The class
A review argues the failure of CETP inhibitors and niacin to reduce cardiovascular events undermines the HDL cardioprotection hypothesis (Drugs 2020)
Original title: The Rise and Fall "ing" of the HDL Hypothesis
This review traces how early epidemiologic studies showing an inverse correlation between HDL cholesterol and coronary heart disease, together with the role of HDL in reverse cholesterol transport, supported the hypothesis that HDL is cardioprotective, while more recent epidemiologic data instead suggest a U-shaped relationship between HDL cholesterol and coronary heart disease. Randomized clinical trials of drugs that substantially raise plasma HDL cholesterol, including nicotinic acid and cholesteryl ester transfer protein (CETP) inhibitors, failed to reduce major adverse cardiovascular events, challenging the cardioprotective HDL hypothesis. The authors propose that HDL quality and function may only be optimal when driven by de novo synthesis of apolipoprotein A-I, and that inhibiting HDL turnover with currently available agents yields ineffective HDL, warranting trials of newer drugs that increase de novo apoA-I production.
Original abstract
Earlier epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDLc) and coronary heart disease (CHD). This observation along with the finding that reverse cholesterol transport is mediated by HDL, supported the hypothesis that the HDL molecule has a cardioprotective role. More recently, epidemiological data suggest a U-shaped curve correlating HDLc and CHD. In addition, randomized clinical trials of drugs that significantly increase plasma HDLc levels, such as nicotinic acid and cholesterol ester transfer protein (CETP) inhibitors failed to show a reduction in major adverse cardiovascular events. These observations challenge the hypothesis that HDL has a cardioprotective role. It is possible that HDL quality and function is optimal only when de novo synthesis of apo A-I occurs. Inhibition of turnover of HDL with currently available agents yields HDL molecules that are ineffective in reverse cholesterol transport. To test this hypothesis, newer therapeutic drugs that increase de novo production of HDL and apo A-I should be tested in clinical trials.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.