Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Meta-Analysis

PCSK9 Inhibitors and Ezetimibe Monotherapy in Patients Not Receiving Statins: A Meta-Analysis of Randomized Trials

Author(s): Benjamin Benhuri, Hiroki Ueyama, Hisato Takagi, Alexandros Briasoulis and Toshiki Kuno*

Volume 19, Issue 4, 2021

Published on: 07 August, 2020

Page: [390 - 397] Pages: 8

DOI: 10.2174/1570161118666200807114559

Price: $65

Abstract

Background: Statins are the mainstay of treatment for low-density lipoprotein cholesterol (LDL-C) lowering, however, some patients cannot tolerate statins because of adverse effects. Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are alternative treatment options. The purpose of this meta-analysis was to compare LDL-C reduction with ezetimibe vs PCSK9i in patients not on statins.

Methods: PubMed and EMBASE were searched until 14th March 2020 for randomized clinical trials (RCTs) assessing the efficacy of ezetimibe vs PCSK9i in patients not on statins. The primary outcome was a reduction in LDL-C levels. A subgroup analysis of statin intolerant patients was also performed.

Results: We identified 8 RCTs that enrolled a total of 1602 patients comparing the two pharmacotherapies. PCSK9i lowered LDL-C levels significantly more than ezetimibe (mean difference (MD): -36.5; 95% confidence interval (CI) [-38.3, -34.7, p<0.00001, I2=4%]. In the statin intolerant subgroup, PCSK9i showed significantly greater reduction in LDL-C levels compared with ezetimibe (MD: -36.1; 95% CI [-39.2, -33.1, p<0.00001, I2=21%]. There were no significant differences in LDL-C reduction between different PCSK9i dosages (140 mg once every 2 weeks vs 420 mg once every 4 weeks) (MD: -1.87; 95% CI [-4.45, 0.71, p<0.16, I2=0].

Conclusion: Among patients who are statin intolerant or not receiving statins, PCSK9i use is associated with significantly lower LDL-C levels than after treatment with ezetimibe. PCSK9i might be useful in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) in this subset of patients.

Keywords: PCSK9, ezetimibe, atherosclerosis, statin intolerance, HMG-CoA, statins.

