The 17th International Symposium
on Atherosclerosis
23-26 May    Amsterdam    The Netherlands
The R3i announces with regret the
retirement of Professor Jean Davignon
from the R3i Trustee Board.
He will remain as
Honorary Vice President of the R3i.
Landmark study
Triglyceride-rich lipoproteins: an important contributor to residual cardiovascular risk in acute coronary syndrome
Focus on...
Targeting apolipoprotein CIII: potential for reducing cardiovascular risk in type 2 diabetes
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
8 July 2015

Beyond the PCSK9 decade: what's next?

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

The last decade in lipid research has been widely regarded as the "PCSK9 decade". Genetic studies have driven the development of novel therapies targeting the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), the first of which are likely to be licensed later this year.
Yet while lowering low-density lipoprotein (LDL) cholesterol beyond current guideline targets is likely to confer additional benefit, as suggested by IMPROVE-IT and by preliminary PCSK9 inhibition trial analyses, such efficacious treatments will not eliminate residual cardiovascular events in high-risk patients, especially those with atherogenic dyslipidaemia characteristic of insulin resistant conditions.
R3i Education Channel

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.

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.

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.

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.

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.

**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: