Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis
Open accessAbstract
Background: Statin-associated muscle symptoms (SAMS) are an obstacle in the prevention of cardiovascular events. A systematic assessment of the evidence of interventions in the setting of SAMS is lacking. Objective: To assess the evidence of strategies of statin-based vs non-statin based therapies in patients with a history of SAMS. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest databases were searched from inception up to February 2024.We included randomized controlled trials (RCTs) and non-randomized studies involving patients with history of prior SAMS, comparing statin-based therapy to a comparator. We followed the PRISMA guideline with multiple authors involved at each stage. A random-effect model was used in the meta-analysis. We defined the primary outcome as incidence of muscle symptoms. The secondary outcomes were proportion of statin discontinuation of statin-based therapy within patients with history of SAMS. The protocol was registered on PROSPERO (CRD42020202619). Results: In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months). Our confidence in the body of evidence using GRADE was moderate for the primary outcome and low-moderate for the secondary outcome. In RCTs among patients with history of SAMS, there was high heterogeneity in the statin regimens and controls (placebo/non-daily dosing/ezetimibe/PCSK9 inhibitors). In RCTs, the meta-analysis showed no difference between statin-based and control groups in the incidence of muscle symptoms (OR 1.19, 95%CI 0.86–1.64, I 2 : 46.3%)). Therapy discontinuation due to muscle symptoms in RCTs was higher in the statin-based than the comparator groups (OR 1.48, 95%CI 1.03–2.12, I 2 = 17.6%). Conclusion: Our findings suggest that patients with a history of SAMS can be re-challenged with statins. More high-quality evidence is needed to strengthen guidelines regarding the management of SAMS.
AI snapshot
Written from the paper’s full text.
TL;DR
In patients with prior statin-associated muscle symptoms (SAMS), pooled RCT evidence found no significant difference in incident muscle symptoms between statin-based therapy and comparators, but statin-based therapy was associated with higher discontinuation due to muscle symptoms. The authors conclude that statin re-challenge may be feasible, while calling for higher-quality and standardized evidence.
Key findings
- Across 23 studies (13 RCTs, 2 prospective and 8 retrospective studies), RCTs included 1,868 participants and non-RCTs included 47,628 participants, with follow-up from 12 weeks to 31 months.
- In RCTs, the incidence of muscle symptoms did not differ significantly between statin-based and control groups: OR 1.19, 95% CI 0.86–1.64, I² = 46.3%.
- Treatment discontinuation due to muscle symptoms was higher in statin-based than comparator groups: OR 1.48, 95% CI 1.03–2.12, I² = 17.6%.
- GRADE certainty was moderate for incident muscle symptoms and low to moderate for discontinuation; the authors describe the resulting recommendation as weak for both outcomes.
Methods
- Systematic review and random-effects meta-analysis following PRISMA, registered on PROSPERO (CRD42020202619), including RCTs and non-randomized studies of adults with a history of SAMS comparing statin-based therapy with a comparator.
- Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest; the abstract reports search up to February 2024, while the Methods state the search was extended to February 2025.
- Primary outcome was incidence of muscle symptoms; secondary outcomes included treatment discontinuation due to muscle symptoms and effectiveness defined as change in LDL-cholesterol from baseline. RCTs were pooled quantitatively; non-randomized studies were summarized qualitatively because of low quality.
Limitations
- The authors report high methodological and statistical heterogeneity, inconsistent SAMS definitions and outcome measurements across studies, diverse comparators, and inability to pool effectiveness data; publication bias could not be assessed statistically because of intervention heterogeneity.
- They note that odds ratios can overestimate effects for common events, that the included population may not represent the general clinical SAMS population, that non-randomized studies were generally of low quality, and that GRADE certainty was only moderate or low to moderate.
- The text also makes evident a discrepancy between the abstract’s February 2024 search end date and the Methods’ February 2025 date, and the authors state that harmonizing SAMS definitions would have required individual participant data beyond the scope of the review.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
131 of 233 cited sources checked · 100 supported · 2 flagged · accuracy not yet measured
- Premisecitation
Intolerance to statins is linked with an elevated risk of cardiovascular disease.
“Intolerance to statins is linked with an elevated risk of cardiovascular disease [3].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] MF Piepoli, 2016, 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), Eur Heart J source
Section 3a.7.12 (pp. 39–40) says statins reduce cardiovascular morbidity and mortality and discusses alternative treatment for patients intolerant to statins. It does not state that statin intolerance itself is linked to an elevated risk of cardiovascular disease; the claim infers that association from the benefits of statin treatment. (LLM, conf=0.79)
Experimental — accuracy not yet measured
- Study design and conductown data
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).”
Quote in the paperNot a substantial claim6 of 8 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
- Premisecitation
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].”
Quote in the paperSubstantial claim6 of 7 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [24] FA Wood, 2020, N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects, N Engl J Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
- Study design and conductown data
Insufficient information was provided regarding the methodology to address carryover effects during the data analysis in two crossover trials.
“Insufficient information was provided regarding the methodology to address carryover effects during the data analysis in two crossover trials [24,43].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [24] FA Wood, 2020, N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects, N Engl J Med source
The trial description (Abstract; page not provided) reports randomized monthly statin, placebo, and no-treatment periods and describes the primary analysis, but it does not address carryover effects or how they were handled in data analysis. Searches for carryover and residual effects found no relevant passage in our copy; the text refers readers to a supplementary methods section not present in the passages reviewed. (LLM, conf=0.68)
Experimental — accuracy not yet measured - cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- Study design and conductown data
Three trials showed some concern on the randomization process.
“Three trials showed some concern on the randomization process [43,46,47].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
Two trials did not provide enough information on pre-specified outcomes to allow assessment of reporting bias.
“Two trials did not provide enough information on pre-specified outcomes to allow assessment of reporting bias [21,47].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
The Methods (Statistical Analyses; page unavailable) describe planned pain analyses, and the Abstract (Trial Registration; page unavailable) gives a registration number. Neither passage assesses whether information on pre-specified outcomes was sufficient to judge reporting bias. A second trial and that comparative assessment are not addressed in this paper. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingcitation
Comparing statin-based therapy to ezetimibe only, two trials found significantly lower LDL-C levels in the statin-based group.
“Comparing statin-based therapy to ezetimibe only, two trials found no significant difference in muscle symptoms, but significantly lower LDL-C levels in the statin-based group [46,48].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
The Discussion reports an exploratory 31.9% LDL-C reduction with atorvastatin, while the Efficacy section reports a 14.6% reduction with ezetimibe (page numbers not provided). That supports a larger reduction in the statin arm, but the paper does not report a statistically significant atorvastatin-versus-ezetimibe comparison. Its reported significant LDL-C comparison is alirocumab versus ezetimibe. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
- Findingcitation
Non-daily vs. daily statin dosing resulted in an odds ratio of 0.58 (95% CI 0.23-1.43) for incidence of muscle symptoms.
“Non-daily vs. daily statin dosing resulted in an OR of 0.58 (95% CI 0.23–1.43). [34,51,52].”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [34] DR Elbourne, 2002, Meta-analyses involving cross-over trials: methodological issues, Int J Epidemiol source
The section on cross-over trials with binary data reports odds ratios for severe hypoglycaemia with insulin lispro versus regular insulin, not muscle symptoms with non-daily versus daily statin dosing. Searches for statin dosing, muscle symptoms, and the stated OR and confidence interval found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [51] T Li, 2015, Design, Analysis, and Reporting of Crossover Trials for Inclusion in a Meta-Analysis, PLoS One source
The Results sections on reporting and meta-analysis inclusion discuss estimates from crossover trials, not statin dosing or muscle symptoms (page numbers unavailable). Searches for the stated odds ratio and for statin muscle symptoms found no passage supporting the claimed result. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [52] M Geissbühler, 2021, Most published meta-regression analyses based on aggregate data suffer from methodological pitfalls: a meta-epidemiological study, BMC Med Res Methodol source
The Methods > Analysis passage describes odds ratios for associations between study characteristics and methodological pitfalls, not statin dosing or muscle symptoms. A search of our copy for non-daily versus daily statin dosing and for the reported OR and confidence interval found no passage addressing that comparison; page numbers were unavailable. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Findingcitation
Comparing statin-based therapy to ezetimibe only, two trials found no significant difference in muscle symptoms.
“Comparing statin-based therapy to ezetimibe only, two trials found no significant difference in muscle symptoms, but significantly lower LDL-C levels in the statin-based group [46,48].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
The Safety and tolerability section reports similar myalgia rates with atorvastatin (27.0%) and ezetimibe (23.4%), and the Discussion reports a larger LDL-C reduction with atorvastatin (31.9%) than with ezetimibe (14.6%). Our copy does not report a statistical test establishing no significant difference in muscle symptoms between those two arms, or a significant LDL-C difference between them. This paper is one trial, so it cannot itself substantiate the claim about two trials. (LLM, conf=0.79)
Experimental — accuracy not yet measured - cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
- Findingcitation
One trial compared statin-based therapy with red-yeast rice and found no difference in muscle symptoms or therapy discontinuation.
“One trial compared a statin-based therapy with red-yeast rice and found no difference in muscle symptoms or therapy discontinuation.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
- Findingown data
Data on treatment discontinuation due to muscle symptoms were available in three parallel-group RCTs and two crossover RCTs.
“Data on treatment discontinuation were available in three parallel-group RCTs [40,46,48], and two crossover RCTs [20,43].”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- Premisecitation
Current guidelines for management of SAMS mostly rely on expert opinions.
“This variability is evident in the current guidelines, which mostly rely on expert opinions. [6,9].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] I Bytyci, 2021, The prevalence of statin intolerance worldwide: a systematic review and meta-analysis with 4,143,517 patients, European Heart Journal source
- cites [9] F Mach, 2020, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk, Eur Heart J source
Section 8.1.4.1 provides suggested management for statin-associated muscle symptoms, and the Monitoring section gives practical steps for patients with muscle symptoms. The guidelines define one evidence level as expert consensus, but our copy does not establish that SAMS guidance—or current SAMS guidelines generally—mostly relies on expert opinion; it also discusses trial evidence relevant to statin intolerance. No page numbers are available in the indexed passages. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingcitation
The outcomes of interest of our systematic review were not the main outcomes or the pre-specified outcomes of some studies.
“The quality of non-randomized study was generally poor and the outcomes of interest of our systematic review were not the main outcomes or the pre-specified outcomes of some studies [20,46,47].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
The paper’s “Primary and Secondary End Points” section identifies LDL-C changes as the coprimary outcomes and says cardiovascular events were adjudicated rather than listing them among the primary efficacy outcomes. This supports the concern if those events were outcomes of interest to the review, but the cited paper cannot establish what outcomes the citing authors’ review sought or whether they were prespecified in other studies. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
The Efficacy outcome measures section identifies LDL-C change as this trial’s primary endpoint, while the Study limitations section says cardiovascular outcomes were being evaluated in another study. This supports the possibility that outcomes extracted from this trial were not its main outcomes, but the cited paper does not identify the systematic review’s outcomes or establish whether those particular outcomes were prespecified. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
In RCTs, the meta-analysis showed no difference between statin-based and control groups in the incidence of muscle symptoms (OR 1.19, 95% CI 0.86-1.64, I2 46.3%).
“In RCTs, the meta-analysis showed no difference between statin-based and control groups in the incidence of muscle symptoms (OR 1.19, 95%CI 0.86–1.64, I2: 46.3%)).”
Quote in the paperSubstantial claim - Findingown data
Therapy discontinuation due to muscle symptoms in RCTs was higher in the statin-based than the comparator groups (OR 1.48, 95% CI 1.03-2.12, I2 17.6%).
“Therapy discontinuation due to muscle symptoms in RCTs was higher in the statin-based than the comparator groups (OR 1.48, 95%CI 1.03–2.12, I2 = 17.6%).”
Quote in the paperSubstantial claim - Findingown data
In RCTs among patients with a history of SAMS, there was high heterogeneity in the statin regimens and controls.
“In RCTs among patients with history of SAMS, there was high heterogeneity in the statin regimens and controls (placebo/non-daily dosing/ezetimibe/PCSK9 inhibitors).”
Quote in the paperNot a substantial claim - Findingown data
The odds ratio for incidence of muscle symptoms was 0.96 (95% CI 0.53-1.73) for statin vs. ezetimibe.
“the odds ratio (OR) was 0.96 (95% CI 0.53–1.73) for statin vs. ezetimibe”
Quote in the paperSubstantial claim - Findingown data
The meta-analysis of incidence of muscle symptoms showed high heterogeneity (overall I2: 46.3%).
“The analysis showed high heterogeneity (overall I2: 46.3%);”
Quote in the paperNot a substantial claim - Findingown data
The odds ratio for incidence of muscle symptoms was 1.57 (95% CI 0.92-2.66) for statin vs PCSK9 inhibitors.
“and 1.57 (95%CI 0.92–2.66) for statin vs PCSK9 inhibitors”
Quote in the paperNot a substantial claim - Findingown data
The only trial comparing non-daily statin dosing to daily dosing had an OR of 0.58 (0.23-1.43).
“The only trial comparing non-daily statin dosing to daily dosing found patterns of lower muscle symptoms incidence in daily dosing but with large confidence intervals and did not report on discontinuation rate (OR 0.58 (0.23–1.43)).”
Quote in the paperNot a substantial claim- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
- Findingown data
The odds ratio for incidence of muscle symptoms was 1.27 (95% CI 0.77-2.08) for statin vs. placebo.
“and 1.27 (95% CI 0.77–2.08) for statin vs. placebo.”
Quote in the paperNot a substantial claim - Findingown data
There was high methodological and statistical heterogeneity in the trials for incidence of muscle symptoms.
“however there was high methodological and statistical heterogeneity in the trials.”
Quote in the paperNot a substantial claim - Findingown data
Statistical heterogeneity for treatment discontinuation was low (I2 = 17.6%).
“Statistical heterogeneity was low (I2 = 17.6%).”
Quote in the paperNot a substantial claim - Findingown data
Overall, the odds ratio for incidence of muscle symptoms was 1.19 (95% CI 0.86-1.64).
“Overall, the OR for the incidence of muscle symptoms was 1.19 (0.86–1.64), however there was high methodological and statistical heterogeneity in the trials.”
- Also stated in: § Discussion · hedged
“the incidence of muscle symptoms appeared similar between groups (OR 1.19); however, the wide confidence interval (0.86–1.64) includes both the possibility of harm and no effect”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Findingown data
The odds ratio for treatment discontinuation due to muscle symptoms was 0.98 (95% CI 0.51-1.90) for statin vs. ezetimibe.
“In the subgroup analysis the OR was 0.98 (95%CI 0.51–1.90) for statin vs. ezetimibe”
Quote in the paperNot a substantial claim - Findingown data
The odds ratio for treatment discontinuation due to muscle symptoms was 1.41 (95% CI 0.57-3.49) for statin vs. placebo.
“and 1.41 (95%CI 0.57–3.49) for statin vs. placebo.”
Quote in the paperNot a substantial claim - Findingown data
Our search in grey literature uncovered an unpublished trial.
“Despite these limitations, our search in grey literature uncovered an unpublished trial.”
Quote in the paperNot a substantial claim - Findingreasoning
The variability is also reflected in the statistical heterogeneity observed in the meta-analysis.
“This variability is also reflected in the statistical heterogeneity observed in the meta-analysis.”
Quote in the paperNot a substantial claim - Findingown data
Within this subgroup, the study by Nissen et al. was the principal contributor to heterogeneity, given its relatively strong effect size (OR = 1.97) and large statistical weight (19.0%).
“Within this subgroup, the study by Nissen et al. was the principal contributor to heterogeneity, given its relatively strong effect size (OR = 1.97) and large statistical weight (19.0%).”
Quote in the paperNot a substantial claim - Findingown data
Subgroup analysis showed that the heterogeneity stems mainly from the analysis of the "Statin versus Placebo or Statin & Ezetimibe versus Ezetimibe" subgroup, which exhibited the highest within-group heterogeneity (I2 = 54.8%).
“Subgroup analysis showed that the heterogeneity stems mainly from the analysis of the “Statin versus Placebo or Statin & Ezetimibe versus Ezetimibe” subgroup, which exhibited the highest within-group heterogeneity (I² = 54.8%).”
Quote in the paperNot a substantial claim - Findingown data
A stratified meta-analysis by statin intensity demonstrated a reduction in heterogeneity when restricted to low-intensity statin trials.
“Consistently, a stratified meta-analysis by statin intensity demonstrated a reduction in heterogeneity when restricted to low-intensity statin trials (S7 File).”
Quote in the paperSubstantial claim - Findingnone given
High-quality evidence such as large RCTs are missing.
“High-quality evidence such as large RCTs are missing.”
Quote in the paperSubstantial claim - Findingown data
A leave-one-out sensitivity analysis did not identify additional major contributors to heterogeneity.
“A leave-one-out sensitivity analysis did not identify additional major contributors to heterogeneity.”
Quote in the paperNot a substantial claim - Findingown data
In patients with a previous history of statin-associated muscle symptoms (SAMS), the incidence of muscle symptoms is similar between statin-based management and various comparator groups.
“We found similar incidence of muscle symptoms between the statin-based management and the various comparator groups in patients with a previous history of SAMS.”
- Also stated in: § Clinical and research impact · hedged
“the incidence of muscle-related symptoms and treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.”
Quote in the paperSubstantial claim- Rests on an assumption: The original main outcome definitions for SAMS used across the included studies are sufficiently comparable to pool in a meta-analysis.
- Also stated in: § Clinical and research impact · hedged
- Findingown data
Treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.
“the incidence of muscle-related symptoms and treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.”
Quote in the paperSubstantial claim- Rests on an assumption: The original main outcome definitions for SAMS used across the included studies are sufficiently comparable to pool in a meta-analysis.
- Findingown data
In patients with prior SAMS, the discontinuation proportions were low compared with the incidence of muscle symptoms.
“In comparison to the incidence of muscle symptoms, the discontinuation proportions were low.”
Quote in the paperSubstantial claim - Premisecitation
The most recent systematic reviews and meta-analyses on this topic evaluated the effectiveness of intermittent, non-daily statin administration compared with daily dosing in patients with or without a history of SAMS.
“The most recent systematic reviews and meta-analyses on this topic evaluated the effectiveness of intermittent, non-daily statin administration compared with daily dosing in patients with or without a history of statin-associated muscle symptoms (SAMS).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] K Awad, 2017, 81Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis, European Heart Journal source
- cites [17] AJ Keating, 2013, Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy, Ann Pharmacother source
- cites [18] ZA Muhammad, 2019, Can alternate-day Statin regimen minimize its adverse effects on muscle and tendon? A systematic review, J Pak Med Assoc
Not checked in the free run.
- Study design and conductnone given
Confidence in the body of evidence using GRADE was moderate for the primary outcome.
“Our confidence in the body of evidence using GRADE was moderate for the primary outcome and low-moderate for the secondary outcome.”
Quote in the paperNot a substantial claim - Premisereasoning
To date, no meta-analysis has exclusively focused on patients with a history of SAMS.
“To date, no meta-analysis has exclusively focused on patients with a history of SAMS, limiting the evidence base for treatment strategies in this specific population at increased risk of statin-associated side effects.”
Quote in the paperSubstantial claim - Study design and conductnone given
Confidence in the body of evidence using GRADE was low-moderate for the secondary outcome.
“Our confidence in the body of evidence using GRADE was moderate for the primary outcome and low-moderate for the secondary outcome.”
Quote in the paperNot a substantial claim - Premisecitation
The results of prior studies revealed conflicting evidence regarding the incidence of muscle symptoms.
“The results revealed conflicting evidence regarding the incidence of muscle symptoms [16,18].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] K Awad, 2017, 81Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis, European Heart Journal source
- cites [18] ZA Muhammad, 2019, Can alternate-day Statin regimen minimize its adverse effects on muscle and tendon? A systematic review, J Pak Med Assoc
Not checked in the free run.
- Interpretationown data
Patients with a history of SAMS can be re-challenged with statins.
“Our findings suggest that patients with a history of SAMS can be re-challenged with statins.”
Quote in the paperSubstantial claim- Rests on an assumption: The definitions of prior SAMS used in the included studies validly identify patients with a history of SAMS.
- Study design and conductnone given
The non-randomized trials included in the review were of low quality.
“As the non-randomized trials were of low quality, we did not include them in the meta-analysis.”
Quote in the paperSubstantial claim - Premisecitation
The discontinuation rate was similar when comparing a same-statin rechallenge, statin switch and a non-statin based therapy.
“This was also reported when comparing a same-statin rechallenge, statin switch and a non-statin based therapy [35].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- Premisecitation
The discontinuation rate was similar across different statin-based therapy intensities.
“When comparing effectiveness and discontinuation rates of different statin-based therapy intensities found that the discontinuation rate was similar across intensities [41,42].”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
A different study reported lower incidence of muscle symptoms when comparing statin-based treatment with fibrates, bile sequestrant or omega-3 fatty acids.
“On the other hand, a different study reported lower incidence of muscle symptoms was reported when comparing statin-based treatment with fibrates, bile sequestrant or omega-3 fatty acids [38].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] EC Fung, 2012, Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge, Cardiovasc Ther source
- Premisecitation
A retrospective cohort study showed that the reduction of LDL-C levels with once-weekly rosuvastatin therapy was still 20%, compared to reduction of 40% with a daily dosage.
“A retrospective cohort study comparing the incidence of muscle symptoms of daily, bi-weekly, and weekly rosuvastatin therapy showed that the reduction of LDL-C levels with once-weekly rosuvastatin therapy was still 20%, compared to reduction of 40% with a daily dosage [45].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] C Meek, 2012, Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study, Curr Med Res Opin source
- Study design and conductreasoning
It was not possible to perform the preplanned subgroup analyses on cardiovascular prevention setting, statin dosing strategy, level of intolerance, co-interventions and presence of statin therapy at inclusion, due to high diversity in study designs and comparators.
“It was not possible to perform the preplanned subgroup analyses on cardiovascular prevention setting, statin dosing strategy, level of intolerance, co-interventions and presence of statin therapy at inclusion, due to high diversity in study designs and comparators.”
Quote in the paperNot a substantial claim - Interpretationown data
This shift likely reflects the fact that Stein et al. was the only study investigating a moderate- to high-intensity statin.
“This shift likely reflects the fact that Stein et al. was the only study investigating a moderate- to high-intensity statin.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Due to the limited availability of data from RCTs, non-randomized trials were included in the systematic review.
“Due to the limited availability of data from RCTs, non-randomized trials were included in the systematic review.”
Quote in the paperSubstantial claim - Study design and conductnone given
The data on effectiveness were too diverse to draw conclusive results.
“although the data on effectiveness were too diverse to draw conclusive results.”
Quote in the paperNot a substantial claim - Interpretationreasoning
N-of-1 trials can help to identify a possible nocebo effect under statin treatment.
“Therefore, n-of-1 trials can help to identify a possible nocebo effect under statin treatment.”
Quote in the paperSubstantial claim - Study design and conductown data
The difference in pooled OR between statin intensities should be interpreted cautiously given that the moderate- to high-intensity subgroup comprised only the single study by Stein et al.
“Although the pooled OR also differed between the intensity, this difference should be interpreted cautiously given that the moderate- to high-intensity subgroup comprised only the single study by Stein et al.”
Quote in the paperSubstantial claim - Interpretationreasoning
The existence of this unpublished study suggests that publication bias may be present.
“The existence of this unpublished study suggests that publication bias may be present, as it indicates a potential discrepancy between published and unpublished research.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
The high methodological and statistical heterogeneity of interventions in our meta-analysis precluded the assessment of publication bias with statistical methods.
“The high methodological and statistical heterogeneity of interventions in our meta-analysis precluded the assessment of publication bias with statistical methods, e.g., using funnel plots or the Egger Test.”
Quote in the paperNot a substantial claim - Premisecitation
When interventions vary greatly, the resulting differences in effect sizes and outcomes introduce substantial variability that can obscure the patterns these methods aim to detect.
“When interventions vary greatly, as in our case, the resulting differences in effect sizes and outcomes introduce substantial variability that can obscure the patterns these methods aim to detect [53].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] N Terrin, 2003, Adjusting for publication bias in the presence of heterogeneity, Stat Med source
- Premisereasoning
The multiple exposures in N-of-1 trials help to control for confounders.
“The multiple exposures help to control for confounders as muscle symptoms are common and could occur incidentally and not be associated with statin.”
Quote in the paperNot a substantial claim - Study design and conductnone given
The findings from non-randomized studies were generally of low quality.
“The findings from non-randomized studies were, however, generally of low quality.”
Quote in the paperSubstantial claim - Interpretationown data
Statin re-challenge may be feasible in patients experiencing SAMS.
“This review suggests that statin re-challenge may be feasible in patients experiencing statin-associated muscle symptoms (SAMS), as the incidence of muscle-related symptoms and treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.”
Quote in the paperSubstantial claim- Rests on an assumption: The original main outcome definitions for SAMS used across the included studies are sufficiently comparable to pool in a meta-analysis.
- Interpretationreasoning
The heterogeneity was largely driven by this single influential study rather than systematic differences across all included studies.
“This suggests that the heterogeneity was largely driven by this single influential study rather than systematic differences across all included studies.”
Quote in the paperSubstantial claim - Interpretationreasoning
The population of trials included in our systematic review may not represent the general population with SAMS in a clinical setting.
“As the trials included in our systematic review focus on patients with a previous history of SAMS, the population may not represent the general population with SAMS in a clinical setting.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
The quality of non-randomized studies was generally poor.
“The quality of non-randomized study was generally poor and the outcomes of interest of our systematic review were not the main outcomes or the pre-specified outcomes of some studies [20,46,47].”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 66
- May combine two claims. 42
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationTwo trials compared statin with ezetimibe against ezetimibe alone.
“two trials statin with ezetimibe against ezetimibe alone [46,48]”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
The Intervention section describes separate alirocumab, ezetimibe, and atorvastatin arms, with placebos used to maintain blinding. It does not describe a statin-plus-ezetimibe arm; the Introduction likewise calls atorvastatin a parallel statin rechallenge arm. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
May combine two claims.
FindingcitationThe 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]”
Quote in the paperSubstantial claim4 of 6 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
In Statin Rechallenge Outcomes, muscle symptoms were significantly more likely with atorvastatin than placebo in both treatment periods (HR 1.34 and 1.96). The same section reports intolerable symptoms with atorvastatin but not placebo in 42.6% of patients, versus 26.5% with placebo but not atorvastatin. The Discussion notes similar symptom rates only during the first 50 days, not across the full comparison. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
The Discussion (page unavailable) reports muscle pain during simvastatin and placebo phases of a crossover trial; its percentages imply broadly similar overall symptom incidence. The paper does not report comparable statin-discontinuation rates between those phases. The discontinuations described in Methods were from a later comparison of statin plus CoQ10 versus statin plus placebo, not statin versus placebo. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
The Abstract Results report similar overall symptom scores during statin and placebo months and no significant difference in stopping frequency. The Discussion gives early tablet-cessation rates of 21.6% and 17.2%, respectively. The paper does not report a separate between-treatment incidence of muscle symptoms; it compares overall symptom scores, so that specific part of the claim is not established. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNon-statin alternative medications such as PCSK9 inhibitors have substantial costs.
“Meanwhile, the non-statin alternative medications such as PCSK9 inhibitors suffer from substantial costs [7]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] I Mercep, 2024, PCSK9 inhibition: from effectiveness to cost-effectiveness, Front Cardiovasc Med source
Classified as probably not a substantial claim.
PremisecitationThe 2015 European Atherosclerosis Society Consensus Panel recommended multiple strategies to optimize statin tolerance in patients with previous SAMS based on expert opinion due to lack of sufficient data.
“The 2015 European Atherosclerosis Society Consensus Panel Statement recommended multiple strategies to optimize statin tolerance in patients with previous SAMS based on expert opinion due to lack of sufficient data [14,15].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [14] ES Stroes, 2015, Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, Eur Heart J source
The 'Statin-based therapies' section recommends lower-dose, alternative, and intermittent statin dosing for patients with prior symptoms, and the Conclusions recommend combining a maximally tolerated statin dose with non-statin therapy. The paper notes methodological limitations in studies of intermittent dosing, but our copy does not say that its multiple recommendations as a whole were based on expert opinion because sufficient data were lacking. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [15] G Bosco, 2023, Management of Statin Intolerant Patients in the Era of Novel Lipid Lowering Therapies: A Critical Approach in Clinical Practice, J Clin Med source
The References section identifies the 2015 European Atherosclerosis Society Consensus Panel statement as a work on SAMS assessment and management. Section 4 discusses multiple strategies for managing statin intolerance, but our copy does not say that the 2015 panel recommended those strategies on expert opinion because sufficient data were lacking. (LLM, conf=0.78)
Experimental — accuracy not yet measured
May combine two claims.
Study design and conductcitationFor cross-over trials, the Becker/Balagtas method was used, ensuring no participants were counted double in the meta-analysis.
“For the implementation of cross-over trials in the meta-analysis, we used the method according to Becker/Balagtas [34]. This method ensures that no participants were counted double in the meta-analysis.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] DR Elbourne, 2002, Meta-analyses involving cross-over trials: methodological issues, Int J Epidemiol source
Classified as probably not a substantial claim.
PremisecitationRecent narrative reviews on the management of SAMS found that further research is needed to close the knowledge gap.
“Recent narrative reviews on the management of SAMS found that further research is needed to close the knowledge gap [19].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] BA Warden, 2023, Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association, J Clin Lipidol source
Classified as probably not a substantial claim. May combine two claims.
Findingown data23 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.”
Quote in the paperSubstantial claim7 of 10 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [24] FA Wood, 2020, N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects, N Engl J Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- cites [36] AFG Cicero, 2016, Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from an internal audit of a university lipid clinic, Curr Med Res Opin source
- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe protocol was registered on PROSPERO (CRD42020202619).
“The protocol was registered on PROSPERO (CRD42020202619) and published elsewhere [27].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] F Villoz, 2021, Tolerability of statin-based management of patients with a history of statin-associated muscle symptoms: protocol for a systematic review, BMJ Open source
May combine two claims.
Study design and conductown dataAll 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment.
“Notably all 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment (S2 File) [35,36,38,41,42,44,45,50].”
Quote in the paperNot a substantial claim2 of 8 sources checked- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- cites [36] AFG Cicero, 2016, Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from an internal audit of a university lipid clinic, Curr Med Res Opin source
- cites [38] EC Fung, 2012, Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge, Cardiovasc Ther source
- cites [41] TN Harrison, 2018, Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management, Cardiovasc Drugs Ther source
- cites [42] JH Kang, 2017, Rechallenging Statin Therapy in Veterans With Statin-Induced Myopathy Post Vitamin D Replenishment, J Pharm Pract source
- cites [44] WM Mampuya, 2013, Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience, Am Heart J source
- cites [45] C Meek, 2012, Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study, Curr Med Res Opin source
- cites [50] K Williams, 2015, The Impact of Statin Intolerance in Lipid Clinic Patients, IJCM source
The Study Design and Setting section describes a retrospective review of 50 lipid-clinic patients, and Study Limitations calls this a small observational study. Neither section assesses eight retrospective studies or attributes low quality to residual confounding from lack of adjustment; searches for those terms found no such assessment in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNine trials assessed statin against placebo.
“nine trials assessed statin against placebo [20–26,43]”
Quote in the paperNot a substantial claim6 of 8 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [24] FA Wood, 2020, N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects, N Engl J Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
May combine two claims.
Study design and conductown dataThe two prospective cohort studies were both of low quality, mainly due to concerns regarding residual confounding and ascertainment of outcomes.
“The two prospective cohort studies were both of low quality, mainly due to concerns regarding residual confounding and ascertainment of outcomes (S2 File) [37,39].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
- cites [39] CJ Glueck, 2006, Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther source
May combine two claims.
Findingown data13 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).”
Quote in the paperNot a substantial claim7 of 10 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
Classified as probably not a substantial claim.
Findingown dataTen 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”
Quote in the paperSubstantial claim7 of 10 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
The Methods (Participants) identify this as a statin crossover trial, and the Results (Participants) report that 36 of 60 participants had previously abandoned statins because of muscle ache. That is a pre-enrollment symptom history, not incidence of muscle symptoms during the trial; the reported trial outcomes concern symptom intensity of any type. This source also cannot establish the citing sentence’s total of ten trials. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataTwo trials used high-intensity statins.