Graphical Abstract
[1]
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 2019; 74(10): 1376-414.
[http://dx.doi.org/10.1016/j.jacc.2019.03.009] [PMID: 30894319]
[2]
Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the european association for cardiovascular prevention & rehabilitation (EACPR). Atherosclerosis 2016; 252: 207-74.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.037] [PMID: 27664503]
[3]
Shaya FT, Sing K, Milam R, et al. Lipid-lowering efficacy of ezetimibe in patients with atherosclerotic cardiovascular disease: a systematic review and meta-analyses. Am J Cardiovasc Drugs 2020; 20(3): 239-48.
[http://dx.doi.org/10.1007/s40256-019-00379-9] [PMID: 31724105]
[4]
Toth PP, Worthy G, Gandra SR, et al. systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc 2017; 6(10)e005367
[http://dx.doi.org/10.1161/JAHA.116.005367] [PMID: 28971955]
[5]
Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother 2010; 44(9): 1410-21.
[http://dx.doi.org/10.1345/aph.1P150] [PMID: 20702755]
[6]
Pirillo A, Catapano AL. Statin intolerance: diagnosis and remedies. Curr Cardiol Rep 2015; 17(5): 27.
[http://dx.doi.org/10.1007/s11886-015-0582-z] [PMID: 25894795]
[7]
Stroes ES, Thompson PD, Corsini A, et al. European atherosclerosis society consensus panel. 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.
[http://dx.doi.org/10.1093/eurheartj/ehv043] [PMID: 25694464]
[8]
Guyton JR, Bays HE, Grundy SM, Jacobson TA. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol 2014; 8(3): 72-81.
[http://dx.doi.org/10.1016/j.jacl.2014.03.002] [PMID: 24793444]
[9]
Colantonio LD, Huang L, Monda KL, et al. Adherence to high-intensity statins following a myocardial infarction hospitalization among medicare beneficiaries. JAMA Cardiol 2017; 2(8): 890-5.
[http://dx.doi.org/10.1001/jamacardio.2017.0911] [PMID: 28423147]
[10]
Rosenson RS, Baker S, Banach M, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol 2017; 70(10): 1290-301.
[http://dx.doi.org/10.1016/j.jacc.2017.07.752] [PMID: 28859793]
[11]
Haukka J, Niskanen L, Partonen T, Lönnqvist J, Tiihonen J. Statin usage and all-cause and disease-specific mortality in a nationwide study. Pharmacoepidemiol Drug Saf 2012; 21(1): 61-9.
[http://dx.doi.org/10.1002/pds.2255] [PMID: 21956915]
[12]
Serban MC, Colantonio LD, Manthripragada AD, 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.
[http://dx.doi.org/10.1016/j.jacc.2016.12.036] [PMID: 28302290]
[13]
Zhan S, Tang M, Liu F, et al. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database of Systematic Reviews 2018; 11CD012502
[http://dx.doi.org/10.1002/14651858.CD012502.pub2]
[14]
Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab in statin-intolerant patients over 3 years: open-label treatment period of the ODYSSEY ALTERNATIVE trial. J Clin Lipidol 2020; 14(1): 88-97.
[http://dx.doi.org/10.1016/j.jacl.2020.01.001] [PMID: 32192644]
[15]
Kuno T, Ueyama H, Takagi H, et al. Meta-analysis of Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention. Am J Cardiol 2020; 125(4): 521-7.
[http://dx.doi.org/10.1016/j.amjcard.2019.11.022] [PMID: 31839147]
[16]
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151(4)W65-94
[http://dx.doi.org/10.7326/0003-4819-151-4-200908180-00136] [PMID: 19622512]
[17]
Koba S, Inoue I, Cyrille M, et al. Evolocumab vs. Ezetimibe in Statin-Intolerant Hyperlipidemic Japanese Patients: Phase 3 GAUSS-4 Trial. J Atheroscler Thromb 2020; 27(5): 471-84.
[PMID: 31748467]
[18]
Koren MJ, Lundqvist P, Bolognese M, et al. MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014; 63(23): 2531-40.
[http://dx.doi.org/10.1016/j.jacc.2014.03.018] [PMID: 24691094]
[19]
Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012; 380(9858): 1995-2006.
[http://dx.doi.org/10.1016/S0140-6736(12)61771-1] [PMID: 23141812]
[20]
Moriarty PM, Thompson PD, Cannon CP, et al. ODYSSEY ALTERNATIVE Investigators. 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.
[http://dx.doi.org/10.1016/j.jacl.2015.08.006] [PMID: 26687696]
[21]
Nissen SE, Stroes E, Dent-Acosta RE, et al. GAUSS-3 Investigators.Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA 2016; 315(15): 1580-90.
[http://dx.doi.org/10.1001/jama.2016.3608] [PMID: 27039291]
[22]
Roth EM, Taskinen M-R, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 2014; 176(1): 55-61.
[http://dx.doi.org/10.1016/j.ijcard.2014.06.049] [PMID: 25037695]
[23]
Stroes E, Colquhoun D, Sullivan D, et al. GAUSS-2 Investigators 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.
[http://dx.doi.org/10.1016/j.jacc.2014.03.019] [PMID: 24694531]
[24]
Sullivan D, Olsson AG, Scott R, 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.
[http://dx.doi.org/10.1001/jama.2012.25790] [PMID: 23128163]
[25]
