Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis

Context Epidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer protein (CETP) inhibitors. Objectives To assess alternative methods to predict clinical response of CETP inhibitors. Methods Meta-regression analysis on raising HDL-C drugs (statins, fibrates, niacin) in randomised controlled trials. Results 51 trials in secondary prevention with a total of 167 311 patients for a follow-up > 1 year where HDL-C was measured at baseline and during treatment. The meta-regression analysis showed no significant association between change in HDL-C (treatment vs comparator) and log risk ratio (RR) of clinical endpoint (non-fatal myocardial infarction or cardiac death). CETP inhibitors data are consistent with this finding (RR: 1.03; P5-P95: 0.99-1.21). A prespecified sensitivity analysis by drug class suggested that the strength of relationship might differ between pharmacological groups. A significant association for both statins (p<0.02, log RR=-0.169-0.0499* HDL-C change, R-2=0.21) and niacin (p=0.02, log RR=1.07-0.185* HDL-C change, R-2=0.61) but not fibrates (p=0.18, log RR=-0.367+0.077* HDL-C change, R-2=0.40) was shown. However, the association was no longer detectable after adjustment for low-density lipoprotein cholesterol for statins or exclusion of open trials for niacin. Conclusions Meta-regression suggested that CETP inhibitors might not influence coronary risk. The relation between change in HDL-C level and clinical endpoint may be drug dependent, which limits the use of HDL-C as a surrogate marker of coronary events. Other markers of HDL function may be more relevant.