosis Treatment Study (FATS) either received usual care with statin therapy alone (n=26) or were enrolled in the 20-year FATS-Observational Study (n=43) and received lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, followed by simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). At follow-up (mean 17.8 years with combination therapy and 19.0 years with usual care), combination therapy was associated with improved lipid control, as shown by greater decreases in total cholesterol (by 42% versus 31% with usual care, p=0.008), low-density lipoprotein cholesterol (by 57% versus 38%, p<0.001), as well as a greater increase in high-density lipoprotein cholesterol (by 38% versus 15%, p = 0.02). These lipid changes were also associated with significantly less CIMT progression (0.902 ± 0.164 versus 1.056 ±- 0.169 mm, p <0.001). These findings support the value of statin combination therapy in providing more comprehensive lipid control and reduced atherosclerosis progression in patients with established coronary artery disease.
Prolonged combination lipid therapy is associated with reduced carotid intima-media thickness: A case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS).

Phan BA, Moore AB, Davis J et al.

Triglycerides: a key predictor of mortality in type 2 diabetes

This study from Italy highlights the need to improve the management of elevated triglycerides in patients with type 2 diabetes. The study included 1,917 patients with type 2 diabetes (mean age 58 years, 59% male), attending the hospital-based outpatient clinic. Over a mean follow-up period of 10 years, there were 95 deaths. Cox proportional hazard analysis showed a direct significant association between triglycerides levels during follow-up and all-cause mortality, independent of confounding factors such as low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, HbA1c, blood pressure, body mass index, fasting glucose, and antihypertensive and glucose-lowering treatment (III vs I tertile: HR:1.87;95% confidence intervals: 1.12-3.12, p=0.016). The authors concluded that more attention should be given to managing elevated triglycerides as part of the cardiovascular risk profile in type 2 diabetes patients.
Plasma triglycerides predict ten-years all-cause mortality in outpatients with type 2 diabetes mellitus: a longitudinal observational study.

Miselli M-A, Dalla Nora E, Passaro A, Tomasi F, Zuliani G.

More from PREDI-MED: Mediterranean diet can reverse metabolic syndrome

The PREDI-MED study previously showed the benefit of a Mediterranean diet in reducing cardiovascular disease (CVD) events in high-risk patients without pre-existing CVD.1 New findings from this group indicate that long-term adherence to a Mediterranean diet may also reverse the metabolic syndrome, specifically reducing obesity and hyperglycaemia. Subjects in the PREDI-MED trial were randomly assigned either a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or advice on following a low-fat diet (the control group). In total, 5,801 subjects were followed over a mean of 4.8 years. In 3,392 subjects who had metabolic syndrome at baseline, 958 (28%) no longer had this phenotype at follow-up. Notably, subjects on a Mediterranean diet supplemented with either olive oil or nuts were more likely to undergo reversion (by 35% [15-58%] or by 28% [8-51%], respectively compared with control, p < 0.001 for each comparison). Subjects on either Mediterranean diet shown significant decreases in central obesity (p<0.05); those allocated to olive oil supplementation also showed a significant decrease in glycaemia (p = 0.02). In 1,919 subjects who did not have metabolic syndrome at entry to the study, there was no difference in the risk of developing metabolic syndrome between the three groups. In conclusion, a Mediterranean diet supplemented with either extra virgin olive oil or nuts is more likely to lead to reversion of the condition, suggesting potential benefit as part of lifestyle intervention in the management individuals with central obesity. 1. Estruch R, Ros E, Salas-Salvadó J et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial.

Babio N Toledo E, Estruch R et al; for the PREDIMED Study Investigators.

USA National Lipid Association publishes recommendations for management of dyslipidaemia

In contrast to the recent ACC/AHA guideline for management of cholesterol,1,2 the NLA recommendations emphasise the importance of cholesterol goals in clinical practice, not only for clinicians to use in monitoring the efficacy of treatment, but also for patients to understand and work toward. These recommendations favour the use of non-HDL cholesterol, which includes all potentially atherogenic lipoproteins, i.e. low-density lipoprotein, intermediate density lipoproteins, very low-density lipoproteins (VLDL) and VLDL remnants, chylomicron remnants, and lipoprotein (a), as the preferable marker for risk for cardiovascular disease and to monitor therapy. The NLA also provides recommendations for the management of elevated triglycerides, closely associated with metabolic syndrome, obesity and diabetes, and an important contributor to residual cardiovascular risk. The use of fibrates, niacin or omega-3 fatty acids can be considered if triglyceride goals are not reached with statins alone.
br> 1. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934. 2. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45.
National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary.

Jacobson TA, Ito MK, Maki KC et al.

ODYSSEY COMBO II: PCSK9 inhibitor alirocumab in high cardiovascular risk patients on statin therapy

In ODYSSEY COMBO II, the addition of the PCSK9 monoclonal antibody therapy, alirocumab, to maximally tolerated statin therapy resulted in superior control of low-density lipoprotein cholesterol (LDL-C) compared with oral ezetimibe in high cardiovascular risk patients with inadequately controlled LDL-C levels. This double-blind, multicentre study enrolled 720 patients (LDL-C =1.81 mmol/L [=70 mg/dL] in patients with established cardiovascular disease (CVD), or =2.59 mmol/L (=100 mg/dL) if no history of CVD but with other risk factors). Patients were randomised 2:1 to either alirocumab 75 mg subcutaneously every 2 weeks (increasing to 150 mg every 2 weeks at Week 12 if LDL-C was =1.81 mmol/L at Week 8) or ezetimibe 10 mg daily. The primary endpoint (% change in LDL-C from baseline to Week 24, intent-to-treat analysis), showed that treatment with alirocumab was significantly superior to ezetimibe (51% versus 21%, p<0.0001). This "treat to target" approach with alirocumab resulted in >75% of alirocumab-treated patients achieving guideline-recommended LDL-C goals (<1.81 mmol/L or<70 mg/dL) at 24 weeks. Consistent LDL-C reductions were maintained over 52 weeks (mean percent LDL-C reduction 50% versus 18% with ezetimibe, absolute LDL-C reduction 2.2 versus 1.4 mmol/L). Treatment with alirocumab was well tolerated with no adverse signal, compared with ezetimibe. In conclusion, the addition of the PCSK9 monoclonal antibody alirocumab significantly improved attainment of LDL-C goal in high CV risk patients.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study.

Cannon CP, Cariou B, Blom D et al.

Antisense inhibitor of apolipoprotein C-III improves the atherogenic lipoprotein profile

ISIS-APOCIIIRx selectively inhibits hepatic synthesis of apolipoprotein (apo)C-III, which has a key role in regulating plasma triglyceride (TG) levels. The current study investigated the effect of treatment with ISIS-APOCIIIRx, either as a single agent or in combination with fibrates, on fasting lipids and lipoproteins in patients with hypertriglyceridaemia (HTG) and 1) with type 2 diabetes on = 1g/day stable metformin and not on TG-lowering medication; 2) not on TG-lowering medication or (3) on stable fibrate therapy. Treatment with ISIS-APOCIIIRx resulted in consistent and significant dose-dependent decreases in apoC-III and TG, as well as increases in high-density lipoprotein cholesterol (HDL-C), with no significant change in non-HDL-C, when given alone or in combination with a fibrate (see Table). These data support further evaluation of ISIS-APOCIIIRx, either alone or in combination with a fibrate, in the management of HTG.

Mean (SD) Percent change from baseline to 13 weeks, after treatment with ISIS-APOCIIIRx

ParameterHTG with diabetes ISIS-APOCIIIRx + metformin (n=7) ISIS-APOCIIIRx (n=11) ISIS-APOCIIIRx + fibrate (n=10)
ApoCIII -88 (6.0)* -80 (9.3)*** -71 (13.0)**
Triglycerides -72 (8.3)* -71 (14.1)*** -64 (8.9)**
HDL-C +40 (19.8)* +46 (24.0)***+52 (23.7)***

*p=0.05, **p=0.01, ***p=0.001
Antisense inhibitor of apoC-III produces significant decreases in apoC-III and triglycerides and increases in HDL-C as a single agent or in combination with fibrates in hypertriglyceridemic patients.

Alexander VJ, Gaudet D, Brisson D et al.

Eur Heart J 2014;35(Abstract Supplement):218-219. Abstract P1275.

K-877, a SPPARM, favourably influences postprandial metabolism of remnant lipoproteins

This experimental animal model showed that the potent and selective peroxisome proliferator-activated receptor alpha (PPARa) agonist, K-877, attenuates fasting and postprandial hypertriglyceridaemia by enhancing lipoprotein lipase (LPL) activity and reducing weight gain. The study used male C57BL/6J mice, which were fed either a western diet (WD), WD containing K-877 (0.0005%) or WD containing fenofibrate (0.05%) for 4 weeks (n=10/group). Compared with the WD group, fasting triglycerides were significantly lower with K-877 (81.0±21.5 versus 32.0±8.7 mg/dL) or fenofibrate (81.0±21.5 versus 29.7±8.8 mg/); p<0.01 for each treatment group versus WD. Additionally, LPL activity was significantly increased in mice treated with K-877 or fenofibrate suggesting that both prevent the accumulation of remnant lipoproteins by increasing LPL activity. Treatment with K-877 or fenofibrate was also associated with less weight gain although dietary intake was similar. These findings from this experimental model indicate that treatment with K-877 improves postprandial hypertriglyceridaemia, and provide a rationale for investigation in humans.
A novel potent and selective PPARalpha agonist, K-877, ameriolates the atherogenic profile of fasting and postprandial hypertriglyceridemia in mice.

Masuda D, Kobayashi T, Nakaoka H et al.

Eur Heart J 2014;35( Abstract Supplement):904. Abstract: P5145.

Atherogenic dyslipidaemia associated with increased coronary artery progression in diabetes

This study highlights the importance of managing atherogenic dyslipidaemia, elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), to reduce atherosclerosis progression in patients with diabetes. A total of 109 patients (mean age 68±9 years, 31% female, 89% on statins) were included. Atheroma burden was assessed using intravascular ultrasound (IVUS), performed at baseline and a median of 1.3 years (474 days) later. The primary endpoints were normalised total atheroma volume (TAV) and percent atheroma volume (PAV), calculated in the target segment in each patient. Patients with inadequate control of both HDL-C (<40 mg/dL or 1.03 mmol/L) and TG (>150 mg/dL or 1.7 mmol/L) showed greatest coronary artery progression, as defined by both the change in TAV (7.7±21.9 mm3 versus -3.8±19.3 mm3 in patients with controlled levels p=0.006) and by the change in PAV (1.2±4.9% versus 0.5±3.4%, p=0.034). These findings emphasise the importance of atherogenic dyslipidaemia as a contributor to residual risk of coronary atherosclerosis in statin-treated patients with diabetes.
Progression of coronary atherosclerosis: importance of adequate lipid control in diabetic patients.

Hernando Marrupe L, Suarez Cuervo A, Hernandez Antolin R et al.

Eur Heart J 2014;35(Abstract Supplement): 393-394. Abstract P2281.

FOCUS: a polypill strategy improves treatment adherence in post-MI patients

The Residual Risk Reduction Initiative has already drawn attention to unmet clinical needs in the management of secondary prevention patients. For example, in the Prospective Urban Rural Epidemiology (PURE) study, only 15% of patients were taking statins 5 years after a myocardial infarction (MI), and use was substantially lower in low to middle income countries.1 These data highlight the need for education and re-thinking of strategies to improve management in these high-risk patients. Subsequently, the use of a once-daily fixed-dose combination - or polypill - including key medications to reduce cardiovascular risk has shown promise in studies of patients with established cardiovascular disease.2 However, to date there has been no direct evaluation of the impact of this polypill strategy on treatment adherence. Consequently, the FOCUS (Fixed Dose Combination Drug for Secondary Cardiovascular Prevention) project aimed to better understand adherence to medication in the post-MI setting.

The study involved two phases:
Phase 1, a comprehensive analysis of factors that determine the appropriate use of preventive interventions including 2,118 patients in 5 countries (Argentina, Brazil, Italy, Paraguay, and Spain);
and Phase 2, a randomised, controlled clinical trial (695 patients from those previously included in Phase I) testing the effect of a fixed combination of aspirin 100 mg, simvastatin 40 mg and ramipril 2.5, 5 or 10 mg, versus treatment with the individual agents, on adherence and control of cardiovascular risk factors.

In Phase I, overall adherence was 45.5% (=20 on the self-reported Morisky-Green questionnaire); younger age, depression, being on a complex medication regimen, poorer health, insurance coverage, and a lower level of social support were all associated with reduced risk of treatment adherence across all five countries. In Phase 2, patients in the polypill group had significantly improved adherence compared with the group receiving the medications separately; after 9 months, adherence (assessed by a score of =20 on the self-reported Morisky-Green questionnaire and high pill count [80-110%]) was 51% vs 41% (p=0.019; intention-to-treat population). There was no difference in mean low-density lipoprotein cholesterol levels at follow-up (89.9 vs 91.7 mg/dL). The authors concluded that the use of a polypill significantly improves treatment adherence compared with concomitant use of three individual therapies. Longer-term trials are required to evaluate whether this improved adherence translates to improved clinical benefit.

1. Yusuf S, Islam S, Chow CK et al. Prospective Urban Rural Epidemiology Study I. Use of secondary prevention drugs for cardiovascular disease in the community in high income, middle-income, and low-income countries (the pure study): A prospective epidemiological survey. Lancet 2011;378:1231-43.
2. Thom S, Poulter N, Field J et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: The umpire randomized clinical trial. JAMA 2013;310:918-29.
A polypill strategy to improve adherence: results from FOCUS (Fixed-dose Combination Drug for Secondary Cardiovascular Prevention) Project.

Castellano JM, Sanz G, Peñalvo JL et al.

Fasting and postprandial triglycerides: similarly effective as predictors for cardiovascular events

This study evaluated the association between fasting and postprandial serum triglycerides (TG) as risk modifiers in patients with coronary artery disease (CAD) treated with a statin. In total, the cohort included 514 patients (median age 68 years, 83% male) with angiographically confirmed, clinically stable CAD, 95% of whom were on a statin (median LDL-cholesterol 105 mg/dL). Both fasting and postprandial TG predicted cardiovascular events:
• Fasting TG (>150 mg/dL versus <106 mg/Dl): Hazard ratio 1.79, 95%-CI 1.31-2.45, p=0.0001
• Nonfasting TG AUC >1120 mg/dL vs. <750 mg/dL: Hazard ratio 1.78, 95%-CI 1.29-2.45, p=0.0003.
Risk prediction by TG was independent of traditional risk factors, medication, glucose metabolism, LDL- and HDL-cholesterol. The authors concluded that postprandial TG does not improve risk prediction over fasting TG in statin-treated patients with CAD.
Fasting serum triglycerides >150 mg/dl independently predict cardiovascular events in patients with coronary artery disease on guideline-recommended medication.

Werner C, Filmer A, Groenewold S et al.

BMI plus visceral adipose tissue improves prediction of cardiovascular risk

Adding a measure of visceral adipose tissue (VAT) to body mass index (BMI) provides a better predictor of cardiovascular risk, according to this study. A total of 369 consecutive patients without a history of cardiovascular disease were enrolled. VAT was assessed using 64-slice computed tomography angiography (CTA), with the percent VAT calculated as VAT/(VAT + subcutaneous adipose tissue) × 100, and its median value was 39.4%. Patients were divided into four groups based on BMI (<25 and 25=) and %VAT (<39.4 and 39.4=). Cardiovascular risk factors were hypertension, hyperglycaemia, and dyslipidaemia. Over the median follow-up of 2020 days, there were 32 cardiovascular events. Cox proportional hazards analysis showed that the risk of a cardiovascular event was higher in patients with both elevated BMI and VAT, after adjustment for confounding factors (see Table). On the basis of these findings, assessing both VAT and BMI may provide added value in cardiovascular risk assessment.
Hazard ratio (% CI) for major adverse cardiovascular events, after adjustment for cardiovascular risk factors

CategoryHR (95% CI)p-value
BMI =25 kg/m2 and higher %VATVs. BMI<25 kg/m2 with lower %VAT4.38, 1.58–12.18 0.005
Vs. BMI<25 kg/m2 with higher %VAT2.74, 1.18–6.35 0.02
Vs. BMI=25 kg/m2 with lower %VAT4.68, 0.98-22.51 0.05

Impact of body mass index and visceral adipose tissue on cardiovascular risk factors and outcomes.

Kunimura A, Uetani T, Harada K et al.

Eur Heart J 2014;35(Abstract Supplement):558. [Abstract P3185].

Incretin-based therapies favourably impact metabolic and cardiovascular risk

There is ongoing debate relating to the effects of incretin-based therapies on cardiovascular risk parameters, including lipids. This meta-analysis of 28 trials (10,171 patients with diabetes) showed that incretin-based therapies significantly reduced triglycerides (-0.29 mmol/L, 95% CI -0.48 to -0.11; p=0.002) and raised high density lipoprotein cholesterol (0.03 mmol/L, 95% Cl 0.0003-0.06; p=0.05, respectively), compared with other diabetes treatments. On the basis of these findings, not only do incretin-based therapies lower blood glucose in patients with type 2 diabetes, but there are also significant positive effects on the lipid profile.
The effect of incretin-based therapies on metabolic and cardiovascular parameters in diabetic patients: A meta-analysis of 28 randomized control trials with 10171 patients.

Klepacka A, Nikfar S, Rizzo M et al.

Eur Heart J 2014;35(Abstract Supplement): 740. [Abstract: P4239]

More from HPS2-THRIVE and AIM-HIGH: Serious harm with niacin

As previously reported, treatment with niacin/laropiprant in the HPS2-THRIVE trial did not improve clinical outcome in adults with cardiovascular disease and well-controlled low-density lipoprotein cholesterol (LDL-C, 63 mg/dL or 1.63 mg/dL) .1 What is especially worrying is that treatment with niacin/laropiprant was also associated with serious harm. As well as the anticipated skin-related adverse effects (p=0.003), there was also a significant increase in gastrointestinal, musculoskeletal, and bleeding complications, loss of glycaemic control in patients with diabetes at baseline, new-onset diabetes, and unexpectedly infectious adverse events (all p<0.001). Moreover, there was also a 9% (95% confidence interval [CI] 1-21%) increase in the risk of death which was of borderline statistical significance (p = 0.08), with similar nonsignificant increases in both vascular and nonvascular mortality. Added to this, a new safety analysis from AIM-HIGH shows an excess of skin-related, gastrointestinal and glycaemic complications, as well as a higher rate of serious bleeding with niacin use. Taken together, these safety issues and lack of clinical benefit, question the role of niacin (where still available) in clinical use. Although the authors of HPS2-THRIVE suggest that niacin might still be relevant some patients, they also emphasise the need to take into consideration the risks of treatment, especially given these safety findings.
1. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34):1279-91.
Safety profile of extended-release niacin in the AIM-HIGH Trial.

Anderson TJ, Boden WE, Desvigne-Nickens P, Fleg JL, Kashyap ML, McBride R, Probstfield JL.

Atherogenic dyslipidaemia linked with residual cardiovascular risk in patients with cerebrovascular disease

In statin-treated patients with a previous cerebrovascular event, the presence of atherogenic dyslipidaemia was associated with a higher residual cardiovascular risk compared with those without this lipid profile. These findings were based on a post hoc analysis from PERFORM (Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack, n=19,100) and SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels; n=4,731). Atherogenic dyslipidaemia was defined as low high-density lipoprotein cholesterol (=40 mg/dL or 1.03 mmol/L) and high triglycerides (=150 mg/dL or 1.7 mmol/L) 3 months after randomization. The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Overall, 10% of subjects in PERFORM (n=1,057) and 9% in SPARCL (n=259) had atherogenic dyslipidaemia after 3 months on statin therapy. In PERFORM, this lipid phenotype was more likely to be associated with Asian ethnicity. During a median follow-up of 2.3 years in PERFORM, 1,123 subjects had major cardiovascular events. The risk of a major cardiovascular event was higher in patients with atherogenic dyslipidaemia at baseline than in those without (hazard ratio [HR], 1.36, 95% CI 1.14–1.63, p<0.001). The presence of atherogenic dyslipidaemia was also associated with an increased risk of incident stroke (HR 1.27, 95% CI 1.04–1.56, p=0.02). In SPARCL, 485 patients had a major cardiovascular event after a median follow-up of 4.9 years. As for the PERFORM data, the risk of this event was higher in patients with atherogenic dyslipidaemia (HR 1.40, 95% CI 1.06–1.85, p<0.017). This association was attenuated but remained significant after multivariable adjustment in PERFORM (HR 1.23; 95% CI, 1.03–1.48, p=0.02)). The authors conclude that atherogenic dyslipidaemia confers a higher residual cardiovascular risk (by ~25% after multivariate adjustment) in patients with pre-existing cerebrovascular disease (stroke or transient ischaemic attack) receiving statin therapy. These data highlight an unmet therapeutic need to address this residual risk.
Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients.

Sirimarco G, Labreuche J, Bruckert E, Goldstein LB, Fox KM, Rothwell PM, Amarenco P; on behalf of the PERFORM and SPARCL Investigators and Committees.

PCSK9, triglycerides and cardiovascular risk

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the recycling of low-density lipoprotein (LDL) receptors and hence plasma levels of LDL cholesterol. In this study of patients with coronary artery disease (CAD), serum triglycerides were correlated with PCSK9 and modified risk prediction by PCSK9. The study enrolled 504 patients with clinically stable CAD documented by coronary angiography (mean age 68 years, 83% male, 95% treated with a statin). The primary outcome was a composite of cardiovascular death and unplanned cardiovascular hospitalization. When the data were analysed according to tertiles of baseline PCSK9 plasma levels, patients in the highest tertile (>622 ng/ml) were at increased risk for the primary outcome compared with those in the lowest tertile (<471 ng/ml); hazard ratio 1.55, 95%-CI 1.11–2.16, p = 0.009). Higher PCSK9 levels were also associated with higher triglycerides (p<0.0001), whereas there was no difference based on tertile analysis of total cholesterol, LDL cholesterol and HDL cholesterol plasma levels. Adjustment for fasting triglycerides attenuated the association of PCSK9 levels with cardiovascular events. These data strongly suggest that higher triglycerides, a component of atherogenic dyslipidaemia, contribute to PCSK9-associated CV risk.
Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment.

Werner C, Hoffmann MM, Winkler K, Böhm M, Laufs U.

Does increased CETP activity underlie the risk of premature atherosclerotic risk in South Asians?

South Asians are known to be at greater risk of developing premature atherosclerotic cardiovascular disease (ASCVD) than other ethnicities. It is thought that a greater prevalence of cardiovascular risk factors earlier in life, including a proatherogenic lipoprotein profile (elevated apolipoprotein B-containing triglyceride-rich lipoproteins, and low high-density lipoprotein cholesterol [HDL-C]), may be a contributing factor. This study evaluated whether the cholesteryl ester transfer protein (CETP), involved in mediating the hetero-exchange of cholesteryl esters and triglycerides between lipoproteins, may be implicated in the pathogenesis of atherogenic dyslipoproteinaemia. CETP activity was measured in healthy individuals of South Asian (N=244) and European Caucasian (N=238) descent, enrolled in the Study of Health Assessment and Risk in Ethnic groups (SHARE). Serum and lipoprotein lipids and apolipoproteins were measured and lipoprotein particle number and size were determined using nuclear magnetic resonance spectroscopy. Atherogenic dyslipoproteinaemia was more severe in South Asian than European subjects. After adjustment for age, sex, body mass index and waist circumference, CETP activity was 30% higher in South Asians than Europeans (p<0.0001). CETP activity was directly associated with serum triglycerides, apoB and LDL particle number, and inversely associated with HDL-C and LDL size. The authors concluded that CETP activity was strongly associated with all of the key elements of atherogenic dyslipidaemia, notably elevated triglycerides, low HDL-C and changes in LDL particle number and size. These findings therefore implicate elevated CETP activity as a contributing factor to the increased atherogenic risk in South Asians.
Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians.

Rashid S, Sniderman A, Melone M, Brown PE, Otvos JD, Mente A, Schulze K, McQueen MJ, Anand SS, Yusuf S.

Elevated triglycerides and CHD risk: the Cohort Norway project

This report from the Cohort Norway project provides further support for a causal role of elevated triglycerides in coronary heart disease, even among individuals with favourable plasma levels of high-density lipoprotein cholesterol (HDL-C). Data from 140,790 Norwegians without coronary heart disease at baseline (1994–2003) and with follow-up data (December 2009) were evaluated. The mean age at baseline was 47.4 years (standard deviation [SD] 14.3) for men and 46.3 years (SD 14.1) for women. A total of 3,219 (4.8%) men and 1,434 (1.9%) women had a myocardial infarction (MI) during follow-up (mean 11.5 years). In age-adjusted analyses, the incidence of MI increased from 21.9 to 58.4 per 10,000 person-years in men and from 7.3 to 32.9 in women from the lowest to the highest triglycerides decile. There was evidence of significant sex interaction for triglycerides impact. When the highest (=2.88 mmol/l) and lowest (<0.7 mmol/l) triglycerides deciles were compared, there was a 4.7-fold excess risk in women compared with 2.8-fold excess risk in men. Even in subjects with a favourable HDL-C level (>1.0 mmol/l for men and >1.3 mmol/l for women), the risk of MI increased with increasing triglycerides quartiles (trend analysis, p<0.001). The authors concluded that high triglycerides levels, despite favourable HDL-C levels, may identify a subset of individuals at risk for CHD.
Non-fasting triglycerides predict incident acute myocardial infarction among those with favourable HDL-cholesterol: Cohort Norway.

Egeland GM, Igland J, Sulo G, Nygard O, Ebbing M, Tel GS.

ICARIA study: Detection of atherogenic dyslipidaemia improves CV risk stratification

Researchers evaluated the prevalence of atherogenic dyslipidaemia (triglycerides =150 mg/dl or 1.7 mmol/L and high-density lipoprotein cholesterol [HDL-C] <40 mg/dl or 1.03 mmol/L in men and <50 mg/dL or 1.29 mmol/L in women) in the ICARIA (Ibermutuamur CArdiovascular RIsk Assessment) study. A total of 70,609 subjects (72% male, mean age 39.2 ± 10 years) were included in this observational cross-sectional study. Overall, 5.7% (95% CI 4.7-6.9) of the study population had atherogenic dyslipidaemia. After adjustment for obesity and alcohol intake, the presence of atherogenic dyslipidaemia was significantly associated with cardiovascular risk (hazard ratio 1.27, 95% CI 1.12-1.45, p=0.0003). The authors concluded that screening for atherogenic dyslipidaemia may improve cardiovascular risk stratification over the current SCORE model.
Prevalence of atherogenic dyslipidemia: Association with risk factors and cardiovascular risk in Spanish working population. "ICARIA" study.

Cabrera M, Sánchez-Chaparro MA, Valdivielso P, Quevedo-Aguado L, Catalina-Romero C, Fernández-Labandera C, Ruiz-Moraga M, González-Santos P, Calvo-Bonacho E; ICARIA (Ibermutuamur CArdiovascular RIsk Assessment) Study Group.

**STOP-PRESS: FIRST trial fails primary endpoint**

In the recently reported FIRST trial, the combination of fenofibric acid plus atorvastatin did not further decrease progression of atherosclerosis, compared with atorvastatin alone, in high-risk patients with mixed dyslipidaemia. The rationale for the FIRST trial has been previously reported on the R3i website. Briefly, this multicentre, double-blind, placebo-controlled study included patients with mixed dyslipidaemia (fasting triglycerides =150 mg/dL or 1.7 mmol/L; high-density lipoprotein cholesterol =45 mg/dL or 1.2 mmol/L [men] or =55 mg/dL or 1.4 mmol/L [women]; low-density lipoprotein cholesterol =100 mg/dL or 2.6 mmol/L once and averaging =105 mg/dL or 2.7 mmol/L) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg) were randomised to fenofibric acid 135 mg/day or placebo. The primary end point, the rate of change from baseline to week 104 of the mean posterior-wall carotid intima-media thickness, measured by ultrasound, was similar in each group (-0.006 mm/y with fenofibric acid plus atorvastatin versus 0.000 mm/y with atorvastatin alone; p=0.22). The study will be discussed in a future Landmark Trial analysis.
Effects of fenofibric acid on carotid intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: randomized, placebo-controlled study (FIRST).

Davidson MH, Rosenson RS, Maki KC et al.

Da Qing Diabetes Prevention Study: importance of sustained lifestyle intervention

Findings from the landmark Da Qing Diabetes Prevention Study show that sustained lifestyle intervention can reduce cardiovascular and all-cause mortality and diabetes in Chinese people with impaired glucose tolerance. This study included 577 adults with impaired glucose tolerance who were enrolled by 33 clinics in Da Qing, China in 1986. Subjects were randomised (1:1:1:1) to a control group (n=138) or lifestyle intervention groups (diet, exercise, or both, n=439). The intervention lasted for 6 years and patients were followed-up after 23 years. The primary outcomes were all-cause mortality, cardiovascular disease mortality and diabetes incidence; 542 (94%) subjects had complete data for mortality. Over the 23-year follow-up period, 174 participants died (121 in the intervention groups versus 53 in the control group). Compared with the control group, the cumulative incidence of cardiovascular disease mortality and all-cause mortality was lower in the intervention group (11.9% versus 19.6%, hazard ratio 0.59, 95% CI 0.36–0.96; p=0.033 for cardiovascular mortality and 28.1% versus 38.4%, hazard ratio 0.71, 95% CI 0.51–0.99; p=0.049 for all-cause mortality). There was significantly greater effect in women than men; lifestyle intervention was associated with 72% reduction in cardiovascular mortality in women (versus 9% in men), and 54% reduction in all-cause mortality (versus 3% in men). These differences may relate to higher smoking rates in men. The incidence of diabetes was also significantly lower in the intervention group (72.6% versus 89.9%, hazard ratio 0.55, 95% CI 0.40–0.76; p=0.001); this effect was similar in both men and women. These findings based on hard outcomes data provide further justification for the importance of sustained lifestyle intervention to control the consequences of impaired glucose tolerance and diabetes, and have important implications for public health policy about diabetes prevention.
Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study.

Li G, Zhang P, Wang J et al.

Intestinal insulin signalling, atherogenic dyslipidaemia and metabolic syndrome

This study investigated the role of intestinal triglyceride-rich lipoprotein overproduction in atherogenic dyslipidaemia in obese subjects. Duodenal samples from 20 obese subjects undergoing bariatric surgery were matched for age, sex, and body mass index irrespective of insulin sensitivity (homeostasis model assessment of insulin resistance). Intestinal insulin signalling was defective in insulin-resistant subjects, as shown by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, possibly as a result of high oxidative stress and inflammation. In addition, the study showed an increase in de novo lipogenesis and apolipoprotein B-48 biogenesis coincident with triglyceride-rich lipoprotein overproduction in insulin-resistant subjects. These subjects also showed high expression levels of liver and intestinal fatty acid-binding proteins and microsomal transfer protein. The authors concluded that dysregulation of intestinal insulin signalling, possibly induced by oxidative stress and inflammation, may represent a key mechanism which contributes to atherogenic dyslipidaemia in patients with metabolic syndrome.
Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.

Veilleux A, Grenier E, Marceau P, Carpentier AC, Richard D, Levy E.

Will lipidomics offer new possibilities as biomarkers of metabolic syndrome susceptibility?

Findings from the San Antonio Family Heart Study (SAFHS) highlight the additive value of the plasma lipidomic profile in metabolic syndrome. This study used a novel statistical approach to quantify the value of the plasma lipidome in explaining metabolic syndrome variability in Mexican American families recruited in the SAFHS, involving two steps: principal components analysis of the high resolution plasma lipidomics data, and construction of a subject-subject lipidomic similarity matrix. The analysis was based on data for 1,206 subjects (from 42 families, mean age 40 years, 60% female), with a high prevalence of type 2 diabetes (~15%), central obesity (~48%) and elevated triglycerides (~41%). The plasma lipidome contributed to 22% variability in insulin sensitivity (HOMA-IR) and 16% – 22% variability in glucose, insulin and waist circumference independent of obesity and measures of lipidaemic status. These findings argue for consideration of the biological pathways involved in lipid/lipoprotein metabolism, in addition to specific lipid/lipoprotein classes, and highlight a potential role for evaluating differences in the plasma lipidome as biomarkers for increased susceptibility to the metabolic syndrome. Indeed, a recent study has shown that the lipidomic approach has allowed for identification of distinct ceramide molecular species strongly associated with fatal outcome of coronary artery disease patients independently of traditional risk factors.1
1. Tarasov K, Ekroos K, Suoniemi M et al. Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J Clin Endocrinol Metab 2014;99:E45-E52.
Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families.

Kulkarni H, Meikle PJ, Mamtani M et al.

Periodontal disease: a novel cardiovascular risk factor?

Analyses from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, suggest that tooth loss and gingivitis may be potential risk markers for cardiovascular disease. The STABILITY trial investigated the potential of darapladib, a selective oral inhibitor of lipoprotein-associated phospholipase A2, for prevention of major cardiovascular events in 15,828 patients with stable coronary heart disease. At baseline, all subjects had a physical examination and blood testing, and completed a lifestyle questionnaire, which included information on dental health. Specifically, the questionnaire collected data on the remaining number of teeth (none, 1–14, 15–20, 21–25, or 26–32 (all)) and frequency of gum bleeding (never/rarely, sometimes, often or always). There was a high overall prevalence of tooth loss; 16% of subjects reported having no teeth, and 41% reported having fewer than 15 remaining teeth. Furthermore, 26% of subjects reported gum bleeding when brushing teeth. Analyses showed that increasing prevalence of tooth loss was significantly associated with higher fasting glucose levels, low-density lipoprotein (LDL) cholesterol levels, systolic blood pressure and waist circumference. Similarly, a higher prevalence of gum bleeding was significantly associated with higher LDL cholesterol levels and systolic blood pressure. In conclusion, the authors suggest that dental health may be a marker of cardiovascular disease risk, although acknowledging that demographic, genetic and socioeconomic disparities may be confounding factors to this association.
Periodontal disease in patients with chronic coronary heart disease: Prevalence and association with cardiovascular risk factors.

Vedin O, Hagstrom E, Gallup D et al.

High prevalence of atherogenic dyslipidaemia in Turkey: a public health issue

An increased prevalence of low plasma concentration of high-density lipoprotein cholesterol (HDL-C) in Turkey is already well recognised. This report highlights the high prevalence of atherogenic dyslipidaemia, especially among the 46-to-65-year-old age group. The study included 4,309 people (aged 20 to 83 years) from both urban and rural regions according to a stratified sampling method. Overall, 36.2% had high low-density lipoprotein cholesterol (LDL-C), 41.5% had low HDL-C, and 35.7% had elevated triglycerides; at least one lipid abnormality was identified in the majority of subjects (79% of men and 80% of women). Moreover, the presence of these lipid abnormalities increased with age, and was highest in the 46-to-65-year-old age group. These findings highlight an unmet need for increased awareness of the high prevalence of dyslipidaemia, including elevated triglycerides and low HDL-C, in this population.
Prevalence of dyslipidemia and associated risk factors in Turkish adults.

Bayram F, Kocer D, Gundogan K et al.

Overprescription of statins: need to target all risk factors to impact CVD

Based on a North European population (=55 years), statin therapy would be recommended for almost all male patients and two-thirds of female patients according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of cholesterol. These estimations exceed predictions for the 2011 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines. Predictions were based on 4,854 subjects in the Rotterdam Study (mean age 65.5 years, 55% women); at baseline, 14% of male and 13% of female subjects were on a statin. For the 2013 ACC/AHA guidelines, there was a shift in the proportion of the study cohort from ‘treatment considered’ to ‘treatment recommended’ categorisations; for men, the relative percentages were 96.4% versus 3.3%, and for women, 65.8% and 14.2%. In contrast, for the 2011 ESC/EAS guidelines, treatment was recommended for 66.1% of men (versus considered in 31.6%) and 39.1% of women (versus considered in 51.4%), based on 10-year risk estimations. Thus, by lowering the cut-off for treatment, the 2013 ACC/AHA guidelines have substantially overestimated the proportion of individuals at high levels of actual cardiovascular disease risk. As well as highlighting the potential risk of statin overprescription, these findings also implicate the need for education and intervention aimed at prevention of risk factor aggregation so as to reduce future cardiovascular disease rates.
Comparison of application of the ACC/AHA Guidelines, Adult Treatment Panel III Guidelines, and European Society of Cardiology Guidelines for Cardiovascular Disease Prevention in a European cohort.

Kavousi M, Leening MJG, Nanchen D et al.

Peripheral microvascular dysfunction predicts residual vascular risk

A previous report by the Residual Risk Reduction Initiative (R3i) highlighted microvascular disease as a predictor of cardiovascular disease (CVD) risk.1 The hyperaemia index, assessed by peripheral artery tonometry, is a measure of microvascular dysfunction, with low levels indicative of impaired reactive hyperaemia. The current study investigated whether this variable (logarithmic transformed data) could be used to stratify for residual coronary risk. The study included 213 coronary artery disease patients on statin therapy (mean age 66.7 years, 74% male, mean LDL cholesterol 70 mg/dL). Over a median follow-up of 2.7 years, coronary events occurred in 4 (4.0%) patients with hyperaemia index = 0.5) versus 18 (15.8%) patients with an index < 0.54 (p = 0.006). Cox regression analysis showed that the hyperaemia index was an independent predictor for coronary events even after adjustment for traditional risk factors, as well as estimated glomerular filtration rate (Hazard ratio 0.79, 95% confidence interval 0.66-0.95, p=0.012). In conclusion, the authors suggest that approaches aimed at improving microvascular dysfunction may offer potential to reduce residual risk in patients with coronary heart disease.
1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-8.
Peripheral microvascular dysfunction predicts residual risk in coronary artery disease patients on statin therapy.

Matsue Y, Yoshida K, Nagahori W, Ohno M, Suzuki M, Matsumura A, Hashimoto Y, Yoshida M.

DYSIS-Middle East: High prevalence of atherogenic dyslipidaemia in statin-treated patients

DYSIS-Middle East, part of the main DYSIS (Dyslipidemia International Study) trial, enrolled 2,182 patients (=45 years) on statin treatment (=3 months) in the United Arab Emirates, Saudi Arabia, Lebanon and Jordan. Most (83%) were classified as being at very high risk of cardiovascular events. Despite statin treatment, only 62% of patients attained guideline-recommended targets for low-density lipoprotein (LDL) cholesterol, and 56% and 49% attained desirable levels for high-density lipoprotein (HDL) cholesterol and triglycerides, respectively. This study highlights the high prevalence of lipid abnormalities among statin-treated patients in this region. Notably, atherogenic dyslipidaemia, i.e. elevated triglycerides with or without low HDL cholesterol, was present in about 50% of patients, indicating the need for improved clinical management.
Results of the Dyslipidemia International Study (DYSIS)-Middle East: Clinical perspective on the prevalence and characteristics of lipid abnormalities in the setting of chronic statin treatment.

Al Sifri SN, Almahmeed W, Azar S, Okkeh O, Bramlage P, Jünger C, Halawa, Ambegaonkar B, Wajih S, Brudi P.

High triglyceride/HDL-C ratio predicts CVD in US population

Both high triglycerides (TG) and a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk for coronary heart disease (CHD). The ratio of TG/HDL-C is also predictive of residual risk for CHD and poorer metabolic control in people with type 2 diabetes. This survival analysis (n=39,447 men) evaluated the potential of the TG/HDL-C ratio (cut-point 3.5), as a predictor for CHD, cardiovascular disease (CVD) and all-cause mortality. The total follow-up was 581,194 person-years. The TG/HDL-C ratio predicted CHD, CVD, and all-cause mortality after adjustment for established risk factors and non-HDL-C. These data reaffirm the role of atherogenic dyslipidaemia as a marker of residual coronary risk.
Triglyceride-to-High-Density-Lipoprotein-Cholesterol Ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men.

Vega GL, Barlow CE, Grundy SM, Leonard D, Defina LF.

High TG/HDL-C ratio is associated with risk of CKD in the Japanese population

As shown by the REALIST-Micro STUDY,1 elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are robustly associated with diabetic kidney disease in patients with type 2 diabetes and controlled low-density lipoprotein cholesterol (LDL-C) levels.1 This cross-sectional study (n=216,007 Japanese adults, 88,516 men 127,491 women) used TG/HDL-C quartile analysis to assess the association with chronic kidney disease (CKD). The TG/HDL-C quartiles were <1.26, 1.26-1.98, 1.99-3.18 and >3.18 in men; <0.96, 0.96-1.44, 1.45-2.22, and >2.22 in women). Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 (low eGFR) and/or proteinuria (defined as urinary protein =1+ on dipstick testing)]. In both men and women, the prevalence of CKD, low eGFR, and proteinuria increased significantly with increasing quartiles of TG/HDL-C (p for trend <0.001). Compared with those in the lowest quartile, subjects in the highest quartile of TG/HDL-C had a significantly greater risk of CKD (adjusted odds ratio: 1.57, 95% confidence interval 1.49-1.65 in men; and 1.41, 1.34-1.48 in women). The increase in risk of CKD with TG/HDL-C was evident irrespective of the presence or absence of hypertension, diabetes and obesity. In conclusion, this analysis of more than 200,000 Japanese men and women reaffirms the link between triglycerides and HDL-C and risk for CKD.
1. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and HDL-cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes: A global case-control study in 13 countries. Circulation 2013 Dec 18. [Epub ahead of print].
Association of the triglycerides to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: Analysis in a large Japanese population.

Tsuruya K, Yoshida H, Nagata M, Kitazono T, Hirakata H, Iseki K, Moriyama T, Yamagata K, Yoshida H, Fujimoto S, Asahi K, Kurahashi I, Ohashi Y, Watanabe T.

Mendelian randomisation study: Does genetically low triglycerides reduce risk?

There is growing evidence (see also Landmark Study) implicating increased triglycerides (TG), a marker for cholesterol in remnant lipoproteins, as a risk factor for cardiovascular disease (CVD). Whether lifelong low levels of TG (due to a genetic aetiology) are associated with reduced mortality is not known. In this study, a Mendelian randomisation approach was used to test this hypothesis based on data from the Copenhagen City Heart Study. The study analysed observational data (n = 13,957) and data based on the presence of genetic variants of lipoprotein lipase leading to low nonfasting TG and remnant cholesterol (n = 10,208). Observational analyses reaffirmed the association between nonfasting TG and all-cause mortality. In analyses based on genetic data, each 1 mmol/L (89 mg/dL) decrease in nonfasting TG was associated with 50% (95% CI 18-70%) reduction in risk for all-cause mortality. The corresponding observational analysis showed a 13% (95% CI 11-15%) reduction in risk. In conclusion, this study shows that low concentrations of nonfasting plasma TG due to the presence of genetic variants in lipoprotein lipase are associated with reduced all-cause mortality. The authors suggest this lower risk might be mediated by reduced amount of cholesterol contained in remnant lipoproteins.
Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study.

Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG.

!!!!Stop Press!!!! Updated R3i Macrovascular Position Paper published
 
Residual macrovascular risk in 2013: what have we learned?

The International Steering Committee of the Residual Risk Reduction Initiative (R3i), comprising 40 leading specialists from North and South America, Europe, the Middle East, Asia and Japan, has today highlighted priorities for action against atherogenic dyslipidaemia, an important contributor to lipid-related residual cardiovascular risk. The R3i defines atherogenic dyslipidaemia as the imbalance between triglyceride-rich apolipoprotein B-containing-lipoproteins, for which triglycerides are a marker, and apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL).

The R3i has identified three key priorities:

• To improve recognition of atherogenic dyslipidaemia in high risk patients, including those with diabetes
• To target atherogenic dyslipidaemia, using non-HDL cholesterol (total cholesterol – HDL cholesterol) for treatment decisions
• To improve management of atherogenic dyslipidaemia, and adherence to guideline-recommended therapies. The addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe to statin therapy are all approaches to reduce non-HDL cholesterol.

The R3i recognises that there is a need for new treatment options that can more effectively target atherogenic dyslipidaemia, and reviews future possibilities in this paper. This paper will have important implications for the routine management of patients who remain at high residual cardiovascular risk despite well controlled low-density lipoprotein (LDL) cholesterol levels.

The full paper is available to read at Cardiovascular Diabetology. The paper will be discussed on the website in a following post.

Residual macrovascular risk in 2013: what have we learned?

Fruchart J-C, Davignon J, Hermans MP, Al-Rubeaan K, Amarenco P, Assmann G, Barter P, Betteridge J, Bruckert E, Cuevas A, Farnier M, Ferrannini E, Fioretto P, Genest J, Ginsberg HN, Gotto AM Jr; Hu D, Kadowaki T, Kodama T, Krempf M, Matsuzawa Y, Millán Núñez-Cortés J, Monfil CC, Ogawa H, Plutzky J, Rader DJ, Sadikot S, Santos RD, Shlyakhto E, Sritara P, Sy R, Tall A, Tan CE, Tokgözoglu L, Toth PP, Valensi P, Wanner C, Zambon A, Zhu J, Zimmet P, for the Residual Risk Reduction Initiative (R3i)

ETC-1002 reduces non-HDL-C in type 2 diabetes patients with hypercholesterolaemia

In this phase 2 proof-of-concept study, ECT-1002 lowered low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) and improved high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia, without deterioration in glycaemic control. ETC-1002 is a small molecule which in nonclinical studies has been shown to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In this single-centre, double-blind, placebo-controlled trial, 60 patients with type 2 diabetes and elevated LDL-C (mean 128 mg/dL or 3.3 mmol/L) were randomly allocated to treatment with ETC-1002 (80 mg once daily for 2 weeks followed by 120 mg once daily for 2 weeks) or placebo for 4 weeks. At the end of the study, ETC-1002 was associated with significant reduction (versus placebo) in LDL-C (by 43%), non-HDL-C (by 32%) and total cholesterol (by 25%) (all p<0.0001), although there was no significant effect on HDL-C (-1.2%). High-sensitivity C-reactive protein was reduced by a median of 41% (versus reduction by 11% on placebo, p=0.0011). ECT-1002 appeared to be well tolerated with no adverse safety signal. In conclusion, ETC-1002 may offer a potential novel therapeutic approach in this high risk patient population.
Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol–lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.

Gutierrez MJ, Rosenberg NL, MacDougall DE et al.

2013

Atherogenic dyslipidaemia linked with hepatic steatosis

This study adds to evidence linking hepatic steatosis with atherogenic dyslipidaemia and resultant increased cardiovascular risk. In total, 6,333 asymptomatic subjects without clinical cardiovascular disease in Brazil were included over the period 2008 to 2010. Hepatic steatosis was diagnosed by ultrasound. Atherogenic dyslipidaemia was defined using 2 definitions: i) criteria for metabolic syndrome or ii) insulin resistance (triglyceride/high-density-lipoprotein (HDL) cholesterol ratio of =2.5 in women and =3.5 in men). Hepatic steatosis was detected in 36% of the sample (mean age 43.5 years, 79% men, average body mass index 26.3 kg/m2). While plasma levels of low-density-lipoprotein (LDL) cholesterol were similar in subjects with and without hepatic steatosis, HDL cholesterol was lower and triglycerides were higher in subjects with steatosis. After multivariate adjustment, hepatic steatosis was significantly and independently associated with atherogenic dyslipidaemia for both definitions: i) odds ratio 2.47, 95% confidence interval [CI] 2.03 to 3.02, and for ii) odds ratio 2.50, 95% confidence interval 2.13 to 2.91). The association between hepatic steatosis and atherogenic dyslipidaemia was independent of obesity, physical activity, hyperglycaemia, and systemic inflammation. This study suggests potential for atherogenic dyslipidaemia as a target of interest for therapeutic intervention in non-alcoholic fatty liver disease/steatosis.
Relation of hepatic steatosis to atherogenic dyslipidemia.

Makadia SS, Blaha M, Keenan T, Ndumele C, Jones S, DeFilippis A, Martin S, Kohli P, Conceicao R, Carvalho J, Nasir K, Blumenthal R, Santos RD

Hypertriglyceridaemia: EAS Consensus Panel recommends simple redefinition to aid management

The European Atherosclerosis Society (EAS) Consensus Panel has called for a streamlined definition of hypertriglyceridaemia. Recent insights into the genetics of hypertriglyceridaemia indicate that phenotypic heterogeneity reflects the cumulative burden of both common small-effect genetic variants, as well as rare heterozygous large-effect variants of genes which are directly or indirectly associated with plasma triglycerides. Taking this into consideration, the EAS Consensus Panel calls for a simplified redefinition, with hypertriglyceridaemia categorised as either mild to moderate (triglycerides 2-10 mmol/L or 175-885 mg/dL), or severe (>10 mmol/L or >885 mg/dL). A multigenic or polygenic basis accounts for mild to moderate hypertriglyceridaemia, whereas severe hypertriglyceridaemia is likely to have a monogenic basis. This redefinition should help to simplify the diagnosis and management of hypertriglyceridaemia in routine practice.
The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.

Hegele RA, Ginsberg HN, Chapman MJ et al.

Renal lipid metabolism and diabetic nephropathy

This study investigated whether altered renal triglycerides and cholesterol metabolism underlies lipid accumulation in human diabetic nephropathy (DN). Kidney biopsies of patients with diagnosed DN (n=34) and normal controls (n=12) were investigated. Heavy lipid deposition observed in kidneys of DN patients was associated with down-regulation of fatty acid ß-oxidation pathways, including peroxisome proliferator-activated receptora (PPAR-a), carnitine palmitoyltransferase I (CPT1), acyl-CoA oxidase (ACO) and liver-type fatty acid binding protein (L-FABP), as well as renal lipoprotein lipase. There was also upregulation of genes for cholesterol uptake receptors, including low-density lipoprotein (LDL) receptor, oxidized LDL receptors and acetylated-LDL receptor, as well as downregulation of genes influencing cholesterol efflux (ATP-binding cassette transporters (ABCA1, ABGC1) and apolipoprotein E). Evidence of a highly significant correlation between estimated glomerular filtration rate, inflammation and lipid metabolism genes, suggests that abnormal lipid metabolism may be implicated in the pathogenesis of DN, which may offer potential for pharmacotherapeutic intervention.
Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.

Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U.

Being sedentary increases cardiometabolic risk

In this report from the ProActive Study, increased sedentary time was independently associated with increased cardiometabolic risk and triacylglycerol in adults at high risk of developing type 2 diabetes. Physical activity (accelerometer measures), adiposity measures and television viewing as a proxi measure of sedentarity (self-reported survey) were assessed at baseline and after a mean of 6.27 (±0.46) years in 171 adults (mean age 42.5 ±6.3 years; 46% men) with a parental history of diabetes. Greater increases in sedentary time were associated with larger increases in clustered cardiometabolic risk (CCMR: 0.08 [95% CI 0.01, 0.15]; CCMR without adiposity component: 0.08 [0.01, 0.16]) and triacylglycerol (0.15 [0.01, 0.29]), independent of baseline sedentary and moderate-to-vigorous physical activity duration, change in moderate-to-vigorous physical activity time and other confounders. However, the association with change in high-density lipoprotein cholesterol did not achieve statistical significance. Change in waist circumference and body mass index did not appear to mediate the association between CCMR without adiposity component and triacylglycerol. Television viewing was not independently associated with any of the cardiometabolic outcomes. These data highlight the potential benefits reducing sedentary time to potentially reduce cardiometabolic risk.
Increasing objectively measured sedentary time increases clustered cardiometabolic risk: a 6 year analysis of the ProActive study.

Wijndaele K, Orrow G, Ekelund U, Sharp SJ, Brage S, Griffin SJ, Simmons RK.

APOE genotype, atherogenic dyslipidaemia and sleep apnoea

There are emerging data that atherogenic dyslipidaemia associated with intermittent hypoxia may contribute to the increased cardiovascular risk associated with obstructive sleep apnoea (OSA). The current study investigated potential links between the effects of apolipoprotein E (APOE) genotype and sleep apnoea severity on atherogenic dyslipidaemia in patients with OSA. In total, 519 subjects were screened, and OSA was identified by polysomnography in 391 subjects. Across all APOE genotype groups, increased severity of OSA was associated with significant increases in serum triglycerides (p<0.05, fully adjusted analyses). APOE genotype and the oxygen desaturation index were both independent predictors of serum triglycerides (p=0.009 and p<0.001, respectively). These findings suggest that OSA has adverse effects on atherogenic dyslipidaemia beyond effects related to APOE genotype.
Effects of APOE genotype on serum lipids in obstructive sleep apnoea.

Tisko R, Sopkova Z, Habalova V, Dorkova Z, Slaba E, Javorsky M, Tkac I, Riha RL, Tkacova R.

Is parental lifespan a factor influencing cardiometabolic risk?

In the general population, the offspring of very elderly individuals have a lower prevalence of major cardiometabolic conditions. This is not solely explained by reduced exposure to conventional risk factors. Consequently, whether parental lifespan may be an additional factor influencing cardiometabolic risk in the offspring was investigated in this cross-sectional study in patients with type 2 diabetes. Of 558 patients screened, 405 (mean age 69 years, 32% female) satisfied the criteria for longevity for at least one parent, i.e. aged =80 years at the time of parental death(s), or age at the time of the study if still alive. Individuals whose parents had a shorter lifespan had more severe insulin resistance and hyperinsulinaemia phenotype; earlier occurrence of diabetes; poorer glycaemic control; and a higher prevalence (by 53%) and greater severity (by 13% of the atherogenic index (log[triglycerides]/high-density lipoprotein cholesterol). Given that offspring of parents with a shorter lifespan did not differ from those with a long lifespan in terms of body mass index, waist circumference, adiposity and visceral fat, suggests that innate and genetic influences may possibly at least partly explain these findings.
Parental brevity linked to cardiometabolic risk in diabetic descendants.

Hermans MP, Ahn SA, Rousseau MF.

HDL functionality, metabolism do not influence aortic valve stenosis risk

The prevalence of aortic valve stenosis (AVS) increases with advancing age. Currently, more than 3% of the very elderly population (>75 years) are affected, although it is likely that this will increase with changing population demographics. Epidemiological data suggest an association between low high-density lipoprotein (HDL) cholesterol concentration and progression of aortic valvular calcium and AVS severity. However, in the light of controversy over the relevance of measurement of HDL cholesterol concentration to cardiovascular risk, it has been proposed that impaired HDL functionality may underlie the risk for AVS. The current report tested this by 1) determining whether genetic variants that are associated with HDL cholesterol concentration are associated with the risk of AVS in a case–control study; and 2) investigating cholesterol efflux capacity, a measure of HDL functionality, and HDL-related parameters in a cohort of this study. In the case-control study, 1,435 single nucleotide polymorphisms in genes associated with HDL cholesterol levels (in or around GALNT2, LPL, ABCA1, APOA5, SCARB1, LIPC, CETP, LCAT, LIPG, APOC4, and PLTP) were genotyped in 382 patients with echocardiographic-confirmed AVS (aortic jet velocity =2.5 m/sec) and 401 controls. None of these variants was predictive of AVS. In a subsample of this cohort (86 patients with AVS and 86 matched controls), measures of cholesterol efflux capacity in apolipoprotein B–depleted serum samples did not differ between cases and controls. Given that HDL cholesterol levels and measures of cholesterol efflux and HDL size were all lower in patients with coronary artery disease than controls, independent of the presence or absence of AVS, suggests a true negative association between parameters of HDL functionality or metabolism and AVS risk, although corroborative studies are needed.
Evaluation of links between high-density lipoprotein genetics, functionality, and aortic valve stenosis risk in humans.

Arsenault BJ, Dubé MP, Brodeur MR, de Oliveira Moraes AB, Lavoie V, Kernaleguen AE, Guauque-Olarte S, Mathieu P, Pibarot P, Messika-Zeitoun D, Bossé Y, Rhainds D, Rhéaume E, Tardif JC.

Remnant cholesterol: state of the art review

This timely review overviews the evidence for remnant cholesterol as a causal risk factor for ischaemic heart disease (IHD), and discusses present and future pharmacotherapeutic approaches. Most recently, in a Mendelian randomisation study of genetic variants associated with elevated remnant cholesterol level, each 1 mmol/L (39 mg/dL) increase in levels of nonfasting remnant cholesterol associated with a 2.8-fold increased risk of IHD, independently of high-density lipoprotein cholesterol levels (this study was discussed on the R3i website earlier this year).1 Furthermore, genetic studies show that elevated levels of remnant cholesterol are causally associated with both low-grade inflammation and IHD (see Landmark Trial). Definitive outcomes evidence from large randomised trials is, however, still awaited.
Remnant cholesterol as a cause of ischemic heart disease: Evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.

Varbo A, Benn M, Nordestgaard BG.

Genetic variants influence hepatic clearance of remnant triglyceride-rich lipoproteins

There are emerging data to support nonfasting (postprandial) triglyceride concentrations, a marker for triglyceride-rich lipoproteins (TRLs) and their remnants, as a clinically significant risk factor for cardiovascular disease. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for clearance of remnant TRLs in mouse models of type 2 diabetes, with uptake of remnant lipoproteins suppressed by accelerated degradation of HSPG due to hepatic induction of a heparan sulfate 6-O endosulfatase (SULF2). However, its relevance in man is uncertain. The current study investigated whether polymorphisms in genes responsible for HSPG assembly and disassembly contribute to atherogenic dyslipoproteinaemia in humans. After a 12-hour fast, 68 healthy subjects (31 men, mean age 46 years) underwent an oral fat load test (57 g fat, 63 g carbohydrates, and 40 g protein, total 934 calories). Blood samples were taken before and 3, 4, 6, and 8 hours after the test meal for analysis of chylomicrons and very low density lipoproteins (VLDL) 1 and 2. Single nucleotide polymorphisms in genes for syndecan-1 and enzymes involved in the synthesis or degradation of HSPG were genotyped in the study subjects. The study showed that genetic variation in rs2281279 in SULF2 associates with postprandial clearance of remnant TRLs and triglyceride levels, and with hepatic SULF2 mRNA levels, in healthy subjects. This study therefore supports the contention that clinically relevant postprandial hyperlipidaemia due to reduced hepatic clearance of remnant TRLs may result from genetic polymorphisms that affect hepatic HSPG, and suggests a novel target for improving atherogenic dyslipoproteinaemia.
Genetic variation in SULF2 is associated with postprandial clearance of triglyceride-rich remnant particles and triglyceride levels in healthy subjects.

Matikainen N, Burza MA, Romeo S, Hakkarainen A, Adiels M, Folkersen L, Eriksson P, Lundbom N, Ehrenborg E, Orho-Melander M, Taskinen MR, Borén J.

Managing residual cardiovascular risk: overview of therapeutic options

Accumulating evidence implicates atherogenic dyslipidaemia, the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels, as an important contributor to lipid-related residual cardiovascular risk. This review discusses current and emerging options for the management of this dyslipidaemia. Following the recent European Medicines Agency suspension of niacin, fibrates (especially fenofibrate) represent the preferred option for add-on therapy to treat elevated triglycerides and low HDL-C. Novel agents, such as monoclonal antibodies against PCSK9, offer opportunities for achieving substantial incremental reductions in low-density lipoprotein cholesterol in excess of 60% in high-risk patients on statin therapy Outcomes trials with the more advanced of these antibody therapies are currently in progress.
Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: A clinical update.

Reiner Z.

NAFLD: Emerging mechanisms and potential targets

Along with rising numbers of patients with metabolic syndrome, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased in line with the obesity epidemic. Currently, there are no established treatments for NAFLD, although ongoing research is targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications. Among potential targets identified to date are farnesoid X receptor (FXR); members of the peroxisome proliferator activated receptor (PPAR) sub-family receptors, currently the target of several drugs under evaluation for the treatment of NAFLD; Pex11, which plays a role in regulating peroxisomal function, and p53, implicated in NAFLD largely through its role in regulating fatty acid oxidation. Most of the potential targets identified to date are at an early stage of clinical investigation, which much work required to elucidate the mechanisms contributing to NAFLD.
Nonalcoholic fatty liver disease: molecular pathways and therapeutic strategies.

Huang YY, Gusdon AM, Qu S.

Retinol binding protein 4 linked with triglycerides in obesity

Retinol binding protein 4 (RBP4) is an adipokine secreted mainly by the liver and adipocytes, which is linked to obesity and its comorbidities, and thus may potentially contribute to the development of insulin resistance. This study investigated the possible role of RBP4 in lipid metabolism in obese patients with varying degrees of insulin resistance. In total, 299 middle-aged morbid obese patients (body mass index 40 kg/m2) were enrolled, and categorised as euglycaemic (n=84), or with metabolic syndrome (n=164) or type 2 diabetes (n=51). RBP4 levels were significantly higher in patients with metabolic syndrome or type 2 diabetes than in euglycaemic subjects (42.9±14.6 or 42.3±17.0 versus 37.4±11.7 µg/ml, respectively). For all subjects, RBP4 correlated with triglycerides (p<0.001) but not with HOMA-IR. There was a significant increase in serum RBP4 levels in patients with high triglycerides (=150 mg/dL or 1.7 mmol/L) independent of insulin resistance. In a subgroup analysis (n=80), RBP4 was also associated with the percentage of small dense high-density lipoprotein, independent of insulin resistance. In summary, the study showed that systemic RBP4 levels could play a role in lipid and lipoprotein metabolism in morbid obesity, increasing triglyceride levels and contributing to the formation of small triglyceride-rich HDL.
Association of serum retinol binding protein 4 with atherogenic dyslipidemia in morbid obese patients.

Rocha M, Banuls C, Bellod L, Rovira-Llopis S, Morillas C, Sola E, Victor VM, Hernandez-Mijares A.

Fenofibrate and diabetic retinopathy

This review of the mode of action of fenofibrate in diabetic retinopathy is timely following the recent Australian approval of fenofibrate to slow progression of early stage diabetic retinopathy (DR) in patients with type 2 diabetes.(1) This approval was based on data from two recent large, well-designed clinical trials - Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes-Eye (ACCORD-Eye) - which demonstrated large reductions in the progression of DR in patients with type 2 diabetes. In both trials, the greatest benefit on DR regression was observed in those patients with early-stage DR at baseline. Multiple mechanisms appear to underpin the benefit of fenofibrate on DR, including pathways influencing lipid and lipoprotein control, inflammation, angiogenesis and cell apoptosis. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signalling under diabetic conditions. Further, in rodent models of diabetes and retinal neovascularisation, fenofibrate improved retinal outcomes. Taken together, these findings provide impetus to establish the benefits of fenofibrate in other major forms of diabetes with high prevalence and incidence of retinopathy, foremost of all in including type 1 diabetes.
1. TGA okays Lipidil for diabetic retinopathy. Available at http://www.medicalobserver.com.au/news/tga-okays-lipidil-for-diabetic-retinopathy
An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes.

Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ, Lamoureux EL.

OSLER trial: mid-term data for PCSK9 monoclonal antibody, evolocumab (AMG 145)

The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study included 1,104 patients with hypercholesterolaemia previously enrolled in four phase II trials (parent trials). Patients were randomised (2:1) to treatment with open-label subcutaneous evolocumab 420 mg every 4 weeks with the standard of care (n=736) or standard of care alone (n=368). The duration of treatment was 52 weeks. Patients who received evolocumab for the first time in OSLER had substantial reduction in low-density lipoprotein cholesterol (LDL-C) levels compared with baseline in the parent trials (mean 52.3%). Patients who received evolocumab in the parent trial and then continued on evolocumab had durable LDL-C responses (reduction by 50.4% at the end of the parent trial and 52.1% at 52 weeks in OSLER). Additionally, patients who started or continued on evolocumab had significant reductions from baseline in the parent trial for triglycerides (by 8.3% and 9.0%, respectively) and lipoprotein(a) (by 32.8% and 29.9%, respectively). Both of these groups had elevation in high-density lipoprotein cholesterol levels at 52 weeks versus baseline in the parent trial (by 8.5% and 9.1%, respectively). In contrast, for patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Rates of adverse events and elevations in creatine kinase and aminotransferases were not appreciably greater in patients who achieved low LDL-C plasma levels on evolocumab. These are promising data from the largest and longest efficacy and safety evaluation of an anti-PCSK9 antibody to date.
Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial.

Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, Civeira F, Somaratne R, Nelson P, Liu T, Scott R, Wasserman SM, Sabatine MS; for the OSLER Investigators

EUROASPIRE III: Atherogenic dyslipidaemia still poorly controlled

Latest data from EUROASPIRE III show that while management of dyslipidaemia in patients with coronary heart disease (CHD) in Europe has improved over the last decade, many patients are still inadequately treated. This report summarizes data from 8,467 CHD patients enrolled by centres in 22 European countries. Despite increasing use of lipid-lowering therapy over the course of the survey, from 32.3% of patients in 1994-1995 to 88.8% of patients in 2006-2007, a high proportion of dyslipidaemic patients still have lipid abnormalities. Notably, 34.7% of patients had elevated fasting triglycerides (= 1.7 mmol/L or 150 mg/dL) and 36.7% had low plasma levels of high-density lipoprotein (< 1.0 mmol/L or 39 mg/dL for men, and <1.2 mmol/L or 46 mg/dL for women). The authors conclude that there is still much to be done to improve the management of dyslipidaemia in Europe.
Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: Findings from the EUROASPIRE III survey.

Reiner Z, De Bacquer D, Kotseva K, Prugger C, De Backer G, Wood D.

Novel therapy: antisense oligonucleotide apolipoprotein C-III inhibitor

Apolipoprotein C-III (apoC-III) is both an independent risk factor and a key regulatory factor influencing plasma triglycerides concentrations, a marker for levels of triglyceride-rich lipoproteins. In addition, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. This report describes the results of treatment with a novel antisense oligonucleotide inhibitor of apo-CIII. In animal studies, inhibition of apoC-III was well tolerated and was not associated with increased liver triglycerides deposition or hepatotoxicity. In a phase I clinical study in healthy subjects, administration of this human apoC-III antisense oligonucleotide (50, 100, 200, and 400 mg dose groups) resulted in dose-dependent median reductions in plasma apoC-III (by 19.7%, 17.3%, 70.5%, and >77.5%, respectively), with concomitant lowering of triglycerides levels (19.5%, 25.0%, 43.1%, and 43.8%). There was no evidence of adverse safety signals. Further study is ongoing.
Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.

Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, Singleton W, Viney N, Geary R, Su J, Baker BF, Burkey J, Crooke ST, Crooke RM.

Potential benefit of dietary n-3 fatty acids on incident AMI in patients with diabetes

Data from the Western Norway B-Vitamin Intervention Trial in 2,378 patients with coronary artery disease (mean age 62 years, 80% male) show that a high dietary intake of n-3 long-chain polyunsaturated fatty acids (mean daily intake 1.12 g, adjusted for energy intake), was associated with a reduced risk of acute myocardial infarction (AMI) in patients with diabetes, independent of glycaemic control. Dietary intake was assessed using a food frequency questionnaire which had been validated previously by using plasma phospholipid fatty acids as a reference. Over a mean follow-up of 4.8 years, 208 subjects (8.7%) experienced a fatal or non-fatal AMI. The incidence of AMI was about 2-fold higher in diabetic patients (n=317) compared with non-diabetic patients (n=1,012) or those with pre-diabetes (n=1,049): 13.6% versus 7.6% or 8.4%, respectively. In diabetic patients, a high intake of n-3 long-chain polyunsaturated fatty acids was associated with reduced risk of AMI (hazard ratio 0.38, 95%CI 0.18, 0.80), whereas there was an increased risk in patients without diabetes (hazard ratio 1.45, 95%CI 0.84, 2.53). The authors concluded that patients with diabetes and coronary artery disease may benefit from a high intake of n-3 long-chain polyunsaturated fatty acids, whereas caution is advised in patients with normal glucose tolerance.
Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study.

Strand E, Pedersen ER, Svingen GF, Schartum-Hansen H, Rebnord EW, Bjørndal B, Seifert R, Bohov P, Meyer K, Hiltunen JK, Nordrehaug JE, Nilsen DW, Berge RK, Nygård O.

Insulin resistance down-regulates key intestinal genes involved in lipoprotein metabolism

Insulin resistance is characterised by elevated levels of triglyceride-rich lipoproteins (TRLs), of both hepatic and intestinal origin. However, the mechanism(s) underlying the accumulation of intestinal apolipoprotein (apo) B-48-containing TRLs in insulin resistance are uncertain. This study investigated the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipoprotein metabolism in insulin resistance. The study included 14 obese men with insulin resistance (plasma triglycerides >1.5 mmol/L or 133 mg/dL) and 10 insulin-sensitive men matched for waist circumference and with triglycerides <1.5 mmol/L. Compared with insulin-sensitive subjects, TRL apoB-48 pool size and production rate were significantly higher (by 102%, p<0.0001 and 87%, p=0.01, respectively) in subjects with insulin resistance. There was also evidence that key genes involved in intestinal lipid and lipoprotein metabolism (sterol-regulatory-element-binding protein-2, hepatocyte nuclear factor 4a, and microsomal triglyceride transfer protein) were down-regulated in subjects with insulin resistance. Whether intestinal gene down regulation is related to relative hyperinsulinism and/or adaptive responses to chronic exposure to high levels of circulating free fatty acids and insulin merits further study.
Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin-resistance.

Couture P, Tremblay AJ, Kelly I, Lemelin V, Droit A, Lamarche B.

Where to HDL? Consensus statement from the National Lipid Association

There is extensive evidence from population studies that there is an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising plasma levels of HDL-C through lifestyle modification and pharmacologic intervention would reduce the risk of CVD, supported by studies in animal models, as well as post hoc analyses from randomized controlled trials. However, recent studies that were designed to test the "HDL hypothesis" have failed to show benefit, leading many to question whether HDL-C is a legitimate therapeutic target. This Consensus Statement from an expert panel convened by the National Lipid Association reviewed the current state of knowledge of HDL particle structure, composition, and function; and identified pertinent questions relating to the role of HDL in either preventing or contributing to atherosclerotic disease. The Panel concluded that while low HDL-C identifies patients at elevated risk, HDL-C is not a therapeutic target at the present time. Risk-stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of lipid-altering therapy in patients at risk, as described by established guidelines.
High-density lipoproteins: A consensus statement from the National Lipid Association.

Toth PP, Barter PJ, Rosenson RS, Boden WE, Chapman MJ, Cuchel M, DAgostino RB Sr, Davidson MH, Davidson WS, Heinecke JW, Karas RH, Kontush A, Krauss RM, Miller M, Rader DJ.

Re-thinking non-HDL-C targets in high-risk patients with residual hypertriglyceridemia?

Current international guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) as a secondary target, especially in individuals with atherogenic dyslipidaemia, characterised by elevated triglyceride-rich remnant lipoproteins, and often associated with insulin-resistant conditions. These triglyceride-rich lipoproteins include very-low density lipoproteins and their remnants, intermediate-density lipoproteins, and chylomicron remnant particles whose combined contribution to atherogenic risk is accounted for by measurement of non-HDL-C rather than low-density lipoprotein cholesterol (LDL-C). Recommended non-HDL-C cut points are 30 mg/dL higher than those for LDL-C. This study evaluated whether there is patient-level discordance between non-HDL-C and LDL-C percentiles at different LDL-C and triglyceride levels. Population percentiles for non-HDL-C and Friedewald-estimated LDL-C values were assigned for 1,310,440 US adults (mean age 59 years, 52% female) with triglycerides <400 mg/dL (4.5 mmol/L). LDL-C cutpoints of 70, 100, 130, 160, and 190 mg/dL (1.8, 2.6, 3.4, 4.1 and 4.9 mmol/L) were at the same population percentiles as non-HDL-C values of 93, 125, 157, 190, and 223 mg/dL (2.4, 3.2, 4.1, 4.9 and 5.8 mmol/L), respectively. The study highlighted a high level of patient-level disconcordance between non-HDL-C and LDL-C percentiles, especially among patients with low LDL-C and hypertriglyceridemia. The use of non-HDL C reclassified a significant proportion of patients in a higher risk category compared with LDL-C, especially at LDL-C levels in the treatment range for high-risk patients with triglycerides =150 mg/dL. Of patients with LDL-C < 70 mg/dL (1.8 mmol/L), 15% were discordant with a non-HDL-C = 100 mg/dL (2.6 mmol/L, guideline-based cut point) and 25% had a non-HDL-C = 93 mg/dL (2.4 mmol/L, percentile-based cutpoint); if patients also had moderately elevated fasting triglycerides in the range 150-199 mg/dL (1.7-2.3 mmol/L), discordance rates were higher, at 22% and 50%, respectively. These findings have implications for residual risk assessment and management.
Non-HDL cholesterol, guideline targets, and population percentiles for secondary prevention in a clinical sample of 1.3 million adults The Very Large Database of Lipids (VLDL-2 Study).

Elshazly MB, Martin SS, Blaha MJ, Joshi PH, Toth PP, McEvoy JW, Al-Hijji MA, Kulkarni KR, Kwiterovich PO, Blumenthal RS, Jones SR.

Inflammation and residual cardiovascular risk

Inflammation plays a key role in the development and progression of atherosclerosis. In a pre-specified post hoc analysis of the SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) study, on-treatment C-reactive protein (CRP) levels were associated with residual risk for major adverse cardiovascular events (MACE) among patients with well controlled LDL-C levels (mean 65.9 mg/dL or 2.7 mmol/L) on potent statin therapy (Hazard ratio 1.28, 95% CI 1.04, 1.56, p=0.02). In addition, there was an incremental association between on-treatment CRP levels and time to first MACE. Multivariable analysis showed that for subjects for whom CRP levels did not increase on statin treatment, there was greater atheroma regression (percent atheroma volume, p=0.01). In contrast, there was no association between on-treatment LDL-C levels and MACE (HR 1.09, 95% CI 0.88, 1.35, p=0.45). These data highlight systemic subclinical inflammation as an important prognostic biomarker and potentially a driver of residual cardiovascular risk in patients with coronary artery disease treated with aggressive statin therapy.
C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events following maximally intensive statin therapy.

Puri R, Nissen SE, Libby P, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ.

AIM-HIGH: Lipoprotein(a) is a contributor to residual cardiovascular risk

Further analysis of AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) study implicate lipoprotein(a) [Lp(a)] as a contributor to residual cardiovascular risk. Both baseline and on-study Lp(a) were predictive of cardiovascular events in the simvastatin+placebo (baseline hazard ratio [HR]= 1.24, p=0.002 and on-study HR=1.21, p=0.017) and the simvastatin+niacin treatment groups (baseline HR=1.25, p=0.001 and on-study HR=1.18 p=0.028). However, baseline apolipoprotein (apo) B100 (apoB) and the ratio of apoB/apoA-I were only predictive of cardiovascular events in the simvastatin+placebo group (HR=1.17, p=0.018 and HR=1.19, p=0.016). These data suggest a role for Lp(a) as a modifiable contributor to residual cardiovascular risk in patients in the AIM-HIGH study.
Relationship of apolipoproteins A-1 and B, and lipoprotein (a) to cardiovascular outcomes in the AIM-HIGH Trial.

Albers JJ, Slee A, OBrien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM.

HDL-C: not an appropriate risk marker in secondary prevention

Recent findings from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study indicate the limitations of low plasma HDL-C as a risk marker in patients with coronary artery disease (CAD). The authors analysed data from 3,141 subjects (70% male, mean age 62.6 years, mean baseline HDL-C concentration 38.9 mg/dL [1.01 mmol/L]). In this cohort, 699 subjects did not have coronary artery disease (CAD), 1,515 had stable CAD and 927 had unstable CAD. Over a median follow-up period of 9.9 years (interquartile range 8.7-10.7 years), there were 590 deaths due to cardiovascular disease. Overall, there was a significant inverse association between plasma HDL-C concentration and cardiovascular mortality (p=0.009), consistent with previous findings. However, when the data were re-analysed according to the presence of CAD at baseline, this association was weakened in patients with stable or unstable CAD. The authors confirmed their findings in a meta-analysis of the LURIC, AtheroGene and ESTHER cohorts (n=12,292).
High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality.

Silbernagel G, Schöttker B, Appelbaum S et al.

News flash!! New International Atherosclerosis Society Position Paper on Management of Dyslipidaemia

The International Atherosclerosis Society (IAS) has updated recommendations for the management of high cholesterol and dyslipidaemia with the aim of reducing the risk for atherosclerotic cardiovascular disease. While recognising that low-density lipoprotein cholesterol (LDL-C) is the major target of lipid-modifying therapy, the IAS also highlights the importance of very low-density lipoprotein cholesterol (VLDL-C), especially in individuals with hypertriglycaeridemia. Non-high density lipoprotein cholesterol (non-HDL-C), the sum of LDL-C and VLDL-C which includes cholesterol in all atherogenic lipoproteins, is an alternative to LDL-C as a target of therapy. Non-HDL-C is also more reflective of atherogenicity in persons with elevated triglycerides. Consequently, the IAS favours adoption of non-HDL-C as the major target of lipid-lowering therapy.
An International Atherosclerosis Society Position Paper: Global Recommendations for the Management of Dyslipidemia

The International Atherosclerosis Society (IAS)

TG/HDL-C ratio: a screening tool to evaluate success in reducing anti-diabetic therapy with weight loss?

Lifestyle interventions underpin diabetes management. In particular, weight loss improves insulin resistance and glycaemic control, which may reduce the need for anti-diabetic therapy in some patients. The current retrospective cohort study suggests that the baseline triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio may be useful in predicting success in reducing anti-diabetic medication use via weight loss. Case records of 121 overweight and obese subjects attending two outpatient weight management centres were analysed. The weight loss intervention consisted of a calorie-restricted diet (~1000 Kcal/day deficit), a behaviour modification plan, and a plan for increasing physical activity. Patients were followed for a mean of 12.5 ± 3.5 months. At the end of follow-up, mean weight loss was 15.4 ± 5.5 kg and mean reduction in HbA1c was 0.5 ± 0.2%. Overall, 81 (67%) patients in the study cohort achieved at least one dose reduction of any anti-diabetic medication. A baseline TG/HDL-C ratio = 3 was shown to be a predictor of successful dose reductions of anti-diabetic medications (81% sensitivity and 83% specificity, 90% positive predictive value), with acceptable reproducibility. The investigators concluded that the TG/HDL-C ratio may be useful as a predictive tool for reducing antidiabetic medication with weight loss and merits further study.
Triglyceride/HDL ratio as a screening tool for predicting success at reducing anti-diabetic medications following weight loss.

Palamaner Subash Shantha G, Kumar AA, Kahan S, Irukulla PK, Cheskin LJ.

Does HDL complexity explain the failure of recent trials?

Robust evidence supports the association between low plasma concentration of high-density lipoprotein (HDL)-cholesterol and increased coronary risk, and provides a firm basis for inclusion of HDL cholesterol in risk assessment scores (PROCAM and SCORE). However, recent clinical-trials investigating agents that target HDL cholesterol, including the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, and niacin, failed to show significant reduction in cardiovascular events in high risk patients with coronary-disease. This state-of-the-art review discusses experimental and translational evidence for several potential anti-atherogenic effects of HDL, including preventive effects on LDL oxidation and its adverse endothelial effects, as well as stimulation of endothelial cell production of nitric-oxide, anti-inflammatory, anti-apoptotic, anti-thrombotic effects, and endothelial-repair processes. These vasoprotective effects of HDL are not only highly heterogenous but appear to be altered in patients with coronary disease, leading to the concept that HDL may become ‘dysfunctional’ in different pathophysiological states. The authors highlight the need for greater understanding of the mechanisms of action of HDL and how these are altered in different disease states. Targeting HDL-mediated anti-atherogenic mechanisms, rather than HDL cholesterol levels, may be a more valid approach. However, this requires appropriate validation in both general and at-risk populations before application becomes a possibility.
High-density lipoproteins and endothelial functions: Mechanistic insights and alterations in cardiovascular disease.

Riwanto M, Landmesser U.

Reconstituted High-Density Lipoprotein (CSL112) improves ABCA1-dependent cholesterol efflux

The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie the inverse correlation between HDL cholesterol and cardiovascular risk. Infusion of CSL112, a reconstituted apolipoprotein AI formulation, into rabbits caused a strong and immediate increase in the ABCA1-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In human plasma, CSL112 increased cholesterol efflux from macrophages to a greater extent than native HDL, predominantly via the ABCA1 transporter. Addition of CSL112 to plasma increased the level of very small HDL, a favourable substrate for ABCA1. As preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, CSL112 may represent a promising candidate for the management of acute coronary syndrome, in addition to current standards of care.
Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux.

Diditchenko S, Gille A, Pragst I, Stadler D, Waelchli M, Hamilton R, Leis A, Wright SD.

Increased burden of metabolic syndrome in HIV

Human immunodeficiency virus (HIV) is associated with increased aortic stiffness and metabolic syndrome phenotype in Caucasian patients. This study also shows an increased burden and severity of metabolic syndrome and arterial stiffness in treatment-naïve HIV patients in Cameroon. The study compared age-matched healthy subjects (controls, n=96) and untreated HIV-positive patients (HIV+, n=108). Variables evaluated included lipids, pulse wave velocity, aortic augmentation index and brachial blood pressure. The prevalence and severity of metabolic syndrome was based on the American Heart Association/National Heart, Lung, and Blood Institute score =3.5 of the following: impaired fasting glucose or diabetes; hypertension; enlarged waist; elevated fasting triglycerides (TGs); decreased high-density lipoprotein cholesterol (HDL-C). Fasting TGs, the atherogenic dyslipidemia ratio [log(TGs)/HDL-C] and the prevalence of metabolic syndrome (47% versus 21%) were all higher in HIV+ patients than controls (p<0.05). Compared with controls, age- and sex-adjusted pulse wave velocity was higher (p = 0.02) and the aortic augmentation index was significantly lower (p = 0.01) in HIV+ patients. Thus, consistent with findings in Caucasians, this study shows an increase in metabolic syndrome, an early marker of atherosclerosis in African HIV patients.
Increased burden and severity of metabolic syndrome and arterial stiffness in treatment-naïve HIV+ patients from Cameroon

Ngatchou W, Lemogoum D, Ndobo P, Yagnigni E, Tiogou E, Nga E, Kouanfack C, Van de Borne P, Hermans MP

Vasc Health Risk Manag 2013;9:1-9.

Pathogenesis of metabolic syndrome in African Americans

Recent findings from the Jackson Heart Study shed new light onto the development of metabolic syndrome in African Americans. In a cohort of the study (n=3,019, mean age, 54 years; 64% women) the association between a biomarker panel (including high-sensitivity C-reactive protein [CRP], leptin, B-natriuretic peptide [BNP], cortisol, aldosterone, endothelin and homocysteine) to the development of metabolic syndrome was investigated. In total, 278 (22.9%) of 1,215 participants without metabolic syndrome at baseline developed the syndrome at follow-up. Development of metabolic syndrome was significantly associated with serum aldosterone (p = 0.004), CRP (p = 0.03), and BNP (p for trend = 0.005). Aldosterone was positively associated with change in all metabolic syndrome risk components, except low high-density lipoprotein (HDL) cholesterol and waist circumference. CRP was directly associated with systolic blood pressure and waist circumference and inversely associated with HDL cholesterol. However, for BNP, there was a U-shape relationship with systolic blood pressure and triglycerides. The authors concluded that this association for BNP and metabolic syndrome components warrants further study.
Aldosterone, C-Reactive Protein, and plasma B-Type Natriuretic Peptide are associated with the development of metabolic syndrome and longitudinal changes in metabolic syndrome components: Findings From the Jackson Heart Study.

Musani SK, Vasan RS, Bidulescu A, Liu J, Xanthakis V, Sims M, Gawalapu RK, Samdarshi TE, Steffes M, Taylor HA, Fox ER

New CVD guidelines from Japan Atherosclerosis Society

New guidelines for the diagnosis and prevention of cardiovascular disease were recently published on-line. While identifying low-density lipoprotein cholesterol (LDL-C) as the main priority for lipid management, the guidelines also highlight the relevance of a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and/or elevated triglycerides – atherogenic dyslipidemia - to cardiovascular risk. Treatment targets for HDL-C are =40 mg/dL and for triglycerides are <150 mg/dL.
Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan -2012 Version

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K.

Low adiponectin increases risk of peripheral artery disease

Evidence from the Health Professionals Follow-up Study links lower adiponectin levels with increased risk of symptomatic lower extremity peripheral artery disease (PAD). This was a prospective, nested case-control study among 18,225 male participants who were free of diagnosed cardiovascular disease at the time of blood sampling (1993-1995). Over the 14-year follow-up period, 143 men developed PAD. Controls were selected in a 3:1 ratio and matched on age, smoking status, fasting status, and date of blood sampling (n=429). At baseline, median (interquartile range) adiponectin concentrations were lower among cases compared with controls (4.1 [3.2-5.5] versus 5.4 [3.8-7.5] µg/mL; p<0.001). After controlling for baseline cardiovascular risk factors, a log-linear inverse association with PAD risk was observed across the range of adiponectin concentrations. For each 1 SD increase in natural log-transformed adiponectin there was a 42% lower risk of PAD (relative risk, 0.58; 95% confidence interval, 0.45-0.74) after adjustment for cardiovascular risk factors. Adjustment for high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C reactive protein, and cystatin C attenuated this risk (relative risk, 0.68; 95% confidence interval, 0.51-0.92), although further adjustment for haemoglobin A1c, triglycerides, and gamma-glutamyltransferase had little impact (relative risk, 0.68; 95% confidence interval, 0.50-0.92). These findings build on other evidence linking low adiponectin levels with increased cardiovascular risk.
Total adiponectin and risk of symptomatic lower extremity peripheral artery disease in men.

