Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials
Open accessAbstract
Objective: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. Design: Series of randomised, placebo controlled n-of-1 trials. Setting: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. Participants: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. Interventions: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. Main outcome measures: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. Results: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo −0.11, 95% confidence interval −0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. Conclusions: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. Trial registration: ISRCTN30952488 , EUDRACT 2016-000141-31, NCT02781064 .
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Most trials used a mean difference in pain intensity between statin and comparator group.
“most trials [22,23,25,40,49] used a mean difference in pain intensity between statin and comparator group”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [25]
The Results (Primary outcome) report a mean difference in symptom scores between statin and placebo periods. But the Methods (Interventions and outcomes) define the measured outcome as muscle symptoms—including pain, weakness, tenderness, stiffness, and cramp—not pain intensity specifically. This paper supports the comparison, but not that characterization of its outcome. (LLM, conf=0.84)
Experimental — accuracy not yet measuredN-of-1 trials demand long-term investment of each individual, which can lead to high rates of missing data.
“On the contrary, n-of-1 trials demand long-term investment of each individual, which can lead to high rates of missing data [22,25].”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [25]
The Methods describe repeated two-month treatment periods, and Results > Numbers analysed reports that 43% of participants did not complete the trial and that symptom reporting fell from 82% in period 1 to 58% in period 6 (page not provided). This supports a lengthy trial with substantial missing data, but the paper does not establish that the time commitment caused the missing data or that this is true of n-of-1 trials generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured23 studies were included for data extraction, with 9 RCTs analyzed quantitatively.
“23 studies were included for data extraction [20–26,35–50], with 9 RCTs analyzed quantitatively.”
New evidence on the management of SAMS has become available from randomized controlled trials and observational data.
“New evidence on the management of SAMS have since become available both from randomized control trials (RCTs) and from observational data [20–26].”
8 out of 13 RCTs were judged at low risk of bias.
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
Most trials used statins with low to moderate intensity.
“Most trials used statins with low to moderate intensity [20,21,24–26,40,43,46,48,49]”
Ten trials provided data on incidence of muscle symptoms.
“Ten trials [20,21,25,26,40,43,46–49] provided data on incidence of muscle symptoms”
Nine trials assessed statin against placebo.
“nine trials assessed statin against placebo [20–26,43]”
The trials comparing statin-based therapy to placebo showed similar between-group incidence of muscle symptoms and statin-discontinuation rate.
“The trials comparing statin-based therapy to placebo showed similar between-group incidence of muscle symptoms and statin-discontinuation rate. [20,21,25,26,43,47]”
Nine trials provided data for treatment discontinuation due to muscle symptoms.
“Nine trials [22,25,26,40,43,46–48] provided data for treatment discontinuation due to muscle symptoms”
In earlier studies, SAMS were assessed through incidence of SAMS and later quantified with the VAS.
“In earlier studies, SAMS were assessed through incidence of SAMS [17,43,46–48] and later quantified with the VAS (visual analogue scale) [22,23,25,40,49].”
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Cited by
Sorted by citations
Chou, R., Cantor, A., Dana, T., Wagner, J., Ahmed, A. Y., Fu, R., & Ferencik, M. (2022) · JAMA · doi:10.1001/jama.2022.12138 · Cited by 287 · see citing works
Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment
Howard, J. P., Wood, F. A., Finegold, J. A., Nowbar, A. N., Thompson, D. M., Arnold, A. D., Rajkumar, C. A., Connolly, S., Cegla, J., Stride, C., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.07.022 · Cited by 198 · see citing works
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Kraut, R., Wierenga, F., Molstad, E., Korownyk, C., Perry, D., Dennett, L., & Garrison, S. (2023) · PLOS ONE · doi:10.1371/journal.pone.0295857 · Cited by 7 · see citing works
Aebi, P. S., Villoz, F., Bührer, J., Lyko, C., Abolhassani, N., Del Giovane, C., Gencer, B., Rodondi, N., & Blum, M. R. (2025) · PLOS One · doi:10.1371/journal.pone.0338575
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
Influential
- Authors
- Herrett, E., Williamson, E., Brack, K., Beaumont, D., Perkins, A., Thayne, A., Shakur-Still, H., Roberts, I., Prowse, D., Goldacre, B., van Staa, T., MacDonald, T. M., Armitage, J., Wimborne, J., Melrose, P., Singh, J., Brooks, L., Moore, M., Hoffman, M., & Smeeth, L.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- University of Oxford (GB)
- University of Dundee (GB)
- Guy's Hospital (GB)
- Royal Free London NHS Foundation Trust (GB)
- University of Southampton (GB)
- National Institute for Health and Care Research (GB)
- Corresponding author
- Smeeth, Liam
- ORCID
- Herrett, Emily
- Williamson, Elizabeth
- Brack, Kieran
- Beaumont, Danielle
- Perkins, Alexander
- Thayne, Andrew
- Shakur-Still, Haleema
- Roberts, Ian
- Prowse, Danielle
- Goldacre, Ben
- van Staa, Tjeerd
- MacDonald, Thomas M
- Armitage, Jane
- Wimborne, Jon
- Melrose, Paula
- Singh, Jayshireen
- Brooks, Lucy
- Moore, Michael
- Hoffman, Maurice
- Smeeth, Liam
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2021-02-24
- Volume
- 372
- Pages
- n135
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC7903384
- OpenAlex
- W3118007133
- Cited by
- 191
- References
- 5
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 29 · 2023: 35 · 2022: 42 · 2021: 40
- FWCI
- 34.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BMJ (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Funders
- National Institute for Health and Care Research (14/49/15, 14/49/159)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statins, atorvastatin, muscle symptoms, statin intolerance, rhabdomyolysis, statin withdrawal, N-of-1 trials, drug tolerability
- MeSH terms
- Atorvastatin, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, United Kingdom, Humans, Male, Middle Aged, Muscular Diseases, Primary Health Care, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Symptom Assessment
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