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Landmark study
IMPROVE-IT finally reports: Lower LDL is better but residual cardiovascular risk remains
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Peroxisome proliferator-activated receptor alpha (PPARα) and its role in diabetic retinopathy: Novel insights
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The National Lipid Association (NLA)
The National Lipid Association (NLA) is a nonprofit, multidisciplinary medical society focused on enhancing the practice of lipid management in clinical medicine.
NEW!
PCSK9 and Atherosclerosis
Downloadable slidekit
Created by Professors Jean Davignon (Vice-President of the R3i foundation), Jean-Charles Fruchart (President of R3i) and Michel Hermans (R3i General Secretary), the latest down-loadable deck of 242 slides discusses the potential role for anti-PCSK9 mAbs in the future management of cardiovascular disease.
Authors review unmet needs in the treatment of dyslipidemia, the
discovery and structure of PCSK9, PCSK9 levels in health and
disease, PCSK9-drug interactions focusing on statin trials, current
approaches to PCSK9 inhibition, and recent results from
anti-PCSK9 mAb pre-clinical and clinical trials.
EDITORIAL
5 January 2015
Post IMPROVE-IT: Where to now for residual risk?
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco
An Editorial from the R3i Trustees

Well, the relief from IMPROVE-IT, reported at the recent American heart Association Scientific Sessions, was palpable (see Landmark trial). We now have evidence that lowering low-density lipoprotein cholesterol (LDL-C) beyond current targets with non-statin therapy in patients with a recent acute coronary syndrome (ACS) provides modest benefit for cardiovascular outcomes. Notably, there was also benefit in patients with diabetes.
However, it is also a salient point that in these very high risk patients, about one-third experienced further events over the 7-year study period, highlighting their persistent very high residual cardiovascular risk. Thus, while lowering LDL-C is the priority, additional therapeutic interventions are needed.
RECENT PUBLICATIONS
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.
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.
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.
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.
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.
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 dabetes mellitus, metabolic syndrome, and mixed dyslipidemia: How similar, how different, and how to treat?
Halcox J, Misra A.