Joosten MM, Joshipura KJ, Pai JK, Bertoia ML, Rimm EB, Mittleman MA, Mukamal KJ.

Sleep apnoea and cardiometabolic risk

Obstructive sleep apnoea (OSA) is an underdiagnosed condition characterised by recurrent episodes of obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia during sleep. This review highlights evidence that OSA exacerbates cardiometabolic risk attributed to obesity and the metabolic syndrome, supported by experimental and clinical evidence. In patients with metabolic syndrome, OSA is independently associated with increased glucose and triglycerides levels, as well as markers of inflammation, arterial stiffness and atherosclerosis. In addition, recent studies showed a marked increase in atherogenic dyslipidemia indices (including HDL-C; apoA-I and log(TG)/HDL-C ratio] together with inflammation, worsening beta-cell function, poorer glycemic control and coronary artery disease risk in individuals with type 2 diabetes and OSA versus those without OSA.1,2
Thus, emerging evidence implicates OSA with an increase in residual vascular risk for microvascular and macrovascular events in type 2 diabetes. Thus, treating OSA is an additional intervention to be considered for reducing residual risk in obese patients.
 
References
1. Hermans MP, Ahn SA, Rousseau MF. Micro- and macrovascular risk and complications in T2DM males with obstructive sleep apnoea. J Clin Metab Diab 2011;2:64-70.
2. Hermans MP, Ahn SA, Mahadeb YP, Rousseau MF. Sleep apnoea syndrome and 10-year cardiovascular risk in females with type 2 diabetes: relationship with insulin secretion and insulin resistance. Diabetes Metab Res Rev 2013;29:227-34.
Obstructive sleep apnea: a cardiometabolic risk in obesity and metabolic syndrome.

Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G.

State of the art review: The potential of the next generation PPARs

This review highlights the central role of peroxisome proliferator-activated receptor (PPAR) agonists in the management of residual vascular risk, especially in people with cardiometabolic disease such as type 2 diabetes. However, the available PPARa-agonists have limited efficacy due to dose-related adverse effects. This review makes the case for a new generation of highly potent and selective PPARa-modulators (SPPARMa) that separate the benefits of the PPARa-agonists from their unwanted side effects. The highly-potent, specific PPARa-agonist (K-877) has emerged as the first SPPARMa. Compared with fenofibrate, K-877 has more potent PPARa-activating efficacy in vitro, improved efficacy in lowering triglycerides and raising high-density lipoprotein cholesterol, and a reduced risk of adverse effects. The review concludes that K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual cardiovascular risk associated with metabolic syndrome and type 2 diabetes.
Selective peroxisome proliferator-activated receptora modulators (SPPARMa): The next generation of peroxisome proliferator-activated receptor a-agonists.

Fruchart JC.

Modelling for causal factors in prediabetes

In this report, structural modeling was used to test a hypothesized model of causal pathways related with prediabetes among older adults in the U.S. The analysis was based on data from 2,230 adults (=50 years) without diabetes included in the morning fasting sample of the 2001–2006 National Health and Nutrition Examination Surveys. Demographic data included age, income, marital status, race/ethnicity, and education. Behavioural data included physical activity (metabolic equivalent hours per week for vigorous, moderate, muscle-strengthening, walking/biking, and house/yard work), and poor diet (refined grains, red meat, added sugars, solid fats, and high-fat dairy). Modeling was used to examine the interrelationships among these variables with family history of diabetes, high blood pressure, body mass index, large waist (waist circumference: women, =35 inches; men, =40 inches), triglycerides =200 mg/dL, and total- and high-density lipoprotein (HDL) (=60 mg/dL) cholesterol. Large waist circumference had the strongest direct effect on prediabetes. Physical activity had direct effects on cardiometabolic risk factors including HDL-cholesterol, triglycerides, and high blood pressure.
A novel use of structural equation models to examine factors associated with prediabetes among adults aged 50 years and older. National Health and Nutrition Examination Survey 2001–2006.

Bardenheier BH, McKeever Bullard K, Caspersen CJ, Cheng YJ, Gregg EW, Geiss LS.

Dysfunctional HDL implicated in the association of ESRD and CVD

Patients with end-stage renal disease (ESRD) are at increased risk of atherosclerosis and cardiovascular morbidity and mortality. The atherogenicity associated with ESRD is driven by inflammation, oxidative stress, and dyslipidemia. Notably, low plasma levels of high-density lipoprotein cholesterol (HDL-C) and HDL dysfunction are the hallmarks of ESRD-related dyslipidemia. Clinical and laboratory studies show that ESRD is associated with significantly reduced apolipoprotein A-I and HDL-C levels, as well as changes in HDL composition. While ESRD is generally associated with reduced HDL functionality (affecting antioxidant and anti-inflammatory properties), in a small proportion of patients HDL may be dysfunctional (pro-oxidant and proinflammatory effects). These findings reinforce the view that standard measurement of plasma HDL-C level is not a dependable indicator of cardiovascular disease burden in ESRD. Moreover, the authors highlight the need for routine markers of HDL function to accurately identify patients with ESRD at risk for cardiovascular disease.
Role of HDL dysfunction in end-stage renal disease: a double-edged sword.

Moradi H, Vaziri ND, Kashyap ML, Said HM, Kalantar-Zadeh K.

Challenges in managing obesity-related lipid disorders in children – a role for fibrates?

Escalation in childhood obesity has led to an increase in the prevalence of combined dyslipidemia, characterized by elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), with normal or mildly-elevated levels of low-density lipoprotein cholesterol (LDL-C). Despite recent National Heart, Lung and Blood Institute (NHLBI) guidelines for the management of primary dyslipidemias in pediatric patients, there is still no general consensus regarding pharmacologic treatment of obesity-related lipid abnormalities in children. Diet and lifestyle modification remain the first line therapy. However, given the challenges of instituting and maintaining lifestyle modification in pediatric patients, it is likely that drug therapy may be also required in many children. Of treatment options currently available, the fibric acid derivatives have a cholesterol lowering profile that is most likely to be effective in obese children with the atherogenic dyslipidemic phenotype of high triglycerides/low HDL-C. However, additional information regarding the short and long-term safety and lipid-lowering vs. reducing hard CV endpoint efficacy of fibrate therapy in children with obesity-related lipid disorders is needed before wider use of these agents can be recommended.
Challenges in the pharmacologic management of obesity and secondary dyslipidemia in children and adolescents.

Kennedy MJ, Jellerson KD, Snow MZ, Zacchetti ML.

Role of apolipoproteins E and AV in clearance of triglyceride-rich lipoproteins

The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. This study evaluated the role of apolipoproteins (apo) E and AV in the clearance of TRL in experimental models. ApoE was shown to be a major determinant of TRL clearance, as indicated by TRL enrichment in apoE deficient mice, decreased binding of apoE-deficient TRLs to HSPGs on human hepatoma cells in vitro, and decreased clearance of apoE-deficient [3H]TRLs in vivo. ApoAV emerged as a candidate based on 6-fold enrichment of apoAV in TRLs accumulating in Ndst1f/fAlbCre+ mice, decreased binding of TRLs to proteoglycans after depletion of apoAV or addition of anti-apoAV monoclonal antibody, and decreased heparan sulfate-dependent binding of apoAV-deficient particles to hepatocytes. Furthermore, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. The authors concluded that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans.

Gonzales JC, Gordts PL, Foley EM, Esko JD.

ADVANCE: Moderate/vigorous activity improves macro- and microvascular outcomes

This report from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial evaluated whether physical activity (varying in intensity and frequency) influenced vascular outcomes in 11,140 patients. Physical activity was categorized as none, mild, moderate or vigorous, and the frequency of activity was categorised by the number of sessions in a week. In total 46% of patients reported moderate to vigorous physical activity for >15 minutes at least once in the previous week. The study end points were major cardiovascular events, microvascular complications and all-cause mortality. Over a median of 5 years of follow up, 1,031 patients died, 1,147 experienced a major cardiovascular event and 1,136 a microvascular event. Compared with patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a reduced risk of cardiovascular events (hazard ratio [HR] 0.78, 95% CI 0.69-0.88, p<0.0001), microvascular events (HR 0.85, 95% CI 0.76-0.96, p0.010) and all-cause mortality (HR 0.83, 95% CI 0.73-0.94, p0.0044). The authors concluded that moderate to vigorous leisure-time physical activity is associated with reduced vascular morbidity and mortality in patients with type 2 diabetes.
The influence of physical activity on vascular complications and mortality in patients with type 2 diabetes mellitus.

Blomster JI, Chow CK, Zoungas S, Woodward M, Patel A, Poulter NR, Marre M, Harrap S, Chalmers J, Hillis GS.

Atherosclerosis: not just a modern disease

There is a general perception that atherosclerosis is related to modern lifestyle and was therefore not present in ancient populations. However, data from a study reported in The Lancet refutes this and raises the possibility of a more basic predisposition to the disease. Whole-body computed tomography scans of 137 mummies from four different regions or populations of various socioeconomic strata and spanning more than 4,000 years - ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands - were imaged. Atherosclerosis was considered definite if a calcified plaque was seen in the wall of an artery, and probable if calcifications were seen along the expected anatomical course of an artery. Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations. Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one or two beds in 34 (25%) mummies, in three or four beds in 11 (8%), and in all five vascular beds in two (1%). Age at the time of death was positively correlated with atherosclerosis (mean 43 [SD 10] years for mummies with atherosclerosis vs. 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p<0·0001). The authors concluded that their findings indicate that atherosclerosis is an inherent component of human ageing and not characteristic of any specific socioeconomic status, diet or lifestyle.
Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations.

Thompson RC, Allam AH, Lombardi GP, Wann LS, Sutherland ML, Sutherland JD, Al-Tohamy Soliman M, Frohlich B, Mininberg DT, Monge JM, Vallodolid CM, Cox SL, Abd el-Maksoud G, Badr I, Miyamoto MI, el-Halim Nur el-din A, Narula J, Finch CE, Thomas GS.

FIELD study: total bilirubin predictive of amputation in type 2 diabetes

A new analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has reports a significant inverse relationship between baseline bilirubin levels and incident total lower-limb amputation, suggesting that a higher bilirubin level may be associated with protection against amputation. Bilirubin is known to exhibit antioxidant and anti-inflammatory properties. Indeed, previous studies have shown that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease. This pre-specified analysis investigated the relationship between baseline plasma total bilirubin levels and amputation events in the FIELD study population (n=9,795). Lower-limb amputation was adjudicated blinded to treatment allocation. The analysis showed a significant inverse association between plasma bilirubin concentrations and lower-limb amputation. Patients with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 µmol/l decrease in bilirubin concentration, 95% CI 1.07 to 1.79, p=0.013). This association was still evident after adjustment for demographic variables, smoking status, y-glutamyltransferase level, HbA1c, study treatment allocation and previous cardiovascular disease (including peripheral arterial disease), amputation or diabetic skin ulcer, as well as microvascular complications (neuropathy, nephropathy and diabetic retinopathy). In summary, these findings implicate total bilirubin as a protective factor/marker for amputation in type 2 diabetes.
FIELD study investigators. Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Chan KH, OConnell RL, Sullivan DR, Hoffmann LS, Rajamani K, Whiting M, Donoghoe MW, Vanhala M, Hamer A, Yu B, Stocker R, Ng MK, Keech AC; FIELD study investigators

Potential of PPAR agonists in reducing cardiovascular risk

Peroxisome proliferator-activated receptor (PPAR) agonists have been shown to have favourable effects on plasma lipoprotein levels, inflammation, and insulin resistance, all of which influence the risk of cardiovascular disease. The mechanisms underlying these effects include PPAR-alpha activation in the enterocyte influencing high-density lipoprotein (HDL) and chylomicron formation; direct effects by PPAR-y agonists on adipocytes and regulatory T cells within visceral adipose; and inhibition by PPAR-d agonists of foam cell formation induced by excessive levels of VLDL remnants. Thus, agonists (either single or dual) of PPAR-alpha, PPAR-y, and PPAR-d have the potential to reduce cardiovascular risk via multiple independent and additive mechanisms, and reduce the burden of atherogenic postprandial lipoproteins, which would be expected to have favourable effects on cardiovascular risk. Consequently, research is focused on the development of compounds that maximize these potential cardiovascular benefits while minimizing any undesirable effects.
Novel benefits of peroxisome proliferator-activated receptors on cardiovascular risk

Millar JS

ALT associated with atherogenic lipoprotein profile

Data from the Insulin Resistance Atherosclerosis Study show that alanine aminotransferase (ALT) is associated with a wide range of atherogenic lipoprotein changes, at least partly associated with insulin resistance, adiposity, glucose tolerance status and chronic inflammation. This analysis included 824 subjects without diabetes (aged 40–69 years) none of whom reported excessive alcohol intake or were treated with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and nuclear magnetic resonance (NMR) spectroscopy was used to assess lipoprotein heterogeneity. The study showed that ALT had a positive relationship with triacylglycerols, the ratio of low-density lipoprotein:high-density lipoprotein (LDL:HDL) cholesterol and apolipoprotein B (apoB). NMR spectroscopy also identified positive associations between ALT and large very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and small LDL subclass particles, as well as VLDL particle size (all p <0.001). There were also negative associations between ALT and large LDL subclass particles (p <0.05) and HDL particle sizes (p <0.01). The associations with IDL, small LDL subclass particles and apoB persisted after adjustment for glucose tolerance status, adiposity, insulin sensitivity and C-reactive protein. Further study to confirm these associations is merited.
The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study

C. Lorenzo, A. J. Hanley, M. J. Rewers, S. M. Haffner

Novel adipokine linked with obesity and the metabolic syndrome

A recent study has investigated the role of WNT1 inducible signalling pathway protein 2 (WISP2), a novel adipokine, highly expressed and secreted by adipose precursor cells, in obesity and the metabolic syndrome. Increased expression of WISP2 and other markers of WNT activation in human abdominal subcutaneous adipose tissue, but not in visceral fat, identified the metabolic syndrome in obese individuals. WISP2 appears to form a cytosolic complex with the peroxisome proliferator-activated receptor y (PPARy) transcriptional activator zinc finger protein 423 (Zfp423). This complex is dissociated by bone morphogenetic protein 4 (BMP4), thereby allowing Zfp423 to enter the nucleus, activate PPARy, and with resultant allocation of precursor cells to the adipose lineage. Secreted Wnt/Wisp2 also inhibits differentiation and PPARy activation, albeit not through Zfp423 nuclear translocation. In summary, these results indicate that adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and WNT signalling, in which WISP2 has a crucial role, thus linking WISP2 with obesity and the metabolic syndrome.
WISP2 regulates preadipocyte commitment and PPARy activation by BMP4

Hammarstedt A, Hedjazifar S, Jenndahl L, Gogg S, Grünberg J, Gustafson B, Klimcakova E, Stich V, Langin D, Laakso M, Smith U.

Better metabolic health with physical activity

Results from a twins study showed that individuals who were persistently physically active had a more favourable metabolome, indicative of improved metabolic health, than those who were inactive. This study included 16 same-sex twin pairs (mean age, 60 years) who were selected from a cohort of twin pairs based on >30-year discordance for leisure-time physical activity. Persistently (=5 years) active and inactive groups in three population-based cohorts (mean ages, 31-52 years) were also studied (1037 age- and sex-matched pairs). Nuclear magnetic resonance spectroscopy was used to quantify the serum metabolome. Persistent physical activity was associated with an improved metabolic profile in twins (p=0.003), with similar findings reported in the population cohorts. There were favourable changes in serum fatty acid composition (with a shift to a less saturated profile, p<0.001) and lipoprotein subclasses (decrease in very low-density lipoprotein particles, and increase in large and very large high-density lipoprotein particles, p<0.001). These findings were not attenuated after adjustment for body mass index. In summary, the results of this study provide further support for the importance of regular physical activity in improving metabolic health.
Long-term leisure-time physical activity and serum metabolome

Kujala UM, Mäkinen VP, Heinonen I, Soininen P, Kangas AJ, Leskinen TH, Rahkila P, Würtz P, Kovanen V, Cheng S, Sipilä S, Hirvensalo M, Telama R, Tammelin T, Savolainen MJ, Pouta A, OReilly PF, Mäntyselkä P, Viikari J, Kähönen M, Lehtimäki T, Elliott P, Vanhala MJ, Raitakari OT, Järvelin MR, Kaprio J, Kainulainen H, Ala-Korpela M.

Risk/benefit issues of potent statins

Statin therapy has been shown to reduce the risk of major cardiovascular events in patients with chronic kidney disease. However, there are also questions whether high-doses of potent statins are associated with acute renal dysfunction. This retrospective observational analysis evaluated the effects of high-potency versus low-potency statins, relying upon data from nine population-based cohort studies and meta-analyses in Canada and the UK (n=2,067,639 patients aged 40 years or older, newly-treated with statins between 1 January 1997 and 30 April 2008). High-potency statin treatment was defined as =10 mg rosuvastatin, =20 mg atorvastatin, and =40 mg simvastatin; all other statins treatments were defined as low-potency. Statins potency groups were further divided into cohorts with or without chronic kidney disease (CKD). The main outcome was relative hospitalization rates for acute kidney injury. Within 120 days of starting treatment, there were 4,691 hospitalizations for acute kidney injury in patients with non-CKD, and 1,896 hospitalizations in those with CKD. In patients with non-CKD, current users of high-potency statins were 34% (95% CI 25-43) more likely to be hospitalized with acute kidney injury. However, in patients with CKD, there was a 10% (95% CI 1-23) increase in admission rate. The authors concluded that use of high-potency statins was associated with an increased rate of diagnosis for acute kidney injury, during the first 4 months of treatment. Thus while statins are the cornerstone of dyslipidemia management, intensive high-dose statin therapy is not without risk. Add-on or combination therapy may be an alternative approach with safety advantages, as well as improving global lipid control.
Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases.

Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, Lafrance J-P, Levy A, Garg AX, Ernst P, Canadian Network for Observational Drug Effect Studies (CNODES).

CT-defined non-alcoholic fatty liver associated with atherogenic dyslipidemia

Investigators from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based prospective cohort study in adults free of clinical cardiovascular disease at baseline, tested for a relationship between non-alcoholic fatty liver disease (NAFLD) and serum lipoprotein size, cholesterol and particle concentrations. NAFLD was considered in the presence of a liver/spleen (L/S) attenuation ratio of <1 on a non-contrast cardiac CT scan, which was present in 17% (569/3362) of subjects. After adjustment for multiple metabolic risk factors, adiposity and measures of insulin resistance, CT-defined NAFLD was independently associated with elevated fasting serum triglycerides and low serum high-density lipoprotein concentration, as well as higher low-density lipoprotein (LDL) particle concentration and lower LDL size. There was no association with LDL cholesterol. With the L/S ratio as a continuous variable, there was a severity-dependent association between atherogenic lipoprotein abnormalities and CT-defined NAFLD. In conclusion, these findings suggest a pathophysiological link between CT-defined NAFLD and atherogenic dyslipidemia.
Nonalcoholic fatty liver disease and serum lipoproteins: The Multi-Ethnic Study of Atherosclerosis

Defilippis AP, Blaha MJ, Martin SS, Reed RM, Jones SR, Nasir K, Blumenthal RS, Budoff MJ.

PRISMA: improvement in metabolic risk in type 2 diabetes

In this multicentre, double-blind, randomized study, 213 patients with type 2 diabetes (HbA1c 6-8%) were randomly allocated to treatment with pioglitazone (n=110) or placebo (n=103), in addition to metformin. Key variables were serum high-density lipoprotein cholesterol (HDL-C) concentration and changes in metabolic syndrome-specific parameters, evaluated from global changes in the independent components and expressed as a single factorial score. Patients in the pioglitazone group had a significant increase in HDL-C versus placebo (6.3 mg/dL vs. 3.0 mg/dL; p<0.01), as well as greater reduction in the extent of metabolic syndrome (- 13.2 vs. -4.9; p=0.006). At study completion, patients treated with pioglitazone also had lower levels of HbA1c (6.41±0.65 vs. 6.96±0.74%; p<0.001), reduction in insulin resistance (HOMA-IR 2.88±1.95 vs. 4.68±3.63; p=0.013) and a decrease in small, dense LDL (by 5.7%). The authors concluded that these beneficial effects of pioglitazone support this glucose-lowering treatment as an option to reduce metabolic risk in patients with type 2 diabetes and metabolic syndrome.
Randomised Italian Study on Metabolic Syndrome (PRISMA): effect of pioglitazone with metformin on HDL-C levels in type 2 diabetic patients.

Genovese S, Passaro A, Brunetti P, Comaschi M, Cucinotta D; PRISMA study group, Egan CG, Chinea B, Bravi F, Di Pietro C. Pioglitazone

New genetic locus for triglycerides in Mexicans

Despite marked predisposition to dyslipidemia and coronary heart disease, there is little understanding of the genetics of lipids in Mexican populations. The authors report a two-stage genome wide association study (GWAS) for atherogenic dyslipidemia, hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) concentration, in 4,361 Mexicans. The study identified a novel Mexican-specific genome-wide significant locus for serum triglycerides near the Niemann-Pick type C1 protein gene (p=2.43×10-08). Furthermore, three European loci for triglycerides (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in this group. Functional analysis showed a direct link between an APOA5 variant (rs964184) and postprandial serum apolipoprotein A-V protein levels, supporting rs964184 as the causative variant in both European and Mexican populations. Although about one-half of the 100 reported associations from European lipid GWAS meta-analysis were also generalised to Mexicans, in 82 of these 100 European loci, a different variant had the strongest regional evidence of association in Mexicans. Thus, results from European GWAS of known lipid loci may not necessarily extend to the Mexican population, highlighting the need for further regional ethnic-specific studies.
Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.

Weissglas-Volkov D, Aguilar-Salinas CA, Nikkola E, Deere KA, Cruz-Bautista I, Arellano-Campos O, Muñoz-Hernandez LL, Gomez-Munguia L, Ordoñez-Sánchez ML, Reddy PM, Lusis AJ, Matikainen N, Taskinen MR, Riba L, Cantor RM, Sinsheimer JS, Tusie-Luna T, Pajukanta P.

Link between atherogenic dyslipidemia and obstructive sleep apnoea syndrome

A recent study highlights an association between obstructive sleep apnoea syndrome (OSAS), atherogenic dyslipidemia and cardiovascular risk in women with type 2 diabetes. The current study included 305 patients (mean age 66 years, mean diabetes duration 15 years, 86% with metabolic syndrome); 25 with and 280 without OSAS. The presence of OSAS was diagnosed by anamnesis, Epworths score, oximetry and polysomnography. There were no differences in age, diabetes duration, education, smoking, and blood pressure between the two groups. Patients with OSAS had significantly higher BMI, waist, relative/absolute fat, and visceral fat (all p<0.0001) and lower skeletal muscle (p 0.0008). These individuals were also more insulin resistant, had lesser residual insulin secretion, increased hyperbolic product loss and poorer glycaemic control (HbA1c 69 vs. 62 mmol/L in those without OSAS, p 0.0099). All components of atherogenic dyslipidemia and inflammatory markers were worse with OSAS, and these patients also had a higher UKPDS risk score for coronary artery disease. In conclusion, the study adds to previous findings linking OSAS, a frequent comorbidity in type 2 diabetes, with central fat, atherogenic dyslipidemia, inflammation, worsening ß-cell function, poorer glycaemic control and CAD risk. This suggests that OSAS may increase residual vascular risk in women with type 2 diabetes.
Sleep apnoea syndrome, hyperbolic product and 10-year cardiovascular risk in females with Type 2 diabetes.

Hermans MP, Ahn SA, Mahadeb YP, Rousseau MF.

What is the future role of novel lipid-modifying therapies?

This review highlights a potential role for novel lipid-modifying treatments, including drugs targeting PCSK9, apolipoprotein B100 antisense oligonucleotides and microsomal transfer protein inhibitors, for reducing residual cardiovascular risk in statin-treated patients. It is well recognised that despite optimal therapy, many patients do not achieve cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. There is therefore a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins, as well as manage atherogenic dyslipidemia. Although statin therapy is the primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic cardiovascular disease.
Is the future of statins aligned with new novel lipid modulation therapies?

Phan BA, Toth PP.

Residual cardiometabolic risk is characterized by elevated visceral adipose tissue and liver fat

Visceral adipose tissue (VAT) and liver fat are strongly associated with type 2 diabetes. This cross-sectional analysis investigated the level of VAT and liver fat in 3,984 patients enrolled in the INSPIRE ME IAA study, based on their treatment status and achievement of the American Diabetes Association (ADA) diabetes management goals. Patients were divided into four groups according to baseline status: 1) those without type 2 diabetes (1,003 men and 1,027 women); 2) those with type 2 diabetes but not treated with diabetes medications (248 men and 191 women); 3) those with type 2 diabetes and treated with oral glucose-lowering drug(s) (591 men and 484 women); and 4) those with type 2 diabetes and treated with insulin (233 men and 207 women). Abdominal and liver adiposity were measured by computed tomography. Fewer patients with high VAT or liver fat achieved the ADA goals for high-density lipoprotein cholesterol (HDL-C) or fasting triglycerides compared with those with low VAT or liver fat. The findings show that lipid-related, non-LDL residual cardiovascular risk exists in type 2 diabetes patients with elevated visceral adipose tissue and liver fat.
Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: results from INSPIRE ME IAA.

Smith J, Nazare JA, Borel AL et al.

An elevated triglyceride/HDL-C ratio is predictive of cardiovascular disease

Data from a population longitudinal prospective observational study show that an elevated ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) was as effective as the presence of the metabolic syndrome in predicting the development of cardiovascular disease (CVD). Investigators surveyed a random sample from this study in 2003 (n=926) and 2012 (n=796, 527 women and 269 men) for new CVD events. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points (2.5 mg/dL and 3.5 mg/dL for low and high risk), and with or without metabolic syndrome, were estimated using Cox proportional hazard ratio. A similar number of subjects were considered at "high" CVD risk based on an elevated TG/HDL-C ratio (30%) or the presence of the metabolic syndrome (35%). The hazard risk, adjusted for age and sex, was higher for "high" vs. "low" risk groups, irrespective of whether risk was based on the presence of the metabolic syndrome (hazard ratio 2.09, 95% CI 1.18-3.72) or an elevated TG/HDL-C ratio ( hazard ratio 2.01, 95% CI 1.14-3.50). These findings reaffirm the relevance of an elevated TG/HDLC- ratio as a predictor for increased risk of CVD.
Identifying cardiovascular disease risk and outcome: use of the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio versus metabolic syndrome criteria

Salazar MR, Carbajal HA, Espeche WG et al

Combination fenofibric acid-statin treatment improves management of atherogenic dyslipidemia

This post hoc analysis evaluated achievement of lipid targets or desirable levels of lipids/lipoproteins after 12-weeks treatment in 2,066 patients with mixed dyslipidemia. Patients were randomized to fenofibric acid 135 mg, rosuvastatin (5, 10, or 20 mg), or the combination. Data were pooled across doses. Combination treatment or rosuvastatin alone had a similar effect on achievement of risk-stratified LDL-C targets. However, the combination was superior to statin for achievement of goals related to measures of total atherogenic burden, with significantly superior achievement of non-HDL-C and apolipoprotein B targets. Additionally, more patients achieved desirable levels of triglycerides (<150 mg/dL) and HDL-C (>40 mg/dL in men and >50 mg/dL in women), with the combination treatment than statin monotherapy (p<0.001 for each analysis). Combination treatment with fenofibric acid plus rosuvastatin provided better comprehensive lipid control than rosuvastatin monotherapy across the spectrum of cardiovascular risk.
Attainment of goal/desirable lipid levels in patients with mixed dyslipidemia after 12 weeks of treatment with fenofibric acid and rosuvastatin combination therapy: A pooled analysis of controlled studies

Roth EM, Rosenson RS, Jones PH et al.

Elevated cardiovascular risk factors evident up to 30 years before diabetes diagnosis

Data from the Framingham Heart Study Offspring cohort provides further support for the importance of targeting risk factors early to reduce the lifetime burden of cardiometabolic risk. This study included subjects free from cardiovascular disease (CVD) and diabetes (fasting plasma glucose =126 mg/dL or treatment) at baseline who were followed-up between 1979 and 2008. CVD risk factors (hypertension, high low-density lipoprotein cholesterol [LDL-C], low high-density lipoprotein cholesterol [HDL-C], high triglycerides, obesity) were measured at the time of diabetes diagnosis and at 10, 20, and 30 years beforehand. In total, 525 participants with new-onset diabetes were identified and matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who developed diabetes had a higher prevalence of hypertension (odds ratio [OR], 2.2; p = 0.003), high LDL-C (OR, 1.5; p = 0.04), low HDL-C (OR, 2.1; p = 0.0001), elevated triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P<0.0001) 30 years before diagnosis. The findings from this study highlight the importance of a proactive approach to reducing lifetime cardiometabolic risk
Early-adulthood cardiovascular disease risk factor profiles among individuals with and without diabetes in the Framingham Heart Study

Rosner Preis S, Pencina MJ, Mann DM et al.

Exercising more and watching less TV reduces the risk of metabolic syndrome in later life.

This longitudinal study based on a cohort in Northern Sweden investigated whether television (TV) viewing and low leisure-time physical activity at age 16 years was predictive of metabolic syndrome in mid-adulthood. TV viewing habits and participation in leisure-time physical activity were assessed by self-administered questionnaires. Evidence of the metabolic syndrome at age 43 years was defined using the International Diabetes Federation criteria. In 888 subjects, the overall prevalence of the metabolic syndrome at age 43 years was 26.9%. The adjusted risk of the metabolic syndrome at age 43 years was over two-fold higher (odds ratio 2.14, 95% CI 1.24–3.71) for those who reported “watching several shows a day” versus “one show/week” at age 16. Additionally those who exercised “several times/month” or less compared with “daily” leisure-time physical activity at age 16 years had an increased risk of metabolic syndrome in later life (odds ratio 2.31 95% CI 1.13-4.69). Increased TV viewing at age 16 years was associated with central obesity, low high-density lipoprotein cholesterol, and hypertension at age 43 years, and low leisure-time physical activity at age 16 years was associated with central obesity and triglycerides at age 43 years. Consistent with other studies, these data highlight the importance of regular physical activity to prevent the metabolic syndrome in later life.
Television viewing and low leisure-time physical activity in adolescence independently predict the metabolic syndrome in mid-adulthood

Wennberg P, Gustafsson PE, Dunstan DW et al.

2012

Should the focus of guidelines change to reflect increasing cardiometabolic disease?

Low-density lipoprotein cholesterol (LDL-C) is the primary lipid target in current guidelines. However, with the pandemic of diabetes, metabolic syndrome and obesity, the value of LDL-C as the key predictor for cardiovascular risk is questioned. Cardiometabolic disease is typically characterised by elevated triglyceride levels, low high-density lipoprotein-cholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common dyslipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. LDL-C may be only modestly elevated. Increasing evidence suggests moving away from a LDL-C target-based approach to a more tailored treatment approach, using for example non-HDL-C as a target as this better reflects the burden of atherogenic lipoproteins.
Combined dyslipidemia: should the focus be LDL cholesterol or atherogenic dyslipidemia?

Rizzo M, Barylski M, Rizvi AA, Montalto G, Mikhailidis DP, Banach M.

EUROASPIRE: Continuing high residual cardiovascular risk in Europe

Results of the mortality follow-up of EUROASPIRE I and II, a survey of the management of secondary prevention patients, highlight the continuing residual cardiovascular (CV) risk in coronary heart disease patients. The study cohort consisted of a consecutive sample of patients aged =70years from 12 European countries. Baseline data gathered in 1995-2000 were linked to subsequent CV mortality in 5,216 patients. During 28,143 person-years of follow-up, 332 patients died from CV disease, representing a CV mortality risk of 12.3 per 1000 person-years in men, and 10.2 per 1000 person-years in women. In multivariate analysis, fasting glucose, total cholesterol and smoking were the strongest independent modifiable predictors of CV mortality. These data highlight that management of secondary prevention patients is far from optimal. Moreover, even with best practice, there remains a high residual CV risk associated with conventional modifiable risk factors.
Residual risk of cardiovascular mortality in patients with coronary heart disease: The EUROASPIRE Risk Categories.

De Bacquer D, Dallongeville J, Kotseva K et al.

High ratio of HDL-apoCIII/ VLDL-apoCIII predictive of coronary risk

In the Chin-Shan Community Cardiovascular Cohort, an elevated ratio of high-density lipoprotein (HDL)-apolipoprotein (apo)CIII/very low-density lipoprotein (VLDL)-apoCIII was a better predictor of coronary artery disease (CAD) than conventional lipids or lipoproteins. This study evaluated the cross-sectional association between apo markers and CAD in 3,602 subjects from 1990 to 2001. These subjects were subcategorised as normolipidemic (total cholesterol <200 mg/dL, triglycerides <150 mg/dL); hypertriglyceridemic (total cholesterol <200 mg/dL, triglycerides =150 mg/dL); hypercholesterolemic (total cholesterol =200 mg/dL, triglycerides <150 mg/dL), and hyperlipidemic (total cholesterol =200 mg/dL, triglycerides =150 mg/dL). Patients with CAD had higher apoB and lower HDL cholesterol and apoAI concentrations than those without, although the differences were not significant in all groups. The ratio of HDL-apoCIII/ VLDL-apoCIII was the only universal determinant for CAD in all groups. In multivariate analyses, the HDL-apoCIII/VLDL-apoCIII ratio was the strongest predictor for CAD among all lipid factors investigated (odds ratio, 2.04; 95% CI 1.46--2.84; P<0.0001). These data therefore suggest that measurement of plasma apoCIII may improve CAD prediction in the general population.
Identification of the HDL-apoCIII to VLDL-apoCIII ratio as a predictor of coronary artery disease in the general population: The Chin-Shan Community Cardiovascular Cohort (CCCC) study in Taiwan.

Chang PY, Lee CM, Hsu HC et al.

Dietary intervention improves metabolic risk profile

Dietary intervention based on a typical Italian Mediterranean diet (IMD) promotes weight loss and improves the cardiometabolic risk profile in patients with metabolic syndrome. In this study, 80 Caucasian Italian subjects with metabolic syndrome were prescribed a balanced hypocaloric IMD. After 6 months, adherence to the IMD decreased body weight (by 10%, p <0.001), body mass index (by 9%, p <0.001) and waist circumference (by 18%, p < 0.001), with resolution of the metabolic syndrome in 52% of patients. There were also decreases in low-density lipoprotein cholesterol (from 128.7 ± 33.2 to 108.8 ± 38.6 mg/dL, p <0.001) and triglycerides (from 169.8 ± 80.8 to 131.0 ± 63.9 mg/dL, p <0.001). These data highlight the value of a hypocaloric IMD for management of cardiometabolic risk.
Body composition changes and cardiometabolic benefits of a balanced Italian Mediterranean Diet in obese patients with metabolic syndrome.

Di Daniele N, Petramala L, Di Renzo L et al.

Elevated apolipoprotein E strongly linked to atherogenic dyslipidemia

In a general population susceptible to metabolic syndrome, elevated apolipoprotein (apo)E concentrations are strongly linked to atherogenic dyslipidemia and elevated apolipoprotein B100 (apoB) levels, irrespective of apoE genotype, and are associated with coronary heart disease (CHD). In this cross-sectional study in 1,127 middle-aged adults, apoE concentrations showed log-linear associations with apoB and apoA-I levels, and waist circumference, independent of C-reactive protein (CRP), insulin resistance (homeostatic model assessment (HOMA) index) and other confounders. The likelihood of atherogenic dyslipidemia and of elevated apoB levels increased 3-fold per 1 standard deviation increase in apoE concentration. ApoA-I, otherwise inversely related to atherogenic dyslipidemia, appeared to promote elevated apoB concentration, suggestive of apoA-I dysfunctionality. Circulating apoE levels were predictive of prevalent and incident coronary heart disease, independent of apoE genotype and CRP (OR 1.32, 95 % CI 1.11; 1.58,). Thus, excess apoE may reflect a pro-inflammatory state and autoimmune activation.
High serum apolipoprotein E determines hypertriglyceridemic dyslipidemias, coronary disease and apoA-I dysfunctionality.

Onat A, Can G, Ornek E et al.

Dual peroxisome proliferator-activated receptor agonists: therapeutic potential in cardiometabolic disease?

Despite best standards of care, patients with type 2 diabetes mellitus remain at high residual risk of cardiovascular disease. Given evidence that peroxisome proliferator-activated receptor (PPAR) alpha agonists are effective in the management of atherogenic dyslipidaemia to reduce cardiovascular risk in type 2 diabetes patients, and that PPAR gamma agonists target glycaemic control and insulin resistance, dual PPAR alpha/gamma agonists may potentially offer therapeutic opportunities to lower this high residual vascular risk. This paper overviews the rationale and evidence for this strategy, including lessons learned from studies with thiazolidinediones, glitazars and investigational dual-PPAR alpha/gamma agonists. The later dual PPAR alpha/gamma agonists have been shown to produce reductions in HbA1c and fasting glucose, and improved management of atherogenic dyslipidaemia. However, data are needed from outcomes studies to evaluate whether these biochemical benefits translate into reduced cardiometabolic risk.
Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects.

Rosenson RS, Wright RS, Farkouh M, Plutzky J.

Am Heart J 2012;164:672-80.

Neck circumference is an indicator of atherogenic dyslipidemia

This study in 490 volunteers (mean age 46 years, 40% male), investigated the association between neck circumference (a surrogate measure of upper-body central adiposity), and biomarkers used to assess cardiovascular risk. Biomarkers evaluated included fasting glucose, total cholesterol, HDL-C, LDL-C, triglycerides, cystatin C, uric acid and hs CRP. Linear and logistic regression models were used to evaluate the association between neck circumference and biomarkers of cardiometabolic risk. The study showed a positive association between neck circumference and systolic and diastolic blood pressure, glucose, triglycerides, uric acid and hs-CRP, and a negative association with HDL-C. The relationship between neck circumference and HDL-C, glucose, triglycerides and uric acid remained significant after adjustment for body mass index and abnormal waist circumference, in addition to traditional cardiovascular risk factors. The findings suggest that neck circumference may have value as a simple means of identifying subjects at high risk for atherogenic dyslipidemia for further screening.
Neck circumference is correlated with triglycerides and inversely related with HDL-cholesterol beyond BMI and waist circumference.

Vallianou NG, Evangelopoulos AA, Bountziouka V et al.

Diabetes Metab Res Rev 2012 Nov 8. doi: 10.1002/dmrr.2369. [Epub ahead of print]

Fibroblast growth factor 21 (FGF21) may be a marker of fenofibrate-mediated reduction in cardiovascular risk

An ancillary study of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study suggests that FGF21 may be useful in assessment of fenofibrate-mediated reduction in cardiovascular risk in type 2 diabetes patients. This study included 216 patients, 108 in each group, who were randomly selected from the FIELD study cohort. Three novel biomarkers - adipocyte-fatty acid-binding protein (A-FABP), FGF21, and retinol-binding protein 4 (RBP4) – which are all downstream targets of peroxisome proliferator-activated receptor (PPAR)-apha or PPAR-gamma - were evaluated for their association with cardiovascular risk. Serum FGF21 and RBP4 levels over 5 years were significantly higher in the fenofibrate group (by 85%, p< 0.001 and 10%, p = 0.032, respectively), compared with placebo. There were no detectable effects on serum A-FABP levels. The effect of fenofibrate treatment on serum FGF21 remained significant after adjusting for fenofibrate-induced changes in glycated haemoglobin, lipids (including total cholesterol and triglycerides), fibrinogen, plasma creatinine and homocysteine. These findings suggest that FGF21 may have a potential role in modulating or assessing fenofibrate-mediated reduction of cardiovascular risk.
Long-term fenofibrate therapy increases fibroblast growth factor 21 and retinol-binding protein 4 in subjects with type 2 diabetes.

Ong KL, Rye KA, OConnell R et al.

J Clin Endocrinol Metab 2012 Nov 8. [Epub ahead of print].

Aminotransferase levels are associated with cardiometabolic risk

New insights from the Framingham Heart Study show that alanine aminotransferase (ALT) levels are correlated with multiple cardiometabolic risk factors beyond the effects of visceral adipose tissue and insulin resistance. This analysis included data from 2,621 subjects (mean age 51, 50% women). In multivariate models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose and triglycerides and lower high-density lipoprotein cholesterol levels (all p<0.01). Each 1 standard deviation increase in ALT was associated with an increased risk of cardiometabolic abnormalities, including diabetes mellitus and the metabolic syndrome. This association was still evident after adjustment for visceral adipose tissue, insulin resistance, and body mass index. Results were similar when only data for non-diabetic subjects with ALT levels <40 U/L were analysed. Given associations between the metabolic syndrome, diabetes and non-alcoholic fatty liver disease, ALT measurement could be a simple measure to refine assessment of cardiometabolic risk.
Aminotransferase levels are associated with cardiometabolic risk above and beyond visceral fat and insulin resistance: The Framingham Heart Study

Porter SA, Pedley A, Massaro JM, Vasan RS, Hoffmann U, Fox CS.

Arterioscler Thromb Vasc Biol 2012 Nov 15. [Epub ahead of print].

Combination fibrate/statin therapy improves short-term cardiovascular events in ACS

In the ACS Israeli Surveys (ACSIS), treatment with the combination of fibrate plus statin reduced the 30-day rate of major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS). The study population comprised 8,982 statin-treated patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 surveys, who were alive on discharge. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination therapy. MACE was defined as a composite of death, recurrent myocardial infarction, recurrent ischaemia, stent thrombosis, ischaemic stroke and urgent revascularization. Patients treated with fibrate/statin therapy had a significantly lower 30-day MACE rate compared with those on statin alone (14 (3.2%) versus 513 (6.0%), p=0.01). Additionally, multivariable analysis identified fibrate/statin combination treatment as an independent predictor of reduced risk of MACE (odds ratio 0.54, 95% CI 0.32-0.94). While acknowledging the limitations of the data, the authors concluded that targeting elevated triglycerides and low HDL cholesterol can reduce the high residual macrovascular risk in ACS patients.
Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: Acute Coronary Syndrome Israeli Surveys data

Tenenbaum A, Medvedofsky D, Fisman EZ et al.

