Landmark study
Landmark positive results in EMPA-REG OUTCOME study with empagliflozin, an inhibitor of sodium–glucose cotransporter 2
Focus on...
Novel antisense apolipoprotein(a) agent offers new potential for targeting lipid-related residual cardiovascular risk
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.
MSDA 2015 Congress
6 November 2015

Residual cardiovascular risk: it’s not just lipids!

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco
An Editorial from the R3i Trustees

What contributes to residual cardiovascular risk? Certainly, lipid and lipoproteins risk factors are important. Much of the focus of the Residual Risk Reduction Initiative (R3i) has been on the management of elevated triglycerides, with or without low circulating levels of high-density lipoprotein cholesterol (HDL-C). In a key meta-analysis of the major fibrate trials, targeting atherogenic dyslipidaemia was associated with a 35% relative reduction in cardiovascular risk versus 6% in individuals without this dyslipidaemia.
R3i Education Channel


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:
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:

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.

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.

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.

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.

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.