High-density lipoprotein cholesterol and residual cardiometabolic risk in metabolic syndrome

Abstract

It has long been recognized that elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of cardiovascular disease (CVD) and that pharmacologic therapy to decrease LDL-C significantly reduces cardiovascular events. Despite the effectiveness of statins for CVD risk reduction, even optimal LDL-lowering therapy alone fails to avert approximately 60% to 70% of CVD cases, and the incidence of CVD mortality continues to grow. A low plasma concentration of high-density lipoprotein cholesterol (HDL-C) is also associated with increased risk of CVD and is 1 component of metabolic syndrome, a cluster of interrelated CVD risk factors. HDL stimulates reverse cholesterol transport from the peripheral tissues to the liver for removal from the body, prevents deleterious effects of LDL on endothelial function, acts as an antioxidant, and also possesses anti-inflammatory, antithrombotic, and antiapoptotic effects. Some of the treatments that increase HDL-C concentrations have been shown to reduce atheroma volume and may prevent the formation of new atherosclerotic lesions, thereby reducing the risk of CVD. For these reasons, increasing HDL-C concentrations has become a potentially attractive therapeutic target for individuals who are at increased risk of CVD, including those with metabolic syndrome. Traditional strategies to increase HDL-C include the use of niacin, statins, and fibric acid derivatives. Pharmacotherapies that have recently been developed and are currently being evaluated include inhibition of the enzyme cholesteryl ester transfer protein (CETP) and antagonism of the endocannabinoid CB1 receptor. Initial studies of CETP inhibitors suggest that these agents may markedly increase HDL-C concentrations. Clinical trials with rimonabant, a CB1 receptor antagonist, have demonstrated significant weight loss as well as increased HDL-C levels and reduced triglyceride levels.