Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial
Open accessAbstract
Despite limited evidence, non-daily dosing of statins is recommended for managing muscle symptoms associated with statin therapy. We assessed the tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients having muscle symptoms associated with atorvastatin therapy. A parallel-group, outcome-assessment-blinded, randomized controlled clinical trial was conducted at Colombo South Teaching Hospital, Sri Lanka. Patients with muscle pain, tenderness or cramps alone or in combination for ≥2 weeks while on daily atorvastatin for ≥1 month, with no alternative cause, were recruited. Patient's regular atorvastatin dose was given every-other-day to those in intervention group (IG) and daily to those in control group (CG). Primary outcomes were assessed at 24 weeks and included composite of myalgia and myositis, LDL-cholesterol level and percentage reduction of LDL-cholesterol from baseline. Number recruited was 49 to IG (women:79.6%; mean-age:60.6 ± 8.7years) and 52 to CG (women:73.1%; mean-age:61.7 ± 9.8years). Mean atorvastatin dose per day was 8.6 mg (SD = 4 mg) and 17.6 mg (SD = 8.4 mg) in IG and CG, respectively. Composite of myalgia and myositis at 24 weeks was 79.6% in IG and 69.2% in CG (OR = 1.7, 95% CI 0.7-4.3; p = 0.234). IG failed to show noninferiority for mean LDL-cholesterol (difference:0.31 mmol/L; upper limit 97.5% CI:0.61 mmol/L; p for noninferiority = 0.989) and for mean percentage reduction of LDL-cholesterol from baseline (difference:3.13%; upper limit 97.5% CI:15.5%; p for noninferiority = 0.718). At 24 weeks, mean creatine kinase and discomfort due to muscle symptoms (assessed with Visual Analogue Scale) were not different between the two groups. Findings of this study do not favor every-other-day atorvastatin as an option for managing patients with muscle symptoms associated with atorvastatin therapy.
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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).”
13 RCTs conducted between 2006-2023 were included, of which five were parallel, five crossover, and three n-of-1.
“We included 13 RCTs conducted between 2006–2023, of which five were parallel RCTs [40,46–49], five were crossover RCTs [20,21,23,26,43] and three were n-of-1 RCTs [22,24,25] (S4 File, Table 1).”
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”
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]”
Data on incidence of muscle symptoms were available in five parallel-group RCTs and three crossover RCTs.
“Data on incidence of muscle symptoms were available in five parallel-group RCTs [40,46–49], and three crossover RCTs [20,21,43].”
Seven trials reported data on effectiveness.
“seven trials [40,43,46–49] reported data on effectiveness”
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”
We were not able to pool the data for effectiveness because only three parallel-group RCTs reported effectiveness with standard deviations, each using a different comparator.
“We were not able to pool the data for effectiveness, as only three parallel-group RCTs [40,47,49] reported effectiveness with standard deviations, with each trial using a different comparator.”
Many studies implemented wash-out periods or a threshold time for SAMS occurrence, which presents a difficulty for cross-over designs and particularly n-of-1 trials.
“Although many studies implemented wash-out periods [23] or a threshold time for SAMS occurrence [22,49], this presents a difficulty for cross-over designs and particularly n-of-1 trials.”
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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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 were not able to pool the data for effectiveness, as only three parallel-group RCTs [40,47,49] reported effectiveness with standard deviations, with each trial using a different comparator.”
Influential
- Authors
- Wijekoon, N., Wijekoon, S., Bulugahapitiya, U., Pathirana, N., Wickramasinghe, M., Paranavitane, S., Kottage, A., Wijayawardena, S., Karunarathne, M., Samarasinghe, M., Sumanadasa, S., & Herath, Y.
- Affiliations
- University of Sri Jayewardenepura (LK)
- Corresponding author
- Wijekoon, Nirmala
- ORCID
- Venue
- Contemporary Clinical Trials Communications
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 20
- Pages
- 100685
- ISSN
- 2451-8654 (ISSN-L)
- PMC
- PMC7726662
- OpenAlex
- W3113137810
- Cited by
- 4
- References
- 4
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Contemporary Clinical Trials Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Sri Jayewardenepura (ASP/01/RE/MED/2015/54)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- atorvastatin, statin-induced myalgia, muscle symptoms, LDL cholesterol, non-inferiority, creatine kinase, tolerability, statin adverse effects, dose reduction, hypercholesterolemia treatment, lipid-lowering therapy, Sri Lanka
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