LAUSR

For many decades, epidemiological studies have supported an inverse relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of cardiovascular disease. This led to focus the efforts not only on the development of lipid-lowering drugs (first of all statins), but also on the development of drugs able to increase HDL-C levels. Among these drugs, fibrates, niacin and cholesteryl ester transfer protein (CETP) inhibitors have played a major role. Despite the observations arising from epidemiological studies, interventional trials with HDL-C-raising drugs have generally failed to demonstrate a beneficial effect on cardiovascular outcomes. Mendelian randomization studies have shown that genetic variants associated exclusively with higher HDL-C levels do not associate with a decreased risk for myocardial infarction (MI). Further, a U-shaped relationship exists between HDLC levels and cardiovascular mortality, where extremely low and extremely high HDL-C levels are associated with higher cardiovascular mortality. All these observations provide a challenge to the rationale for pharmacological interventions aimed at increasing HDL-C levels to reduce cardiovascular risk. In their study, Riaz and colleagues performed a large meta-analysis to evaluate the impact of HDL-Craising pharmacological interventions on the risk of cardiovascular outcomes. They analyzed data from 31 randomised controlled clinical trials using fibrates, niacin and CETP inhibitors in more than 150,000 patients. Looking at the lipid profile, fibrates and niacin greatly reduced triglyceride (TG) levels, whereas HDL-C levels were only marginally increased (3.30 and 7.65 mg/dl, respectively); CETP inhibitors greatly induced HDL-C levels (56.30 mg/dl), and all of these drugs similarly reduced low-density lipoprotein cholesterol (LDL-C) levels ( 10 mg/dl). Overall, cardiovascular mortality was not affected by treatment with these drugs (relative risk (RR) 0.94, 95% confidence interval (CI) 0.89–1.00), while a significant reduction in MI risk (RR 0.87, CI 95% 0.82–0.93) was observed, mainly driven by trials with fibrates (RR 0.80, 95% CI 0.73– 0.87). Neither niacin nor CETP inhibitor trials showed a reduction in this parameter. Interestingly, the analysis based on the use, or not, of statins as background therapy showed that cardiovascular mortality and MI risk were significantly reduced in trials with no statin as background therapy (mainly fibrate trials), whereas adding a HDL-C-raising drug to a background statin therapy failed to show a clinical benefit, in line with a previous meta-analysis. It is likely that fibrates may induce a positive clinical impact through their effect on TGs, which is most marked compared with the effect on HDL-C (only marginal) or LDL-C levels. Since increased levels of TGs are not associated with increased risk for coronary heart disease when adjusted for other lipid factors, it is likely that not TGs per se, but instead the cholesterol content in remnant lipoproteins represents an independent risk factor for ischaemic heart disease. Thus, since the benefit of fibrate therapy is primarily due to lowering of the atherogenic apolipoprotein B (apoB)-containing lipoproteins, which is reflected in lowering of plasma apoB, it is likely that the benefit of fibrates reported in this meta-analysis is related to a possible effect on remnant lipoproteins rather than the minimal effect on HDL-C. In a Mendelian randomization study, variants related to the CETP gene have been identified to generate a genetic risk score. The CETP score was associated with higher HDL-C levels, lower LDL-C and concordantly lower apoB levels and a lower risk of major vascular events; this association was similar to that observed with the hydroxyl-methylglutaryl coenzyme A reductase (HMGCR; the target of statins) score. In patients with higher scores for both CETP