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
article
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.
Topics
3Leiden.CETP miceABCA1 degradation inhibitorsAPOEApolipoprotein A-I inducerApolipoprotein A-I MilanoApolipoprotein A-I mimeticAtherosclerosisCardiovascular diseaseCETP inhibitionClinical outcomeClinical trialsDelipidated HDLFibratesGlitazonesHamsterHDL-cholesterolLCATLDL-cholesterolMouseMyocardial infarctionNiacinNon-HDL-cholesterolPPAR agonistsRabbitReconstituted HDLSR-BI inhibitorAgents affecting lipid metabolismATP binding cassette A1 degradation inhibitorCardiovascular agentCholesterol ester transfer proteinCholesterol ester transfer protein inhibitorDalcetrapibFibric acid derivativeGlitazar derivativeGlitazone derivativeHigh density lipoprotein cholesterolLiver X receptor agonistLow density lipoprotein cholesterolNicotinic acidPeptide derivativePeroxisome proliferator activated receptor agonistPlaceboReceptor blocking agentScavenger receptor BI inhibitorUnclassified drugAdverse outcomeCardiovascular riskCholesterol blood levelClinical trial (topic)Disease associationDrug effectDrug targetingHeart infarctionHumanMeta analysisMortalityNonhumanProtein expressionRandomized controlled trial (topic)Risk managementRisk reductionSystematic reviewTreatment response
TNO Identifier
528362
ISSN
00142999
Source
European Journal of Pharmacology, 763, pp. 48-63.
Pages
48-63
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