Abstract
Purpose
Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2 years in statin-intolerant patients.
Methods
Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC.
Results
A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97–5.02 mmol/L (192–194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events.
Conclusion
Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.
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References
Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104(2):109–24.
Koskinas KC, Siontis GCM, Piccolo R, Mavridis D, Raber L, Mach F, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J. 2018;39(14):1172–80.
Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014;168(1):6–15.
Irwin JC, Khalesi S, Fenning AS, Vella RK. The effect of lipophilicity and dose on the frequency of statin-associated muscle symptoms: a systematic review and meta-analysis. Pharmacol Res. 2018;128:264–73.
Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403–14.
Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther. 2007;29(8):1761–70.
Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. The National Lipid Association’s Muscle Safety Expert P. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S58–71.
Stock J. Statin-associated muscle symptoms EAS Consensus Panel paper focuses on this neglected patient group. Atherosclerosis. 2015;242(1):346–50.
Harrison TN, Hsu JY, Rosenson RS, Levitan EB, Muntner P, Cheetham TC, et al. Unmet patient need in statin intolerance: the clinical characteristics and management. Cardiovasc Drugs Ther. 2018;32(1):29–36.
Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012–22.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.
Knopp RH, Dujovne CA, Le Beaut A, Lipka LJ, Suresh R, Veltri EP, et al. Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies. Int J Clin Pract. 2003;57(5):363–8.
Kusters DM, Caceres M, Coll M, Cuffie C, Gagne C, Jacobson MS, et al. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia. J Pediatr. 2015;166(6):1377–84 e1–3.
Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497–506.
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.
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.
Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Kassahun H, et al. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol. 2017;2:598–607.
Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, et al. Clinical pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin Pharmacokinet. 2018;57(7):769–79.
Wasserman SM, Sabatine MS, Koren MJ, Giugliano RP, Legg JC, Emery MG, et al. Comparison of LDL-C reduction using different evolocumab doses and intervals: biological insights and treatment implications. J Cardiovasc Pharmacol Ther 2018:1074248418774043.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.
Blom DJ, Djedjos CS, Monsalvo ML, Bridges I, Wasserman SM, Scott R, et al. Effects of evolocumab on vitamin E and steroid hormone levels: results from the 52-week, phase 3, double-blind, randomized, placebo-controlled DESCARTES study. Circ Res. 2015;117(8):731–41.
Serban MC, Colantonio LD, Manthripragada AD, Monda KL, Bittner VA, Banach M, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol. 2017;69(11):1386–95.
Zhang H, Plutzky J, Shubina M, Turchin A. Continued statin prescriptions after adverse reactions and patient outcomes: a cohort study. Ann Intern Med. 2017;167(4):221–7.
Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758–69.
Rosenson RS, Baker S, Banach M, Borow KM, Braun LT, Bruckert E, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol. 2017;70(10):1290–301.
Gandra SR, Villa G, Fonarow GC, Lothgren M, Lindgren P, Somaratne R, et al. Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States. Clin Cardiol. 2016;39(6):313–20.
Acknowledgments
This work was supported by Amgen Inc., Thousand Oaks, CA, USA. The authors thank Wanda Krall, PhD (on behalf of Amgen Inc.), and Tim Peoples, MA, ELS, CMPP (Amgen Inc.) for editorial assistance.
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Amgen Inc. funded this analysis and provided support for the manuscript.
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L.C. has conducted research with Amgen and Esperion, has been a consultant for Amgen, and has been an unpaid consultant for Lilly. R.D. is a former employee of Amgen Inc. and a current employee and stockholder of Esperion. E.S.G.S. has received lecture fees for institution from Amgen, Sanofi, Chiesi, Novartis, and Ionis/Akcea. E.A.S. has received consultancy and expert witness fees from Amgen, and consultancy fees from The Medicines Company, AstraZeneca, Moderna, CVS/Caremark, and Gemphire. D.S. has received research support from Amgen, Merck, and Amarin; advisory board fees from Amgen, Merck, Abbott/Mylan, and Sanofi; and modest honoraria for educational programs from Abbott/Mylan and AbbVie. A.R. and R.S. are employees of Amgen and hold Amgen stock/stock options. R.S. is an inventor on at least one pending patent involving evolocumab. A.F. is a contractor for Amgen Inc. R.S.R. has received research support for institution from Akcea, Amgen, AstraZeneca, The Medicines Company, Regeneron, and Sanofi; has served on advisory boards for Akcea, Amgen, CVS Caremark, Regeneron, and Sanofi; has received honoraria from Akcea, Kowa, and Pfizer; and has received royalties from UpToDate, Inc.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Cho, L., Dent, R., Stroes, E.S. et al. Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies. Cardiovasc Drugs Ther 32, 365–372 (2018). https://doi.org/10.1007/s10557-018-6817-7
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DOI: https://doi.org/10.1007/s10557-018-6817-7