HDL and CETP Inhibition: Will This DEFINE the Future?

OPINION STATEMENT: The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit.