The New Face of Hyperlipidemia and the Role of PCSK9 Inhibitors
Purpose of Review
To review the clinical rationale for use of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors in clinical practice.
Despite widespread use of statins for lipid lowering, many patients at high cardiovascular risk continue to demonstrate unsatisfactory cholesterol levels and experience clinical events. This highlights the ongoing need to develop additional strategies to achieve more effective risk reduction in a greater number of patients. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in the regulation of low-density lipoprotein metabolism. Inhibitory approaches that reduce PCSK9 activity have been demonstrated to produce substantive reductions in LDL cholesterol levels, when administered as either monotherapy or in addition to statin therapy. More recently, PCSK9 monoclonal antibodies have been reported to reduce cardiovascular event rates in large scale clinical trials.
Increasing evidence suggests that PCSK9 inhibitors can produce effective lipid lowering in high risk patients. Ongoing work will identify those patients most likely to derive cost effective risk reduction with their use.
KeywordsLipids Cardiovascular risk Clinical trials PCSK9
Compliance with Ethical Standards
Conflict of Interest
Stephen J. Nicholls has received research support from AstraZeneca, Amgen, Anthera, Athernova, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx and Sanofi-Regeneron; and is a consultant for Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Omthera, Roche, Takeda, Pfizer, Sanofi-Regeneron and Novo Nordisk.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 1.Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–72.CrossRefGoogle Scholar
- 12.Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541–8.CrossRefGoogle Scholar
- 23.•• Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: The glagov randomized clinical trial. JAMA. 2016;316(22):2373–84 Demonstration that PCSK9 inhibition produces incremental regression of coronary atherosclerosis in statin-treated patients. CrossRefGoogle Scholar
- 24.•• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722 Benefit of evolocumab on cardiovascular events. Google Scholar
- 28.Ridker PM, Amarenco P, Brunell R, Glynn RJ, Jukema JW, Kastelein JJ, et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: rationale and design of the studies of PCSK9 inhibition and the reduction of vascular events (SPIRE) lipid lowering and SPIRE cardiovascular outcomes trials. Am Heart J. 2016;178:135–44.CrossRefGoogle Scholar
- 30.Giugliano RP, Keech A, Murphy SA, Huber K, Tokgozoglu SL, Lewis BS, et al. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol. 2017;2(12):1385–91.CrossRefGoogle Scholar
- 31.Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50.CrossRefGoogle Scholar
- 33.https://www.tctmd.com/news/two-fourier-subgroup-analyses-show-added-benefit-evolocumab-those-pad-prior-mi. Accessed January 29, 2018.
- 34.Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation. 2018;137(4):338–50.CrossRefGoogle Scholar