PLoS One 2012;7:e35298.

HDL functionality: relevance to atheroprotection

In addition to a role in cellular cholesterol efflux and cholesterol homeostasis, experimental studies have shown that high-density lipoprotein (HDL) exhibit a number of novel biological activities which are potentially atheroprotective. These include attenuation of apoptosis, anti-oxidant effects, anti-inflammatory actions in both endothelial cells and leukocytes, as well as beneficial effects on the endothelium and platelets. Moreover, there is emerging evidence to indicate that HDL have beneficial effects on glucose homeostasis and pancreatic ß-cell function. These actions of HDL have been observed both in vitro and in vivo. Assessment of HDL functionality may offer therapeutic possibilities. However, before this is feasible, further work to investigate how best to assess these novel actions of HDL are needed.
Novel biological functions of high-density lipoprotein cholesterol.

Mineo C, Shaul PW

Circ Res 2012;111:1079-90.

Genetic predisposition to atherogenic dyslipidaemia linked with type 2 diabetes risk

This study evaluated genetic predisposition to elevated triglycerides and/or low high-density lipoprotein (HDL) cholesterol in 2,447 patients with type 2 diabetes and 3,052 control subjects included in the Nurses Health Study and the Health Professionals Follow-up Study. The evaluation was based on three genotype scores derived from established loci for blood lipids (low-density lipoprotein [LDL] cholesterol, HDL cholesterol, and triglycerides). Both the HDL cholesterol and triglyceride genotype scores were linearly related to elevated type 2 diabetes risk; there was no association for the LDL cholesterol genotype score. Comparing the extreme scores (lowest versus highest quartiles), the lowest quartile of the HDL cholesterol score and highest quartile of the triglyceride score was associated with 39% (95% CI 17-65%) and 19% (95% CI 1-41%) increased risk for type 2 diabetes. In conclusion, the findings of this study show that genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.
Genetic predisposition to dyslipidemia and type 2 diabetes risk in two prospective cohorts

Qi Q, Liang L, Doria A, Hu FB, Qi L.

Diabetes 2012;61:745-52.

Atherogenic ratio: an index of residual macrovascular risk in women with type 2 diabetes

A previous study showed that the atherogenic ratio, log(triglycerides [TG])/high-density lipoprotein (HDL) cholesterol), has practical application in assessment of residual macrovascular risk in men with type 2 diabetes. However, it is not known whether this index is also appropriate for assessment of residual cardiovascular risk in women with type 2 diabetes. This cross-sectional study included 340 female patients with type 2 diabetes (mean age 67 years, mean diabetes duration 15 years, mean HbA1c 7.9%). Overall the prevalence of atherogenic dyslipidaemia (TGs =150 mg/dL and HDL cholesterol <50 mg/dL) was 35%. The presence of atherogenic dyslipidaemia was strongly associated with cardiometabolic abnormalities, residual risk of future coronary events, as well as ß-cell function loss, poorer glycaemic control and a higher frequency of microvascular disease. Thus, the atherogenic ratio, log(TG)/HDL cholesterol, represents a simple means of grading residual macrovascular risk, as well as identifying worsening glucose control.
The atherogenic dyslipidemia ratio [log(TG)/HDL-C] is associated with residual vascular risk, beta-cell function loss and microangiopathy in type 2 diabetes females.

Hermans MP, Ahn SA, Rousseau MF.

Lipids in Health and Disease 2012, 11:132 doi:10.1186/1476-511X-11-132.

Persistent high prevalence of atherogenic dyslipidemia in Indians living in urban areas

Data from a cross-sectional study in India showed a persistent high prevalence of cardiovascular risk factors, including low HDL cholesterol and elevated triglycerides, among urban Indian subjects. In a cross-sectional study of 739 subjects (evaluated over the period 2009-2010), there were high prevalences of smoking (21% in men), low physical activity (70% in men and 52% in women), overweight/obesity (46% and 51%) and hypertension (40% and 25%). One-third of subjects had total cholesterol =200 mg/dL, 25% of men and 55% of women had low high-density lipoprotein (HDL) cholesterol (<40 mg/dL in men and <50 mg/dL in women), and about one-quarter had metabolic syndrome. There were age-related increases in the prevalence of measures of obesity, systolic blood pressure, total cholesterol, non-HDL cholesterol and triglycerides (p<0.01 for trend). Compared with the periods 2002-2003 and 2005-2006 there was evidence of an increasing trend in the prevalence of high non-HDL cholesterol and triglycerides.
Persistent high prevalence of cardiovascular risk factors in the urban middle class in India. Jaipur Heart Watch-5.

Gupta R, Sharma KK, Gupta A et al.

FABP4: potential marker of incident atherogenic dyslipidemia

Adipocyte fatty acid-binding protein (FABP4) plasma levels have been previously linked to metabolic changes that are associated with obesity, including the development of atherogenic dyslipidemia. This was investigated in a substudy of the PREDIMED study (Effects of the Mediterranean diet on the primary prevention of cardiovascular diseases), a large prospective multicentre study in Spain investigating the effect of dietary intervention in individuals at high risk of cardiovascular disease. FABP4 plasma levels were measured at baseline and the incidence of atherogenic dyslipidemia was evaluated over a median 4-year follow-up period in 578 subjects. FABP4 plasma levels were associated with new-onset atherogenic dyslipidemia during follow-up (p=0.02) in women but not in men. Women in the highest tertile for plasma FABP4 levels had more than 2-fold increased risk of developing atherogenic dyslipidemia (hazard ratio 2.54, 95% CI 1.31 to 4.93, p for trend 0.008). The authors concluded that FABP4 may be a potential predictive marker of subsequent development of atherogenic dyslipidemia in women.
FABP4 predicts atherogenic dyslipidemia development. The PREDIMED study.

Cabré A, Babio N, Lazaro I et al.

Atherogenic dyslipidaemia implicated in cardiovascular risk in familial hypercholesterolaemia?

Familial hypercholesterolaemia is due to genetic defect in either the LDL receptor, apolipoprotein (apo) B100 (the LDL receptor ligand), or PCSK-9 (proprotein convertase subtilisin/kexin type 9, a degrader of the LDL receptor). The condition is characterised by markedly elevated LDL cholesterol levels and increased cardiovascular risk. However, this study in 555 FH patients, also implicates the atherogenic index (log[triglycerides/HDL-cholesterol]) as a contributor to coronary heart disease risk.
The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of cardiovascular disease in patients with familial hypercholesterolemia.

Soška V, Jarkovský J, Ravcuková B et al.

Clin Biochem 2012;45:96-100.

Higher triglyceride-HDL ratio predisposes to diabetes

This general population study included data from 687 individuals followed over 15 years. Overall, 74 (10.8%) individuals developed diabetes over this period. After adjustment, both elevated triglycerides (odds ratio [OR] 1.29, p =0.047) and a higher triglyceride-HDL cholesterol (OR 1.34, p=0.01) were shown to be predictive for the onset of diabetes. These data highlight the relevance of assessment of the triglyceride-HDL cholesterol in determining the risk of diabetes in a general population in China.
Higher ratio of triglyceride to high-density lipoprotein cholesterol may predispose to diabetes mellitus: 15-year prospective study in a general population.

He S, Wang S, Chen X et al.

Metabolism 2012;61:30-6.

Elevated triglycerides and low HDL predictive of cardiovascular events in China

Data from the Chinese Multi-provincial Cohort Study in 30,378 participants (35-64 years) followed over 15 years highlight atherogenic dyslipidaemia as an important contributor to cardiovascular risk in people with well-controlled LDL cholesterol (<130mg/dL or 3.4 mmol/L). Elevated triglycerides were associated with an increased risk of coronary events (Hazard ratio [HR] 1.74, 95% CI 1.25-2.42, p=0.001), and low HDL cholesterol was associated with an increased risk of ischaemic stroke (HR=1.54, 95% CI 1.18-2.03, P=0.002) only in individuals with low LDL cholesterol. The authors called for a renewed focus on managing elevated triglycerides and low HDL cholesterol in individuals at LDL cholesterol goal to reduce this residual cardiovascular risk.
Impact of diabetes, high triglycerides and low HDL cholesterol on risk for ischemic cardiovascular disease varies by LDL cholesterol level: A 15-year follow-up of the Chinese Multi-provincial Cohort Study.

Liu J, Wang W, Wang M et al.

Diabetes Res Clin Pract 2012;96:217-24.

Elevated triglycerides predictive of onset and severity of diabetic nephropathy

In a systematic review, elevated triglycerides were highlighted as a valid predictor for the onset or progression of nephropathy in patients with type 2 diabetes. The review included 15 studies evaluating 27 biomarkers; six studies with sufficient methodological quality were analysed. In addition to elevated triglycerides, other valid biomarkers for predicting the onset and progression of nephropathy included plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, and von Willebrand factor. The authors highlighted the need for further study of these predictors.
Validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes: a systematic review.

Hellemons ME, Kerschbaum J, Bakker SJ et al.

Diabet Med 2012;29:567-77.

Elevated triglycerides predictive of distal peripheral neuropathy

Data from Sri Lanka in 528 people with type 2 diabetes (over one-third newly diagnosed) highlight elevated triglycerides as a risk factor for distal peripheral neuropathy. This was assessed using the Diabetic-Neuropathy-Symptom (DNS) score in new cases, and both the DNS and Toronto-Clinical-Scoring-System (TCSS) in individuals with established type 2 diabetes. The sample had a mean age of 55 years, 37% were males, and 18% lived in urban areas. The prevalence of distal peripheral neuropathy was about one-quarter, both in individuals newly diagnosed (29%) or with established type 2 diabetes (24%). In those with established diabetes, foot ulcers (odds ratio [OR] 10.4; 95%CI 1.8-16.7), female (OR 6.7; 95%CI 2.0-9.8) and smoking (OR 5.9; 95%CI 1.4-9.7) were the strongest predictors for distal peripheral neuropathy. Among other predictors identified, higher triglycerides were associated with a 60% increase in risk for distal peripheral neuropathy (OR 1.6; 95%CI 1.2-2.0).
The prevalence, patterns and predictors of diabetic peripheral neuropathy in a developing country.

Katulanda P, Ranasinghe P, Jayawardena R et al.

Diabetol Metab Syndr. 2012 May 29;4:21. [Epub ahead of print].

Emerging role for metabolic syndrome components in diabetic neuropathy?

A Review in Lancet Neurology has highlighted the emerging role of components of the metabolic syndrome, including low HDL cholesterol and elevated triglycerides, in diabetic neuropathy. Diabetic neuropathy is a common microvascular complication which detrimentally influences patient quality of life, as well as increasing the risk of lower limb amputation. This complication is also an important contributor to the cost of diabetes care. In this review, the authors emphasise the limitations of current standards of care, and highlight associations between elevated triglycerides or low HDL cholesterol, as well as other components of the metabolic syndrome, and diabetic neuropathy. Given the growing burden of this diabetes complication, and the fact that all components of the metabolic syndrome are modifiable by lifestyle or pharmacological interventions, there is a strong case for further investigating these potential risk factors in diabetic neuropathy.
Diabetic neuropathy: clinical manifestations and current treatments.

Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL

Lancet Neurol 2012;11:521-34
2011

Association between the atherogenic index (logarithm of the triglyceride/HDL-cholesterol ratio) and cardiovascular disease in patients with familial hypercholesterolemia

A study conducted in 555 heterozygous familial hypercholesterolemia patients shows significantly higher triglycerides levels in those with cardiovascular disease compared with those without. The association between CVD and the atherogenic index was also significant. The atherogenic index is also a good surrogate for the presence of atherogenic small LDL and small HDL particles.
The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of cardiovascular disease in patients with familial hypercholesterolemia.

Soska V, Jarkovsky J, Ravcukova B, Tichy L, Fajkusova L, Freiberger T

Significant regression of coronary atherosclerosis in patients treated with maximal doses of atorvastatin and rosuvastatin: the SATURN trial

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) compared the effect of maximal doses of atorvastatin (80 mg daily) or rosuvastatin (40 mg daily) on the progression of coronary atherosclerosis assessed by intravascular ultrasonography in patients with at least one vessel with 20% stenosis on coronary angiography. Among the 1,039 patients eligible for analysis after 104 weeks of treatment, those in the rosuvastatin group had lower LDL-C levels (62.6 vs. 70.2 mg/dL [1.62 vs. 1.82 mmol/L], P<0.001), and higher HDL-C levels (50.4 vs. 48.6 mg/dL [1.30 vs. 1.26 mmol/L], P=0.01) than those in the atorvastatin group. Both statins induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for percent atheroma volume (P=0.07) and 64.7% and 71.3%, respectively, for total atheroma volume (P=0.02). Both high-dose statin regimens were well tolerated. Although treatment with rosuvastatin was associated with a more favorable lipid profile, there were no significant between-group differences in the rates of major clinical events. These rates were extremely low for such a population: 1.6% for myocardial infarction, 0.4% for stroke and 0.3% for cardiovascular death during 24 months follow-up at a central site. These results confirm that intensive lipid-lowering with statins is associated with favorable clinical outcomes but suggest that no substantial additional benefit can be obtained once a LDL-C level as low as 70 mg/dL has been reached in this high-risk population. However, the study was not powered to detect between-group differences in major adverse clinical events.
Effect of Two Intensive Statin Regimens on Progression of Coronary Disease

Stephen J. Nicholls, M.B., B.S., Ph.D., Christie M. Ballantyne, M.D., Philip J. Barter, M.B., B.S., Ph.D., M. John Chapman, Ph.D., D.Sc., Raimund M. Erbel, M.D., Peter Libby, M.D., Joel S. Raichlen, M.D., Kiyoko Uno, M.D., Marilyn Borgman, R.N., Kathy Wolski, M.P.H., and Steven E. Nissen, M.D.

Intensive glucose lowering treatment challenged by a meta-analysis

The authors of a meta-analysis published in the British Medical Journal report that compared to standard treatment, intensive glucose lowering treatment did not significantly affect all-cause mortality or cardiovascular death. However, the intensive treatment significantly reduced by 15% the risk of nonfatal myocardial infarction and by 10% the risk of microalbuminuria (P<0.01 for both comparisons) – with no effect on the other microvascular complications of diabetes. The intensive treatment was also associated with a more than twofold increase in the risk of severe hypoglycemia (P<0.01). “The harm associated with severe hypoglycemia might counterbalance the potential benefit of intensive glucose lowering treatment,” the authors write.
Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials

Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al

A review on microvascular residual risk and recent fenofibrate trials

This review published by Prof. Michel P. Hermans analyses the current evidence on the residual risk of microvascular complications of diabetes persisting in patients treated according to current standards of care. In the second part of his review, the author comments on the beneficial impact on microngiopathies reported in recent fenofibrate trials and their potential implications for the management of microvascular residual risk in diabetic patients.
Prevention of microvascular diabetic complications by fenofibrate: lessons from FIELD and ACCORD

Michel P. Hermans

New nomenclature of HDL particles

In a recently published article, Prof. Robert Rosenson, a member of the R3i International Steering Committee, and other prominent lipidologists designate “HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients.” But the authors stress that HDL cholesterol measurement does not reflect the physicochemical and functional heterogeneity of HDL particles. To refine cardiovascular risk prediction and assessment of agents that modulate HDL particle structure, these authors propose a new nomenclature of HDL subfractions based on their physical properties. Accordingly, one might be dealing, in the near future, with very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL), not to forget the pre-ß-1 HDL.
HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.

Rosenson RS, Brewer HB Jr, Chapman MJ, et al

Triglycerides and cardiovascular disease: a scientific statement from the AHA

On behalf of the American Heart Association, a panel of experts published a scientific statement based on a comprehensive review of data establishing the links between triglycerides and cardiovascular disease. Owing to the conclusions of the panel, the optimal and normal fasting TG levels are <100 and <150 mg/dL, respectively., commensurate with a non-fasting level of <200 mg/dL. The panel also recommends measurements of non-HDL-cholesterol (non-HDL-C), apolipoprotein B100 (apoB), or both, in those with prominent TG/HDC abnormalities.
Triglycerides and Cardiovascular Disease

Miller M, Stone NJ, Ballantyne C, et al

Lipid biomarkers, but not nonlipid biomarkers predict major cardiovascular events in patients treated with atorvastatin

In a nested case-control study from the Treating to New Targets (TNT) trial, fasting plasma levels of standard lipids and of 18 nonlipid biomarkers were determined after an 8-week run-in period on atorvastatin 10 mg and again 1 year after being randomized to 10 or 80 mg atorvastatin in 507 patients who experienced major cardiovascular events (MCVEs) during the 4.9 years of study follow-up, and in 1,020 control subjects. LDL-C , HDL-C, and triglycerides were all predictive of recurrent MCVEs (p = 0.009). Concentrations of many of the 18 nonlipid biomarkers were lowered by atorvastatin therapy (independent of dose). However, almost none of the nonlipid biomarkers, such as C-reactive protein and lipoprotein(a), were predictive whether measured after the 8-week run-in period or after 1 year of treatment with 10 or 80 mg atorvastatin.
Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers

Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, Kastelein JJ; TNT Study Investigators.

2010

Atherogenic lipid profile in patients with inflammatory bowel disease

A retrospective study evaluated the lipid profiles of 393 patients with inflammatory bowel diseases (IBD: Crohn’s disease and ulcerative colitis). Compared with men of similar age and body mass index, men with IBD had significantly lower total cholesterol and HDL-C and higher LDL-C and triglycerides. The same type of comparison showed that in women with IBD, total cholesterol, HDL-C, and triglycerides were significantly decreased and LDL-C significantly increased. High circulatory levels of inflammatory cytokines in patients with IBD may decrease lipoprotein lipase activity, with a lipoprotein profile characterized by increased triglycerides and decreased HDL cholesterol levels, also observed in patients with systemic lupus erythematosus.
Dyslipidemia and lipoprotein profiles in patients with inflammatory bowel disease

Sappati Biyyani RS;Putka BS; Mullen KD

Despite statin therapy, a large proportion of patients with diabetes do not reach lipid-lowering goals

The Dyslipidemia International Study (DYSIS) evaluated over 22,000 statin-treated outpatients aged 45 years or older in Europe and Canada. Patients with diabetes represented 39.5% of that population. 58.5% were at LDL-C goal. Of those not at LDL-C goal, 16.2% had normal HDL-C and TGs. 3.9% had high TGs, 8.3% had low HDL-C with high TGs and 3.2% had low HDL-C. 25.4% had low HDL-C and/or high TGs. The CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) also showed that only 55.3% of patients using lipid-lowering drugs achieved the LDL-C target recommended in the 2003 European guidelines. Therefore, patients with diabetes who are treated with a statin remain at high risk for cardiovascular events based on their achieved lipid values. A need for wider and more intensive lipid therapy with lifestyle management is demonstrated.
Centralized Pan-European survey on the under-treatment of hypercholesterolaemia (CEPHEUS): overall findings from eight countries.

Hermans MP, Castro Cabezas M, Strandberg T, Ferrieres J, Feely J, Elisaf M, Michel G, Sansoy V.

