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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

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Author: Kühnast, S. · Fiocco, M. · Hoorn, J.W.A. van der · Princen, H.M.G. · Jukema, J.W.
Source:European Journal of Pharmacology, 763, 48-63
Identifier: 528362
doi: doi:10.1016/j.ejphar.2015.03.089
Keywords: Biology · 3Leiden.CETP mice · ABCA1 degradation inhibitors · APOE · Apolipoprotein A-I inducer · Apolipoprotein A-I Milano · Apolipoprotein A-I mimetic · Atherosclerosis · Cardiovascular disease · CETP inhibition · Clinical outcome · Clinical trials · Delipidated HDL · Fibrates · Glitazones · Hamster · HDL-cholesterol · LCAT · LDL-cholesterol · Mouse · Myocardial infarction · Niacin · Non-HDL-cholesterol · PPAR agonists · Rabbit · Reconstituted HDL · SR-BI inhibitor · Agents affecting lipid metabolism · ATP binding cassette A1 degradation inhibitor · Cardiovascular agent · Cholesterol ester transfer protein · Cholesterol ester transfer protein inhibitor · Dalcetrapib · Fibric acid derivative · Glitazar derivative · Glitazone derivative · High density lipoprotein cholesterol · Liver X receptor agonist · Low density lipoprotein cholesterol · Nicotinic acid · Peptide derivative · Peroxisome proliferator activated receptor agonist · Placebo · Receptor blocking agent · Scavenger receptor BI inhibitor · Unclassified drug · Adverse outcome · Cardiovascular risk · Cholesterol blood level · Clinical trial (topic) · Disease association · Drug effect · Drug targeting · Heart infarction · Human · Meta analysis · Mortality · Nonhuman · Protein expression · Randomized controlled trial (topic) · Risk management · Risk reduction · Systematic review · Treatment response · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences


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. © 2015 Elsevier B.V. All rights reserved.