Clinical Outcomes in Trials Evaluating Lipid-Lowering Drugs
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While statins have formed the cornerstone of strategies for cardiovascular prevention, the residual risk related to low-density lipoprotein cholesterol (LDL-C) and other lipoprotein factors provides a landscape for development of new therapies. However, a number of lipid-modifying therapies have failed to reduce cardiovascular event rates in contemporary clinical trials of statin-treated patients. The factors considered in outcome measure selection for clinical trials of novel lipid-lowering therapies are reviewed. Evaluation of lipid-modifying drugs in clinical trials spans a spectrum from their effects on conventional circulating lipid parameters through to their impact on atherosclerotic plaque and ultimately clinical outcomes. The design of these trials has an important impact on the result and ultimate interpretation of these studies.
Compliance with ethical standards
No external funding was used in the preparation of this manuscript.
Conflicts of interest
Stephen J. Nicholls has received research support from Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Resverlogix, Roche, and Sanofi-Regeneron and is a consultant for AstraZeneca, Boehringer Ingelheim, CSL Behring, Kowa, Eli Lilly, Merck, Takeda, Pfizer, Roche, and Sanofi-Regeneron. Alex Brown has received research support from Sanofi-Regeneron. Julie Butters, Liddy Griffith, and Susan Kim have no potential conflicts to disclose.
- 3.Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–934.CrossRefPubMedGoogle Scholar
- 13.AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med. 2011;365(24):2255–67.Google Scholar
- 14.HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–12.Google Scholar
- 18.Kallend DG, Reijers JA, Bellibas SE, et al. A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease. Eur Heart J Cardiovasc Pharmacother. 2016;2:23–9.CrossRefPubMedGoogle Scholar
- 20.The Medicines Company discontinues development of MDCO-216, its investigational cholesterol efflux promoter [press release]. Parsippany, NJ: The Medicines Company. http://www.themedicinescompany.com/investors/news/medicines-company-discontinues-development-mdco-216-its-investigational-cholesterol. Accessed 7 Nov 2016.
- 26.Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001;357:577–81.CrossRefPubMedGoogle Scholar
- 44.Gibson CM, Korjian S, Tricoci P, et al. Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): a phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. Am Heart J. 2016;180:22–8.CrossRefPubMedGoogle Scholar
- 50.Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. J Am Coll Cardiol. 2015;65:1552–61.CrossRefPubMedGoogle Scholar