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.

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.

• Authors: Susan Kühnast, Marta Fiocco, José W A van der Hoorn, Hans M G Princen, J Wouter Jukema
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 763 Issue Pt A Pg. 48-63 (Sep 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25989133 (Publication Type: Journal Article, Meta-Analysis, Review, Systematic Review)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Cholesterol, HDL
• Cholesterol, LDL

Topics

• Animals
• Cardiovascular Diseases (drug therapy, metabolism)
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Drug Evaluation, Preclinical
• Humans
• Randomized Controlled Trials as Topic