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Announcing a new member of the R3i Board of Trustees
Professor Pierre Amarenco, Professor of Neurology at Paris-Diderot, Sorbonne University in Paris, France, joins the Board of Trustees.
Landmark study
More questions about HDL: CHI-SQUARE trial with HDL-mimetic fails
Focus on...
APOC3: a potential target for residual cardiovascular risk?
PCSK9 slidekit
LINKS
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.
R3i activities on Kyoto 2014 congress
MSDA Kyoto 2014: A highlight of R3i activities
In 2014, the Residual Risk Reduction Initiative (R3i), together with the Japan Atherosclerosis Society (JAS), Japan Diabetes Society (JDS) and Japan Society for the Study of Obesity (JASSO), welcome clinicians and researchers to Kyoto, Japan for the 9th Annual Metabolic Syndrome, type 2 Diabetes and Atherosclerosis (MSDA) Congress, 12-14 September, 2014.
Preventive cardiology
R3i session
September 18, 2014   13h - 14h
J. Ch. Fruchart (France) Residual risk idea
H. Ginsberg (USA) Statins, fibrates and diabetes mellitus
R. Ceska (Czech Republic) Complex reduction of cardiometabolic risk in clinical practice
K. Parhofer (Germany) Secondary hyperlipidaemias - focused on endocrine diseases
EDITORIAL
24 July 2014
Lipid-related residual cardiovascular risk: a new therapeutic target on the horizon
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans
An Editorial from the R3i Trustees

Current therapeutic options are insufficient to address the high level of residual cardiovascular risk in high-risk patients that persists despite best-evidence-based treatments. As reinforced in the recent Call to Action position statement,1 the R3i believe that atherogenic dyslipidaemia, elevated triglycerides and low plasma high-density lipoprotein (HDL) cholesterol, is an important contributor to lipid-related residual cardiovascular risk. However, it is also clear that we need novel strategies to target this.
R3i Goes Global:
Latin America launch at SOCESP March 22, 2014
Over 6,000 cardiologists attended the Sociedade de Cardiologia do Estado de Sao Paulo Congress (SOCESP), a clear indication of the tsunami of cardiometabolic disease facing this region.
sao-paolo SOCESP 2014

‘Latin America poses a real challenge, due to escalating rates of obesity, diabetes and cardiometabolic disease. Integration of Latin America within the R3i provides an important opportunity to target the high residual cardiovascular and microvascular risk in this region.‘

- Prof. Jean-Charles Fruchart, President, R3i Foundation

R3i Goes Global
Key interviews from SOCESP 2014
RECENT PUBLICATIONS
• 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.