Plenary speakers in the spotlight: Bengt Jönsson, John Kastelein

Professor John Kastelein

NEW PERSPECTIVES IN HYPOLIPIDEMIC TREATMENT

John J.P. Kastelein is Professor of Medicine and chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he holds the Strategic Chair of Genetics of Cardiovascular Disease. His current research interests focus on the aetiology, diagnosis, prevention and treatment of hypertriglyceridaemia, hypercholesterolaemia and low HDL cholesterol, with a key interest in the genetic basis of dyslipidaemia.

There is unequivocal evidence that a low plasma level of high-density lipoprotein (HDL) cholesterol is a cardiovascular risk factor. This has provided the rationale for the HDL hypothesis: that raising plasma HDL cholesterol levels may translate to improved cardiovascular benefit. Possible therapeutic strategies in development include cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein (apo) A-1 mimetics, and reconstituted HDL or apoA-1. Emerging data with a number of novel CETP inhibitors are promising, although there is still uncertainty regarding the extent of HDL cholesterol raising required and whether this translates to reduction in cardiovascular events.

Recently, there has been emerging evidence that the functionality of HDL, rather than plasma concentrations, may be more relevant to atheroprotection. HDL are highly heterogeneous in terms of structure, intravascular metabolism and biological activity. Thus, improving HDL functionality may offer the potential to reverse the process of atherosclerosis. Here, apoA-I mimetic peptides, either in single or tandem formulation, hold promise, given evidence that they have anti-inflammatory, antioxidant, and antiatherogenic activities.

The results of ongoing trials with these investigational agents will be fundamental to addressing outstanding uncertainties regarding the HDL hypothesis, and whether improving HDL functionality rather than plasma levels is more relevant.

Key references

1. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE.Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109.

2. 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. Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers. J Am Coll Cardiol 2011;57:63-9.

3. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study Group. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2010;376:333-9.

Forrás: The European Atherosclerosis Society website