2009

Refocusing on HDL as a therapeutic target

Data from the Framingham Offspring study support HDL cholesterol as a therapeutic target. Raising HDL cholesterol reduced cardiovascular risk across the spectrum of patients receiving lipid therapy. Clinical benefits were greater at lower HDL cholesterol values. These data reinforce the value of treating low HDL cholesterol to reduce lipid-related cardiovascular risk.
Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels

Grover SA;Kaouache M;Joseph L;Barter P;Davignon J;

TG/HDL-C: a key predictor of coronary risk

A high TG/HDL cholesterol ratio is a strong epidemiological measure of atherogenic dyslipidemia as well as a surrogate marker of insulin resistance. It better predicts occurrence of a first heart attack than LDL cholesterol, according to data from the MEtabolic Syndrome Active Subjects (MESYAS) study. In overweight male patients, a high TG/HDL cholesterol ratio increases coronary risk by up to 50%. These data not only highlight the role of non-LDL lipids in coronary risk, but also underline the usefulness of this simple BMI-independent cardiometabolic risk predictor.
Usefulness of triglycerides-to-high-density lipoprotein cholesterol ratio for predicting the first coronary event in men

Cordero A;Andres E;Ordonez B;Leon M;Laclaustra M;Grima A;Luengo E;Moreno J;Bes M;Pascual I;Civeira F;Pocovi M;Alegria E;Casasnovas JA;MEtabolic Syndrome Active Subjects Study Investigators;

Cholesterol treatment has improved, but high-risk women are still undertreated

In the Lipid Treatment Assessment Project (L-TAP) 2, dyslipidemic men and women aged at least 20 years on stable lipid-lowering therapy were assessed in 9 countries to compare LDL-C goal attainment between genders. Of 9,955 patients (45.3% women) evaluated, women had a significantly lower success rate for reducing LDL-C than men (71.5% vs 73.7%, P=0.014). This was due entirely to the difference in the high-risk/coronary heart disease (CHD) group (LDL-C goal <100 mg/dL, 62.6% vs 70.6%, P<0.0001). Among CHD patients with at least 2 additional risk factors, only 26.7% of women and 31.5% of men (P = 0.021) attained the optional LDL-C goal of <70 mg/dL. HDL-C was <50 mg/dL in 32.2% of women and <40 mg/dL in 26.8% of men (P<0.0001), including 38.2% of women and 29.8% of men in the high risk/CHD group. Despite cholesterol treatment improving substantially since the original L-TAP a decade ago, when only 39% of women attained their LDL-C goal, high-risk women are undertreated compared to men.
Low- and high-density lipoprotein cholesterol goal attainment in dyslipidemic women: The Lipid Treatment Assessment Project (L-TAP) 2

Santos RD;Waters DD;Tarasenko L;Messig M;Jukema JW;Ferrieres J;Verdejo J;Chiang CW;L-TAP 2 Investigators;

An HDL-related factor predicts vascular events in coronary patients treated with statins

In an Austrian based study, vascular events were recorded over 5.6 years in 491 consecutive statin-treated patients with angiographically proven stable coronary artery disease, covering 2750 patient-years. Low HDL-C (standardized adjusted hazard ratio (HR) 0.73; p=0.001), low apolipoprotein A1 (HR, 0.77; p=0.003), a small LDL particle diameter (HR, 0.76; p=0.002), and high triglyceride levels (HR, 1.20; p=0.007) predicted vascular events, but not total cholesterol, LDL-C, or apolipoprotein B. Factor analysis in the lipid profiles revealed an HDL-related factor and an LDL-related factor. The HDL-related factor (HR, 0.69; p<0.001) but not the LDL-related factor (p=0.455) predicted vascular events. Patients with type 2 diabetes (n=116) were at a higher vascular risk than non-diabetic subjects (38.6% vs. 24.1%; p<0.001), and like in the total population the HDL-related factor (0.59; p<0.001) but not the LDL-related factor (p=0.591) predicted vascular risk in diabetic patients.
Factors predicting cardiovascular events in statin-treated diabetic and non-diabetic patients with coronary atherosclerosis

Drexel H;Aczel S;Marte T;Vonbank A;Saely CH;

Lower HDL-cholesterol is a strong and independent predictor of both cardiac and all-cause death in patients with left ventricular dysfunction

A total of 686 consecutive patients hospitalized in Pisa, Italy, as a result of left ventricular dysfunction (73% classified as New York Heart Association [NYHA] class I-II), completed a lipid profile and underwent coronary angiography, and were followed for a mean period of 23 months. Half of the patients (52%) had HDL-C values less than 40 mg/dl; in multivariate analysis, they showed the greater risk for cumulative mortality (hazard ratio (HR) 1.77, P<0.05) and for cardiac death (HR 2.06, P<0.05). This greater risk was observed in particular in patients with low HDL-C levels but without significant coronary stenosis.
Low high-density lipoprotein predicts death in patients with mild left ventricular dysfunction regardless of coronary atherosclerosis

Sampietro T;Bigazzi F;Puntoni M;Minichilli F;Landi P;Dal Pino B;Carpeggiani C;LAbbate A;

Epicardial endothelial dysfunction correlates with LDL and HDL particle size

Coronary endothelial function was assessed in 490 patients of both genders and endothelial dysfunction (epicardial constriction >20% or increase in coronary blood flow <50% in response to intracoronary acetylcholine) was diagnosed in 273 patients. Measurement of lipoprotein particle subclasses using nuclear magnetic resonance revealed that epicardial endothelial dysfunction was significantly correlated with total (p=0.03) and small LDL particles (p<0.01) and inversely correlated with total and large HDL particles (p<0.01).
Coronary artery endothelial dysfunction is positively correlated with low density lipoprotein and inversely correlated with high density lipoprotein subclass particles measured by nuclear magnetic resonance spectroscopy

Ford MA;McConnell JP;Lavi S;Rihal CS;Prasad A;Sandhu GS;Hartman SJ;Lerman LO;Lerman A;

High plasma HDL-C levels protect against risk of stroke

Owing to follow-up data collected from 93 695 persons aged 19 to 77 years in 8 European countries (1 234 252 total observation-years), the risk of stroke was increased by 9% in men and by 10% in women with each year of age, and by 28% in men and 25% in women with each 10-mm Hg increase in systolic blood pressure. Smoking increased the risk of stroke by 104% in women and 82% in men. Conversely, high HDL-C levels decreased risk of stroke by 42% in women and 20% in men.
Relative risks for stroke by age, sex, and population based on follow-up of 18 European populations in the MORGAM Project

Asplund K;Karvanen J;Giampaoli S;Jousilahti P;Niemela M;Broda G;Cesana G;Dallongeville J;Ducimetriere P;Evans A;Ferrieres J;Haas B;Jorgensen T;Tamosiunas A;Vanuzzo D;Wiklund PG;Yarnell J;Kuulasmaa K;Kulathinal S;MORGAM Project;

Additive effects of routine blood pressure lowering and intensive glucose control on mortality and albuminuria in patients with type 2 diabetes

The ADVANCE trial was a factorial randomized trial of the antihypertensive combination perindopril-indapamide versus placebo, and intensive glucose control (target hemoglobin A1c = 6.5%) versus standard glucose control in patients with type 2 diabetes. A recent analysis shows that, during an average 4.3-years of follow-up, the effects of the two treatments were independent and additive. Compared with no intervention, combined antihypertensive and glucose-lowering treatment reduced all-cause mortality by 18% (p=0.04), new or worsening nephropathy by 33% (p=0.005), new-onset macroalbuminuria by 54% (p<0.0001) and new-onset microalbuminuria by 26% (P < 0.001). However, there was no significant reduction in new-onset or worsening retinopathy.
Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial

Zoungas S;de Galan BE;Ninomiya T;Grobbee D;Hamet P;Heller S;MacMahon S;Marre M;Neal B;Patel A;Woodward M;ADVANCE Collaborative Group;Cass A;Glasziou P;Harrap S;Lisheng L;Mancia G;Pillai A;Poulter N;Perkovic V;Travert F;

Two-fold increase in risk of chronic kidney disease in Taiwanese subjects with hypertriglyceridemia

Data from18,422 subjects aged 40 years or more involved in a medical screening program showed a high prevalence (24.2%) of chronic kidney disease in middle-aged and elderly Taiwanese subjects. Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2. The multiadjusted odds ratio of chronic kidney disease in participants with serum triglycerides = 200 mg/dL was 1.901 (p < 0.05).
Hypertriglyceridemia: an independent risk factor of chronic kidney disease in Taiwanese adults

Lee PH;Chang HY;Tung CW;Hsu YC;Lei CC;Chang HH;Yang HF;Lu LC;Jong MC;Chen CY;Fang KY;Chao YS;Shih YH;Lin CL;

High rate of silent coronary artery disease in patients with diabetic retinopathy

Diagnostic tests, including an exercise treadmill test and exercise thallium scintigraphy or coronary computed tomography detected a significant stenotic coronary artery disease in 55 (25.7%) out of 214 outpatients with diabetic retinopathy. Coronary artery disease was not previously suspected in these patients. Forty-two patients showed indications of coronary revascularization (coronary artery bypass grafting in 17 and percutaneous coronary intervention in 25).
Detecting occult coronary artery disease followed by early coronary artery bypass surgery in patients with diabetic retinopathy: Report from a diabetic retinocoronary clinic

Ohno T;Kinoshita O;Fujita H;Kato S;Hirose A;Sigeeda T;Otomo K;Ando J;Kadowaki T;Araie M;Nagai R;Takamoto S;

Low HDL cholesterol levels are associated with cardiovascular disease in hypertensive Spanish women

A cross-sectional study conducted in 11,042 hypertensive Spanish women aged 55 years or above showed a 24.7% prevalence of CVD in women with a low high-density lipoprotein cholesterol (HDL-C) concentration (<46 mg/dL) vs. a 18.4% prevalence in those with a normal concentration (p< 0.001). After adjustment for other risk factors, CVD prevalence was increased by 42% in women with low HDL-C levels compared to those with normal levels (p < 0.001). The study revealed an independent inverse association between HDL-C levels (in quintiles) and the prevalence of CVD, particularly for HDL-C levels <58 mg/dL.
High-density lipoprotein cholesterol and cardiovascular disease in Spanish hypertensive women. The RIMHA study

Coca A;Cea-Calvo L;Lozano JV;Inaraja V;Fernandez-Perez C;Navarro J;Bonet A;Redon J;Representación del Grupo de los Investigadores del Estudio RIMHA;

Is decreased HDL particle size associated with increased CHD risk?

A nested prospective case-control study conducted in the EPIC-Norfolk cohort included 1035 healthy men and women aged 45-79 years who developed fatal or nonfatal coronary heart disease (CHD), who were matched to 1920 controls remaining free of CHD over a follow-up period of 6 years. Men in the highest quartile of HDL particle size had an unadjusted odds ratio (OR) for future CHD of 0.75 (95% CI, 0.57-0.97) compared to those in the lowest quartile. For women, the equivalent OR was 0.50 (0.35-0.71). However, after additional adjustment for diabetes, body mass index, systolic blood pressure, LDL- and HDL-cholesterol levels, the ORs were 1.43 (1.01-2.03) in men and 0.84 (0.52-1.35) in women. The difference between unadjusted and adjusted ORs, the authors conclude, indicate that the association between HDL particle size and CHD risk is largely explained by traditional cardiovascular risk factors.
HDL particle size and the risk of coronary heart disease in apparently healthy men and women: The EPIC-Norfolk prospective population study

Arsenault BJ, Lemieux I, Després JP, Gagnon P, Wareham NJ, Stroes ES, Kastelein JJ, Khaw KT, Boekholdt SM.

Incidence of chronic kidney disease reduced by 24% in patients with type 2 diabetes and high HDL cholesterol levels

During a 5-year follow-up, chronic kidney disease (CKD) developed in 11.8% of 1987 patients with type 2 diabetes in whom kidney function was normal or near normal at baseline. Higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio, 0.76; 95% coefficient interval, 0.61-0.96; p=0.025) independently of potential confounding risk factors (age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of anti-hypertensive, anti-platelet, lipid-lowering or hypoglycemic medications).
Higher HDL cholesterol levels are associated with a lower incidence of chronic kidney disease in patients with type 2 diabetes.

Zoppini G, Targher G, Chonchol M, Perrone F, Lippi G, Muggeo M.

Significant reduction of non-fatal stroke but nonsignificant decrease in primary end point of cardiovascular events in peripheral artery disease patients on aspirin

To investigate the effect of aspirin on cardiovascular event rates in secondary prevention patients with peripheral artery disease, data were extracted from 18 prospective randomized controlled trials involving 5269 patients, among whom 8.9% of those treated with aspirin and 11% of those in the control groups experienced a cardiovascular event (non-fatal myocardial infarction, stroke or cardiovascular death). Odds ratio calculation yielded a 12% reduction in cardiovascular events, which was not significant. Aspirin was not associated with significant reductions in all-cause or cardiovascular mortality, myocardial infarction or major bleeding. However, there was a 34% reduction in non-fatal stroke events.
Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials

Berger JS;Krantz MJ;Kittelson JM;Hiatt WR;

A meta-analysis of 32 studies shows that elevated triglycerides are an independent risk factor for coronary heart disease

A systematic review of 32 population-based studies investigating the association between baseline serum levels of triglycerides and HDL-C and the development of coronary heart disease (CHD: coronary events or coronary death) was carried out. The independent association between elevated triglycerides and risk of CHD was statistically significant in 16 out of of 30 populations without pre-existing CHD. Triglycerides and HDL-C were mutually exclusive predictors of coronary events in 12 out of 20 analyses of patients without pre-existing CHD. The association between triglycerides and primary CHD independently of HDL-C makes the authors suggest that both lipid abnormalities may be considered in cardiovascular risk prediction and as targets for preventive cardiocascular intervention.
The independent relationship between triglycerides and coronary heart disease

Morrison A;Hokanson JE;

Ethnic differences in lipid profile changes associated with physical activity

Levels of activity were measured in 8764 African-American and white Caucasian participants of the Atherosclerosis Risk in Communities (ARIC) study aged 45-64 years at baseline. After 9 years of follow up, increases in the level of activity were associated with increases in HDL cholesterol in all participants and decreases in triglycerides among white participants. LDL cholesterol decreased in women of both ethnicities, while the association with total cholesterol was limited to African-American women.
Longitudinal impact of physical activity on lipid profiles in middle-aged adults: the atherosclerosis risk in communities (ARIC) study

Monda KL;Ballantyne CM;North KE;

High prevalence of hypertriglyceridemia but low use of TG-lowering medications in the US

Among 5610 individuals aged 20 years or older participating in the National Health and Nutrition Examination Survey conducted from 1999 to 2004, 33.1% had a triglycerides (TG) concentration =150 mg/dL, and 17.9% had TG concentration =200 mg/dL. Only 2.6% of participants with a TG concentration =150 mg/dL and 3.6% of those with a TG concentration =200 mg/dL used a prescription medication primarily aimed at reducing hypertriglyceridemia (fenofibrate, gemfibrozil, or niacin).
Hypertriglyceridemia and its pharmacologic treatment among US adults

Ford ES;Li C;Zhao G;Pearson WS;Mokdad AH;

HDL-C =60 mg/dL associated with more than 50% decrease in 8-year mortality after percutaneous coronary intervention in patients LDL-C <70 mg/dL

In 3,616 consecutive patients with LDL-cholesterol levels <70 mg/dL who underwent percutaneous coronary intervention, multivariate analysis showed that all-cause mortality over the subsequent 8 years was decreased by 32%, 45%, and 55% in patients with HDL-cholesterol levels of 40 to 49, 50 to 59, and =60 mg/dL, respectively, compared with those with HDL-cholesterol <40 mg/dL (multivariate analysis).
Relation of high-density lipoprotein cholesterol to mortality after percutaneous coronary interventions in patients with low-density lipoprotein <70 mg/dl

Kini AS;Muntner P;Moreno PR;Mann D;Krishnan P;Kim MC;Rafael OC;Farkouh ME;Sharma SK;

Preventing cardiovascular risk associated with triglycerides in patients with acute coronary syndromes

Despite its proven clinical efficacy in primary and secondary prevention of cardiovascular events, statin therapy is not sufficient to adequately address all lipid-related cardiovascular risk factors. The increased risk associated with elevated triglyceride levels should also be taken into account and combined statin and fibrate therapy should be contemplated in selected patients with acute coronary syndromes.
Triglycerides and cardiovascular events in ACS: the need for combined lipid-altering therapies.

Rosenson RS, Pitt B

2008

ApoB/apoA-1 ratio best predictor of major coronary events in the IDEAL

The main objective of the IDEAL trial was to compare the efficacy of high-dose potent statin therapy (atorvastatin 80 mg/day) with that of usual-dose average-potency statin therapy (simvastatin 20-40 mg/day) in the prevention of recurrent coronary events in patients with coronary heart disease. An analysis was also performed to study the relationships between on-treatment levels of lipoprotein components and clinical outcome. The on-treatment ratio of apoB (the main apolipoprotein of atherogenic low-density lipoproteins) to apoA-1 (the main apolipoprotein component of atheroprotective high-density lipopoproteins) was the best predictor of subsequent major coronary events.
Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease. Insights from the Incremental Decrease in End-points through Aggressive Lipid-lowering Trial (IDEAL)

Holme I;Cater NB;Faergeman O;Kastelein JJ;Olsson AG;Tikkanen MJ;Larsen ML;Lindahl C;Pedersen TR;on behalf of the Incremental Decrease in End-Points Through Aggressive Lipid-Lowering Study Group;

Statin therapy reduces major cardiovascular events in individuals with normal LDL-C and elevated CRP levels

Circulating CRP level is a marker of low-grade systemic inflammation. The JUPITER study reports a 44% reduction (p<0.00001) in relative risk of major CVD events (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedure, or confirmed death from cardiovascular causes) in apparently healthy patients with LDL-C <130 mg/dL and C-reactive protein (CRP) = 2.0 mg/L, treated with rosuvastatin 20 mg per day. However, the absolute risk reduction in this CVD low-risk population was only 0.9%.
JUPITER Study Group.Collaborators (1332) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ;

Low-dose aspirin does not reduce the risk of first cardiovascular events in Japanese patients with type 2 diabetes

Japanese investigators report no significant difference in the rate of first cardiovascular events (composite outcome: fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral artery disease) in 2,359 type 2 diabetes patients treated or not treated with low-dose aspirin (81 or 100 mg per day) as antiplatelet agent for a mean follow-up of 4.37 years. The authors do not draw firm conclusions, as they estimate that their study was underpowered due to an unexpected low rate of events.
Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.

Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators.

Nonfasting triglycerides predict increased risk of cardiovascular events

A cross-sectional study conducted in 42,710 individuals aged 20-95 years living in Copenhagen, 1166 of whom developed cardiovascular events during 14 years of follow-up, shows that triglycerides levels were increased up to 6 hours after last meal (normal food intake). Highest versus lowest tertile of nonfasting triglycerides was associated with an increased risk of cardiovascular events, as were nonfasting levels of all other recognized lipid risk factors.
Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction.

Langsted A, Freiberg JJ, Nordestgaard BG.

In high-risk patients intolerant to angiotensin-converting enzyme inhibitors: Favourable effects of telmisartan

A total of 5,926 patients received the angiotensin-receptor blocker telmisartan 80 mg/d or placebo for a median duration of 56 months in order to assess whether telmisartan 80 mg/d was effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage. Telmisartan was well tolerated. Although the compound had no significant effect on the primary outcome (composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke.
Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.

The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators.

Ezetimibe/simvastin + fenofibrate in patients with mixed hyperlipidemia: favourable effects of on atherogenic lipoprotein subclasses

This 12-week study evaluated the effects on lipoprotein subclasses of ezetimibe/simvastatin with or without co-administration of fenofibrate in 611 patients with mixed hyperlipidemia. Fenofibrate reduced cholesterol mass within VLDL and IDL, shifting cholesterol from dense LDL subfractions to the more buoyant subfractions and HDL, whilst ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without modifying the LDL particle distribution profile. Following co-administration, the drug effects were complementary with more pronounced reductions in VLDL, IDL and LDL, preferential loss of more dense LDL subfractions and increased HDL.
VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate.

Farnier M, Perevozskaya I, Taggart WV, Kush D, Mitchel YB.

Intensive lipid lowering in patients with coronary artery disease, diabetes, and chronic kidney disease associated with marked reduction in cardiovascular events

Following 8-week open-label therapy with 10 mg/d of atorvastatin, 10,001 CHD patients received double-blind therapy with either 80 mg/d or 10 mg/d of atorvastatin for a median duration of 4.8 years. In contrast to previous observations, 80 mg of atorvastatin reduced the relative risk of major cardiovascular events by 35% in patients with diabetes and chronic kidney disease (CKD), and by 10% in those with diabetes and normal glomerular filtration rate, as compared to the low-dose regimen. In patients with diabetes and CKD, the absolute risk reduction was substantial, yielding a number needed to treat of 14 to prevent one major cardiovascular event over 4.8 years.
Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease.

Shepherd J, Kastelein JP, Bittner VA, Carmena R, Deedwania PC, Breazna A, Dobson S, Wilson DJ, Zuckerman AL, Wenger NK; Treating to New Targets Steering Committee and Investigators.

Retinopathy: an independent predictor of coronary heart disease-related mortality

Among 199 diabetic subjects and 2,768 non diabetic subjects included in the Australian Blue Mountains Eye Study, retinopathy lesions were assessed from retinal photographs and cumulative coronary heart disease (CHD) deaths were ascertained from national death records. During the 12-year follow-up, the presence of retinopathy increased CHD mortality rate by an equivalent amount as the presence of diabetes itself. Both in subjects with diabetes and in those without, even after adjusting for cardiovascular disease risk factors, retinopathy remained an independent predictor of CHD death.
Retinopathy Predicts Coronary Heart Disease Mortality.

Liew G, Wong T, Mitchell P, Cheung N, Wang JJ.

Very low HDL-C levels linked to a worse prognosis in non-ST-segment elevation acute coronary syndromes

HDL-C levels were evaluated in 93,263 patients with non-ST-segment elevation acute coronary syndromes included in the CRUSADE initiative. Compared to patients with normal and high HDL-C levels, those with very low HDL-C levels (18.1% of study population) were more likely to be younger, male, obese and diabetic, and had the greatest risk of multi-vessel coronary disease on angiography and in-hospital mortality. According to the authors, strategies designed to raise HDL-C levels warrant further investigation in these high-risk patients.
Patterns and prognostic implications of low high-density lipoprotein levels in patients with non-ST-segment elevation acute coronary syndromes.

Roe MT, Ou FS, Alexander KP, Newby LK, Foody JM, Gibler WB, Boden WE, Ohman EM, Smith SC Jr, Peterson ED.

Persistence of abnormal lipid profile in approximately 60% of patients achieving total and LDL-cholesterol targets

A study performed in 98 UK practices reveals a large proportion of persisting dyslipidemia in patients with pre-existing CVD or diabetes and with both total cholesterol and LDL cholesterol at target levels, irrespective of the presence or absence of statin therapy. Low HDL-C levels were measured in 22.5% of such patients and high triglycerides in 37.2%. The authors suggest that such patients remain exposed to a significant residual cardiovascular risk, and that lipid management may often require intervention beyond simple total cholesterol lowering.
Abnormal lipids in high-risk patients achieving cholesterol targets: a cross-sectional study of routinely collected UK general practice data

Belsey J, de Lusignan S, Chan T, van Vlymen J, Hague N.