Skip to main content
NCBI home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021 Mar;25(16):1–62. doi: 10.3310/hta25160

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs.

Emily Herrett, Elizabeth Williamson, Kieran Brack, Alexander Perkins, Andrew Thayne, Haleema Shakur-Still, Ian Roberts, Danielle Prowse, Danielle Beaumont, Zahra Jamal, Ben Goldacre, Tjeerd van Staa, Thomas M MacDonald, Jane Armitage, Michael Moore, Maurice Hoffman, Liam Smeeth
PMCID: PMC8020196  PMID: 33709907

Abstract

BACKGROUND

Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis.

OBJECTIVES

To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related.

DESIGN

A series of 200 double-blinded N-of-1 trials.

SETTING

Participants were recruited from 50 general practices in England and Wales.

PARTICIPANTS

Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms.

INTERVENTIONS

Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo.

MAIN OUTCOME MEASURES

The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful.

RESULTS

A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods.

CONCLUSIONS

Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial.

FUTURE WORK

We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications.

LIMITATIONS

This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Plain language summary

Statins are one of the most commonly prescribed drugs in the UK. There is strong evidence that they are effective in safely reducing heart disease; however, there is some doubt about whether or not statins cause muscle pain, stiffness or weakness. This research has been carried out to understand the effect of statins on muscle symptoms. To answer our question, we asked 200 volunteers from across England and Wales to participate in the study. Patients who joined the study either had recently stopped taking statins because of muscle symptoms or were considering stopping because of muscle symptoms. Patients who participated were randomly assigned to a sequence of six 2-month treatment periods during which they received either statins or a placebo. Neither patients nor their general practitioner knew which tablet they were receiving. This helped to reduce bias in the data. At the end of each treatment period, patients were asked to report any muscle symptoms, or any other symptoms, that they experienced. The key result of this work is that patients reported no difference, on average, in their muscle symptoms between periods of taking a statin and periods of taking a placebo. We also assessed the impact on the patient’s quality of life by looking at how statins affected the following areas: general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. As with muscle symptoms, there was no evidence of a difference between statin and placebo periods. The majority of patients who finished the trial decided to continue using statins after the trial. Future research should be carried out to assess different statin doses, as higher doses are often used following a heart attack. In addition, further work is needed to see how the approach we used could be adopted into everyday clinical care.

Full text of this article can be found in Bookshelf.

References

  1. Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ 2021;372:N135. https://doi.org/10.1136/bmj.n135 doi: 10.1136/bmj.n135. [DOI] [PMC free article] [PubMed]
  2. Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397–405. https://doi.org/10.1016/S0140-6736(14)61368-4 doi: 10.1016/S0140-6736(14)61368-4. [DOI] [PubMed]
  3. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2016;393:407–15. doi: 10.1016/S0140-6736(18)31942-1. [DOI] [PMC free article] [PubMed]
  4. 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;388:2532–61. https://doi.org/10.1016/S0140-6736(16)31357-5 doi: 10.1016/S0140-6736(16)31357-5. [DOI] [PubMed]
  5. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123. https://doi.org/10.1136/bmj.f6123 doi: 10.1136/bmj.f6123. [DOI] [PubMed]
  6. Malhotra A. Saturated fat is not the major issue. BMJ 2013;347:f6340. https://doi.org/10.1136/bmj.f6340 doi: 10.1136/bmj.f6340. [DOI] [PubMed]
  7. Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, Turchin A. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526–34. https://doi.org/10.7326/0003-4819-158-7-201304020-00004 doi: 10.7326/0003-4819-158-7-201304020-00004. [DOI] [PMC free article] [PubMed]
  8. Garavalia L, Garavalia B, Spertus JA, Decker C. Exploring patients’ reasons for discontinuance of heart medications. J Cardiovasc Nurs 2009;24:371–9. https://doi.org/10.1097/JCN.0b013e3181ae7b2a doi: 10.1097/JCN.0b013e3181ae7b2a. [DOI] [PMC free article] [PubMed]
  9. Nielsen SF, Nordestgaard BG. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study. Eur Heart J 2016;37:908–16. https://doi.org/10.1093/eurheartj/ehv641 doi: 10.1093/eurheartj/ehv641. [DOI] [PubMed]
  10. Schaffer AL, Buckley NA, Dobbins TA, Banks E, Pearson SA. The crux of the matter: did the ABC’s catalyst program change statin use in Australia? Med J Aust 2015;202:591–5. https://doi.org/10.5694/mja15.00103 doi: 10.5694/mja15.00103. [DOI] [PubMed]
  11. Matthews A, Herrett E, Gasparrini A, Van Staa T, Goldacre B, Smeeth L, Bhaskaran K. Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data. BMJ 2016;353:i3283. https://doi.org/10.1136/bmj.i3283 doi: 10.1136/bmj.i3283. [DOI] [PMC free article] [PubMed]
  12. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA 2002;287:622–7. https://doi.org/10.1001/jama.287.5.622 doi: 10.1001/jama.287.5.622. [DOI] [PubMed]
  13. Vinogradova Y, Coupland C, Brindle P, Hippisley-Cox J. Discontinuation and restarting in patients on statin treatment: prospective open cohort study using a primary care database. BMJ 2016;353:i3305. https://doi.org/10.1136/bmj.i3305 doi: 10.1136/bmj.i3305. [DOI] [PMC free article] [PubMed]
  14. De Vera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol 2014;78:684–98. https://doi.org/10.1111/bcp.12339 doi: 10.1111/bcp.12339. [DOI] [PMC free article] [PubMed]
  15. 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;9:758–69. https://doi.org/10.1016/j.jacl.2015.08.006 doi: 10.1016/j.jacl.2015.08.006. [DOI] [PubMed]
  16. Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006;114:2788–97. https://doi.org/10.1161/CIRCULATIONAHA.106.624890 doi: 10.1161/CIRCULATIONAHA.106.624890. [DOI] [PubMed]
  17. Wieseler B, Wolfram N, McGauran N, Kerekes MF, Vervölgyi V, Kohlepp P, et al. Completeness of reporting of patient-relevant clinical trial outcomes: comparison of unpublished clinical study reports with publicly available data. PLOS Med 2013;10:e1001526. https://doi.org/10.1371/journal.pmed.1001526 doi: 10.1371/journal.pmed.1001526. [DOI] [PMC free article] [PubMed]
  18. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248–61. https://doi.org/10.1056/NEJMoa0706201 doi: 10.1056/NEJMoa0706201. [DOI] [PubMed]
  19. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. https://doi.org/10.1016/S0140-6736(02)09327-3 doi: 10.1016/S0140-6736(02)09327-3. [DOI]
  20. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181–92. https://doi.org/10.1016/S0140-6736(11)60739-3 doi: 10.1016/S0140-6736(11)60739-3. [DOI] [PMC free article] [PubMed]
  21. 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;36:1012–22. https://doi.org/10.1093/eurheartj/ehv043 doi: 10.1093/eurheartj/ehv043. [DOI] [PMC free article] [PubMed]
  22. American College of Cardiology. Statin Intolerance Tool. URL: http://tools.acc.org/StatinIntolerance/#!/ (accessed 10 October 2019).
  23. Laufs U, Filipiak KJ, Gouni-Berthold I, Catapano AL, SAMS expert working group. Practical aspects in the management of statin-associated muscle symptoms (SAMS). Atheroscler Suppl 2017;26:45–55. https://doi.org/10.1016/S1567-5688(17)30024-7 doi: 10.1016/S1567-5688(17)30024-7. [DOI] [PubMed]
  24. Guyatt G, Sackett D, Taylor DW, Chong J, Roberts R, Pugsley S. Determining optimal therapy – randomized trials in individual patients. N Engl J Med 1986;314:889–92. https://doi.org/10.1056/NEJM198604033141406 doi: 10.1056/NEJM198604033141406. [DOI] [PubMed]
  25. Herrett E, Williamson E, Beaumont D, Prowse D, Youssouf N, Brack K, et al. Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care. BMJ Open 2017;7:e016604. https://doi.org/10.1136/bmjopen-2017-016604 doi: 10.1136/bmjopen-2017-016604. [DOI] [PMC free article] [PubMed]
  26. National Institute for Health and Care Excellence (NICE). Cardiovascular Disease: Risk Assessment and Reduction, Including Lipid Modification. NICE Clinical Guideline 181. London: NICE; 2014.
  27. McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988;18:1007–19. https://doi.org/10.1017/s0033291700009934 doi: 10.1017/s0033291700009934. [DOI] [PubMed]
  28. Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. PLOS ONE 2011;6:e28124. https://doi.org/10.1371/journal.pone.0028124 doi: 10.1371/journal.pone.0028124. [DOI] [PMC free article] [PubMed]
  29. Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Acad Emerg Med 1996;3:142–6. https://doi.org/10.1111/j.1553-2712.1996.tb03402.x doi: 10.1111/j.1553-2712.1996.tb03402.x. [DOI] [PubMed]
  30. Gallagher EJ, Liebman M, Bijur PE. Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001;38:633–8. https://doi.org/10.1067/mem.2001.118863 doi: 10.1067/mem.2001.118863. [DOI] [PubMed]
  31. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012;6:208–15. https://doi.org/10.1016/j.jacl.2012.03.003 doi: 10.1016/j.jacl.2012.03.003. [DOI] [PubMed]
  32. Keech A, Collins R, MacMahon S, Armitage J, Lawson A, Wallendszuset K, et al. Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 1994;15:255–69. https://doi.org/10.1093/oxfordjournals.eurheartj.a060485 doi: 10.1093/oxfordjournals.eurheartj.a060485. [DOI] [PubMed]
  33. Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Hals EK, et al. Assessment of pain. Br J Anaesth 2008;101:17–24. https://doi.org/10.1093/bja/aen103 doi: 10.1093/bja/aen103. [DOI] [PubMed]
  34. Pocock SJ. Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation. Controlled Clin Trials 1997;18:530–45. https://doi.org/10.1016/S0197-2456(97)00008-1 doi: 10.1016/S0197-2456(97)00008-1. [DOI] [PubMed]
  35. Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, et al. N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med 2020;383:2182–4. https://doi.org/10.1056/NEJMc2031173 doi: 10.1056/NEJMc2031173. [DOI] [PubMed]
  36. Cholesterol Treatment Trialists’ Collaboration. Protocol for analyses of adverse event data from randomized controlled trials of statin therapy. Am Heart J 2016;176:63–9. https://doi.org/10.1016/j.ahj.2016.01.016 doi: 10.1016/j.ahj.2016.01.016. [DOI] [PMC free article] [PubMed]
  37. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014;12:51. https://doi.org/10.1186/1741-7015-12-51 doi: 10.1186/1741-7015-12-51. [DOI] [PMC free article] [PubMed]
  38. 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;389:2473–81. https://doi.org/10.1016/S0140-6736(17)31075-9 doi: 10.1016/S0140-6736(17)31075-9. [DOI] [PubMed]
  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;167:221–7. https://doi.org/10.7326/M16-0838 doi: 10.7326/M16-0838. [DOI] [PubMed]
  40. Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, Cho L. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597–603. https://doi.org/10.1016/j.ahj.2013.06.004 doi: 10.1016/j.ahj.2013.06.004. [DOI] [PMC free article] [PubMed]
  41. He Y, Li X, Gasevic D, Brunt E, McLachlan F, Millenson M, et al. Statins and multiple noncardiovascular outcomes: umbrella review of meta-analyses of observational studies and randomized controlled trials. Ann Intern Med 2018;169:543–53. https://doi.org/10.7326/M18-0808 doi: 10.7326/M18-0808. [DOI] [PubMed]

RESOURCES