Guglielmi V, Bellia A, Pecchioli S, et al. Effectiveness of adherence to lipid lowering therapy on LDL-cholesterol in patients with very high cardiovascular risk: A real-world evidence study in primary care. Atherosclerosis 2017; 263: 36-41.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.05.018] [PMID: 28599257]
[26]
Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013; 158(7): 526-34.
[http://dx.doi.org/10.7326/0003-4819-158-7-201304020-00004] [PMID: 23546564]
[27]
Alonso R, Cuevas A, Cafferata A. Diagnosis and management of statin intolerance. J Atheroscler Thromb 2019; 26(3): 207-15.
[http://dx.doi.org/10.5551/jat.RV17030] [PMID: 30662020]
[28]
Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Arch Med Sci 2015; 11(1): 1-23.
[http://dx.doi.org/10.5114/aoms.2015.49807] [PMID: 25861286]
[29]
Bruckert E, Hayem G, Dejager S, Yau C, Bégaud 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.
[http://dx.doi.org/10.1007/s10557-005-5686-z] [PMID: 16453090]
[30]
Bitzur R, Cohen H, Kamari Y, et al. Intolerance to statins: mechanisms and management. Diabetes Care 2013; 36(Suppl. 2): S325-30.
[http://dx.doi.org/10.2337/dcS13-2038]
[31]
Grundy SM. Can statins cause chronic low-grade myopathy? Ann Intern Med 2002; 137(7): 617-8.
[http://dx.doi.org/10.7326/0003-4819-137-7-200210010-00015] [PMID: 12353951]
[32]
Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis 2019; 290: 140-205.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.014] [PMID: 31591002]
[33]
Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy: a systematic review. Ann Intern Med 2014; 160(7): 468-76.
[http://dx.doi.org/10.7326/M13-2526] [PMID: 24514899]
[34]
Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med 2009; 265(5): 568-80.
[http://dx.doi.org/10.1111/j.1365-2796.2008.02062.x] [PMID: 19141093]
[35]
Knopp RH, Dujovne CA, Le Beaut A, Lipka LJ, Suresh R, Veltri EP. EP. Ezetimbe Study Group 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.
[PMID: 12846338]
[36]
Cicero AF, Tartagni E, Ertek S. Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data. Expert Opin Drug Saf 2014; 13(8): 1023-30.
[http://dx.doi.org/10.1517/14740338.2014.932348] [PMID: 24961142]
[37]
Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR. Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors. Clin Res Cardiol Suppl 2019; 14(S1): 45-50.
[http://dx.doi.org/10.1007/s11789-019-00099-z] [PMID: 30838555]
[38]
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 2016 acc expert consensus decision pathway on the role of non-statin therapies for ldl-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American college of cardiology task force on expert consensus decision pathways. J Am Coll Cardiol 2017; 70(14): 1785-822.
[http://dx.doi.org/10.1016/j.jacc.2017.07.745] [PMID: 28886926]
[39]
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.
[http://dx.doi.org/10.7326/M16-0838] [PMID: 28738423]
[40]
Bradley CK, Shrader P, Sanchez RJ, Peterson ED, Navar AM. The patient journey with proprotein convertase subtilisin/kexin type 9 inhibitors in community practice. J Clin Lipidol 2019; 13(5): 725-34.
[http://dx.doi.org/10.1016/j.jacl.2019.06.008] [PMID: 31371271]
[41]
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376(18): 1713-22.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[42]
Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the odyssey outcomes trial. J Am Coll Cardiol 2019; 73(4): 387-96.
[http://dx.doi.org/10.1016/j.jacc.2018.10.039] [PMID: 30428396]
[43]
Spitthöver R, Röseler T, Julius U, et al. Real-world study: Escalating targeted lipid-lowering treatment with PCSK9-inhibitors and lipoprotein apheresis. J Clin Apher 2019; 34(4): 423-33.
[http://dx.doi.org/10.1002/jca.21695] [PMID: 30817043]
[44]
Patel J, Martin SS, Banach M. Expert opinion: the therapeutic challenges faced by statin intolerance. Expert Opin Pharmacother 2016; 17(11): 1497-507.
[http://dx.doi.org/10.1080/14656566.2016.1197202] [PMID: 27254275]
[45]
Doshi JA, Puckett JT, Parmacek MS, Rader DJ. prior authorization requirements for proprotein convertase subtilisin/kexin type 9 inhibitors across US private and public payers. Circ Cardiovasc Qual Outcomes 2018; 11(1)e003939
[http://dx.doi.org/10.1161/CIRCOUTCOMES.117.003939] [PMID: 29326146]
[46]
Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P. Updated cost-effectiveness analysis of evolocumab in patients with very high-risk atherosclerotic cardiovascular disease. JAMA Cardiol 2019; 4(7): 691-5.
[http://dx.doi.org/10.1001/jamacardio.2019.1647] [PMID: 31166576]
[47]
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372(25): 2387-97.
[http://dx.doi.org/10.1056/NEJMoa1410489] [PMID: 26039521]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy