Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raisingA systematic review and meta-analysis of relevant preclinical studies and clinical trials

详细信息    查看全文

• 作者：Susan Kü ; hnast^a ; ^b ; ^c ; Marta Fiocco^d ; ^e ; José ; W.A. van der Hoorn^a ; ^b ; ^c ; Hans M.G. Princen^a ; ¹ ; ^{hans.princen@tno.nl" class="auth_mail" title="E-mail the corresponding author} ; J. Wouter Jukema^b ; ¹
• 关键词：Cardiovascular disease ; Clinical outcome ; Myocardial infarction ; LDL-cholesterol ; Non-HDL-cholesterol ; HDL-cholesterol ; Atherosclerosis ; Clinical trials ; APOE*3Leiden.CETP mice ; Mouse ; Rabbit ; Hamster ; Niacin ; Fibrates ; Glitazones ; PPAR agonists ; CETP inhibition ; SR-BI inhibitor ; ABCA1 degradation inhibitors ; Reconstituted HDL ; Delipidated HDL ; Apolipoprotein A-I Milano ; Apolipoprotein A-I mimetic ; Apolipoprotein A-I inducer ; LCAT
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：15 September 2015
• 年：2015
• 卷：763
• 期：part_PA
• 页码：48-63
• 全文大小：1518 K

文摘

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 (R²=0.258, P=0.045; R²=0.760, P<0.001), but not for HDL-C (R²=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.