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.
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.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands; Department of Cardiology, LUMC, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Kühnast
authors.affiliation: Department of Medical Statistics and Bioinformatics, LUMC, Leiden, The Netherlands; Mathematical Institute, Leiden University, Leiden, The Netherlands.
authors.forename: Marta
authors.initials: M
authors.lastname: Fiocco
authors.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands; Department of Cardiology, LUMC, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.affiliation: TNO-Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands. Electronic address: hans.princen@tno.nl.
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.affiliation: Department of Cardiology, LUMC, Leiden, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D016032:Randomized Controlled Trials as Topic
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL
keywords: ABCA1 degradation inhibitors; APOE*3Leiden.CETP mice; Apolipoprotein A-I Milano; Apolipoprotein A-I inducer; Apolipoprotein A-I mimetic; Atherosclerosis; CETP inhibition; Cardiovascular disease; Clinical outcome; Clinical trials; Delipidated HDL; Fibrates; Glitazones; HDL-C-raising pharmaceutical interventions; HDL-cholesterol; Hamster; LCAT; LDL-cholesterol; Meta-analysis; Mouse; Myocardial infarction; Niacin; Non-HDL-cholesterol; PPAR agonists; Preclinical studies; Rabbit; Randomised controlled trials; Reconstituted HDL; SR-BI inhibitor; Systematic review