DOI:10.1097/MOL.0000000000000476 Although the causal relationship between apolipoprotein-B (apoB) containing lipoproteins, particularly LDL, and atherosclerotic vascular disease has been amply reinforced by recent trials [1 & ], interventions to raise HDL… Click to show full abstract
DOI:10.1097/MOL.0000000000000476 Although the causal relationship between apolipoprotein-B (apoB) containing lipoproteins, particularly LDL, and atherosclerotic vascular disease has been amply reinforced by recent trials [1 & ], interventions to raise HDL have proved ineffective in lowering Cardiovascular disease (CVD) risk, and in some cases, problematic due to potentially harmful adverse actions. The latest randomized controlled trial of an HDL-cholesterol increasing agent was the REVEAL study, which investigated the effect of the Cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on preventing coronary events [2 && ]. More than 30 000 participants with atherosclerotic vascular disease on background intensive statin treatment were randomized to 100 mg of anacetrapib once daily or matching placebo. After a follow-up of 4.1 years, the anacetrapib group had a 9% lower risk (95% confidence interval 3–15%) for the primary endpoint. HDL-cholesterol on the CETP inhibitor was elevated by 104%, whereas non-HDLcholesterol levels decreased by 18%: results in line with a large phase 3 trial by Ballantyne et al. [3]. Using estimates of benefit derived from statin trials, it was predicted that a non-HDL-cholesterol reduction of 18% should lead to about a 10% relative risk reduction for coronary events, as was observed. As with other trials of drugs in this class, there was no evidence that the benefits of anacetrapib therapy derived from its HDL increasing capacity, but rather from its action on non-HDL-cholesterol (i.e. apoB containing lipoproteins) [2 && ]. Randomized controlled trials investigating other CETP inhibitors have demonstrated a variable LDL-cholesterol lowering effect, but no significant reduction in the incidence of cardiovascular events. In a complementary approach, Ference et al. [4 & ] performed a Mendelian randomization ‘trial’ to investigate the association between changes in lipoprotein levels and risk of cardiovascular events by first examining common variants within the CETP gene alone and then by combining these with variants in the HMGCR gene (to mimic statin therapy). Key
               
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