The use of statins in the primary prevention of cardiovascular disease (CVD) is increasing in older adults. Nonetheless, good clinical evidence for the safety and tolerability of statins in this population is limited.
We aimed to evaluate the safety and tolerability of statins in older adults without overt CVD, focusing on statin-related muscle symptoms.
Double-blinded randomised controlled trials (RCTs) of statins published before January 2012 were identified from a Cochrane review updated to 2012. Trials published between January 2012 and July 2018 were identified through the CENTRAL, MEDLINE and EMBASE databases. Eligible trials were limited to those including individuals aged ≥ 65 years without overt CVD, who were followed for at least 1 year. Trials had to have reported at least one of the outcomes of interest. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects models.
We identified 11 trials, including 18,192 participants (mean age 73.7 years; 43% females). Compared with placebo, statins neither increased the risks of muscle-related symptoms (RR 1.01; 95% CI 0.90–1.12), total adverse events (AEs) and serious AEs nor led to more total permanent treatment discontinuations and discontinuations due to AEs or specifically due to muscle-related symptoms. No evidence of heterogeneity was observed in any of these outcomes.
This meta-analysis of RCTs found no excess incidence of muscle-related symptoms, total AEs, serious AEs and treatment discontinuations attributable to statin treatment compared with placebo among older adults without CVD.
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Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3168–209.
Mortensen MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol. 2018;71(1):85–94.
Hawley CE, Roefaro J, Forman DE, Orkaby AR. Statins for primary prevention in those aged 70 years and older: a critical review of recent cholesterol guidelines. Drugs Aging. 2019;36(8):687–99.
Mortensen MB, Falk E, Schmidt M. Twenty-year nationwide trends in statin utilization and expenditure in Denmark. Circ Cardiovasc Qual Outcomes. 2017;10(7).
Ofori-Asenso R, Ilomaki J, Zomer E, Curtis AJ, Zoungas S, Liew D. A 10-year trend in statin use among older adults in Australia: an analysis using national pharmacy claims data. Cardiovasc Drugs Ther. 2018;32(3):265–72.
Salami JA, Warraich H, Valero-Elizondo J, Spatz ES, Desai NR, Rana JS, et al. National trends in statin use and expenditures in the US Adult Population From 2002 to 2013: insights From the medical expenditure panel survey. JAMA Cardiol. 2017;2(1):56–65.
Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and the need for more evidence. JAMA. 2016;316(19):1971–2.
Golomb BA. Implications of statin adverse effects in the elderly. Expert Opin Drug Saf. 2005;4(3):389–97.
Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf. 2018;17(1):25–37.
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. Aetiol Manag Eur Heart J. 2015;36(17):1012–22.
Curfman G. Risks of statin therapy in older adults. JAMA Intern Med. 2017;177(7):966.
Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep. 2010;12(3):213–20.
Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532–61.
Zhou Z, Albarqouni L, Breslin M, Curtis AJ, Nelson M. Statin-associated muscle symptoms (SAMS) in primary prevention for cardiovascular disease in older adults: a protocol for a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2017;7(9):e017587.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816.
Grundy SM. Can statins cause chronic low-grade myopathy? Ann Intern Med. 2002;137(7):617–8.
Definitions http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf. World Health Organisation. Accessed 15 Jan 2019.
Higgins J GS. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane collaboration. 2011.
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.
Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. http://handbook-5-1.cochrane.org. The Cochrane collaboration. Accessed 15 Jan 2019.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.
Wang J, Chen D, Li DB, Yu X, Shi GB. Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention: a meta-analysis. Medicine (Baltimore). 2016;95(39):e4950.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.
Higgins JP, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med. 2004;23(11):1663–82.
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21):2021–31.
Yusuf S, Lonn E, Pais P, Bosch J, Lopez-Jaramillo P, Zhu J, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med. 2016;374(21):2032–43.
Group MBHPSC, Armitage J, Bowman L, Collins R, Parish S, Tobert J. Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people. BMC Clin Pharmacol. 2009;9:6.
Furberg CD, Adams HP, Jr., Applegate WB, Byington RP, Espeland MA, Hartwell T, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation. 1994;90(4):1679–87.
Bruckert E, Lievre M, Giral P, Crepaldi G, Masana L, Vrolix M, et al. Short-term efficacy and safety of extended-release fluvastatin in a large cohort of elderly patients. Am J Geriatr Cardiol. 2003;12(4):225–31.
Chan P, Tomlinson B, Lee CB, Pan WH, Lee YS. Beneficial effects of pravastatin on fasting hyperinsulinemia in elderly hypertensive hypercholesterolemic subjects. Hypertension. 1996;28(4):647–51.
Collier DJ, Poulter NR, Dahlof B, Sever PS, Wedel H, Buch J, et al. Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian cardiac outcomes trial lipid-lowering arm. J Hypertens. 2011;29(3):592–9.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96.
Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O’Leary DH, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA. 2007;297(12):1344–53.
Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, et al. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab. 2007;92(12):4671–7.
Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809–16.
Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006;29(7):1478–85.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623–30.
Teng M, Lin L, Zhao YJ, Khoo AL, Davis BR, Yong QW, et al. Statins for primary prevention of cardiovascular disease in elderly patients: systematic review and meta-analysis. Drugs Aging. 2015;32(8):649–61.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.
Iwere RB, Hewitt J. Myopathy in older people receiving statin therapy: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(3):363–71.
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.
Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152(8):488–96 (W174).
Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395–410.
Ofori-Asenso R, Ilomaki J, Tacey M, Si S, Curtis AJ, Zomer E, et al. Predictors of first-year nonadherence and discontinuation of statins among older adults: a retrospective cohort study. Br J Clin Pharmacol. 2019;85(1):227–35.
Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526–34.
Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473–81.
Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287(5):622–7.
Bitzur R, Cohen H, Kamari Y, Harats D. Intolerance to statins: mechanisms and management. Diabetes Care. 2013;36(Suppl 2):S325–30.
The authors thank Dr. Frank Brouwers for providing unpublished individual patient data from PREVEND IT, AstraZeneca for providing the data from the METEOR trial and Pfizer for providing the data from the BONE and ASPEN trials.
No sources of funding were used to conduct this study or prepare this manuscript.
Conflict of interest
MN has participated on an advisory board for Amgen, who make a lipid-lowering agent. ZZ, LA, AC and MB have no conflicts of interest that are directly relevant to the content of this article.
Not applicable for this meta-analysis.
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Zhou, Z., Albarqouni, L., Curtis, A.J. et al. The Safety and Tolerability of Statin Therapy in Primary Prevention in Older Adults: A Systematic Review and Meta-analysis. Drugs Aging (2020). https://doi.org/10.1007/s40266-019-00736-y