LDL and apoB
Meta-analysis finds LDL-C and non-HDL-C, not HDL-C, predict lesion reduction across CETP-expressing animal and human trials (Eur J Pharmacol 2015)
Original title: Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raising: A systematic review and meta-analysis of relevant preclinical studies and clinical trials
This systematic review and meta-analysis compared non-HDL-C/LDL-C-lowering with HDL-C-raising strategies for preventing atherosclerosis, spanning preclinical studies in cholesteryl ester transfer protein-expressing animals and clinical outcome trials including AIM-HIGH, HPS2-THRIVE, and dal-OUTCOMES, all of which failed to meet their primary goals. In preclinical data, total cholesterol and non-HDL-C were significantly associated with atherosclerotic lesion area (R2 = 0.258, P = 0.045 and R2 = 0.760, P < 0.001, respectively), but HDL-C was not (R2 = 0.030, P = 0.556). In clinical trials, non-fatal myocardial infarction risk was significantly reduced overall (pooled odds ratio 0.87 [0.81-0.94]) and after excluding trials with off-target adverse effects (0.85 [0.78-0.93]), but all-cause mortality was unaffected (odds ratio 1.05 [0.99-1.10]). Change in LDL-C, but not HDL-C, showed a trend toward association with reduced myocardial infarction risk (P = 0.066 versus P = 0.955). The authors conclude LDL-C and non-HDL-C lowering has a well-established protective role, while the benefit of raising HDL-C remains undefined.
Original abstract
Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R(2)=0.258, P=0.045; R(2)=0.760, P<0.001), but not for HDL-C (R(2)=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99-1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.