“two trials used high-intensity statins [23,47]”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationMost 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]”
Quote in the paperNot a substantial claim8 of 10 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
The Abstract (page unavailable) says GAUSS-3 used atorvastatin 20 mg in its statin-rechallenge phase, consistent with moderate-intensity statin use in this trial. It does not establish that most of the trials cited used low- to moderate-intensity statins; its subsequent treatment phase compared two nonstatin drugs. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [24] FA Wood, 2020, N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects, N Engl J Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
The Methods (Procedures and medications; page unavailable) state that this trial used atorvastatin 20 mg, and Study limitations say it tested one statin at one dose. The paper does not classify that dose by intensity or establish what most trials used; it supports the claim only as an example of a trial using that dose. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationOne trial assessed statin against red yeast rice.
“one trial statin against red yeast rice [40]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationTwo trials assessed statin against PCSK9 inhibitors.
“two trials statin against PCSK9 inhibitors [46,47]”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataData 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].”
Quote in the paperSubstantial claim5 of 8 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [21] BA Taylor, 2015, A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy, Atherosclerosis source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataTwo trials used symptom intensity expressed as a nocebo ratio.
“two trials [24,26] used symptom intensity expressed as a nocebo ratio”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationThe effectiveness of red-yeast rice in LDL-C reduction was similar compared to pravastatin.
“However, the effectiveness of red-yeast rice in LDL-C reduction was similar compared to pravastatin [40].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSeven trials reported data on effectiveness.
“seven trials [40,43,46–49] reported data on effectiveness”
Quote in the paperNot a substantial claim3 of 6 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
May combine two claims.
FindingcitationWhen comparing statin-based therapy to PCSK9 inhibitors, neither of the two studies found a difference in discontinuation rate or incidence of muscle symptoms.
“When comparing statin-based therapy to PCSK9 inhibitors, neither of the two studies found a difference in discontinuation rate or incidence of muscle symptoms [46,47].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
The Safety and tolerability section (page unavailable) reports no statistically significant difference between alirocumab and atorvastatin in discontinuation due to skeletal muscle-related adverse events (P = .24). But it reports significantly fewer skeletal muscle-related adverse events with alirocumab (HR 0.61, P = .042), contrary to the claim about muscle symptoms. This paper cannot establish what the other cited study found. (LLM, conf=0.93)
Experimental — accuracy not yet measured - cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMost 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”
Quote in the paperNot a substantial claim4 of 5 sources checked- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
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 measured - cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataNine 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”
Quote in the paperNot a substantial claim4 of 8 sources checked- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [26] JP Howard, 2021, Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment, J Am Coll Cardiol source
The Results section ('Early stopping of tablet months caused by intolerable symptoms'; page unavailable) reports early tablet stopping for statin and placebo, so this trial provided discontinuation data. But stopping was recorded for intolerable symptoms generally, not specifically for muscle symptoms. This paper also cannot establish the citing sentence’s aggregate count of nine trials. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
May combine two claims.
PremisecitationThe other prospective cohort study compared statin-based therapy combined with a herbal tincture (Berberis aristata and Silybum marianum) to ezetimibe and the herbal tincture, and found no significant difference in incidence of muscle symptoms.
“The other prospective cohort study compared statin-based therapy combined with a herbal tincture (Berberis aristata and Silybum marianum) to ezetimibe and the herbal tincture, and found no significant difference in incidence of muscle symptoms [37].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataWe included eight retrospective cohort studies and two prospective cohort studies.
“We included eight retrospective cohort studies [35,38,39,41,42,44,45,50] and two cohort prospective studies [36,37] (S4 File, Table 2).”
Quote in the paperSubstantial claim3 of 10 sources checked- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- cites [38] EC Fung, 2012, Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge, Cardiovasc Ther source
- cites [39] CJ Glueck, 2006, Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther source
- cites [41] TN Harrison, 2018, Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management, Cardiovasc Drugs Ther source
- cites [42] JH Kang, 2017, Rechallenging Statin Therapy in Veterans With Statin-Induced Myopathy Post Vitamin D Replenishment, J Pharm Pract source
- cites [44] WM Mampuya, 2013, Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience, Am Heart J source
- cites [45] C Meek, 2012, Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study, Curr Med Res Opin source
- cites [50] K Williams, 2015, The Impact of Statin Intolerance in Lipid Clinic Patients, IJCM source
- cites [36] AFG Cicero, 2016, Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from an internal audit of a university lipid clinic, Curr Med Res Opin source
- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
May combine two claims.
Study design and conductown dataWe 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.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe reduction in LDL-C levels was also around 20% with intermittent dosing of statin-therapy in a different study.
“In comparison, the reduction in LDL-C levels was also around 20% with intermittent dosing of statin-therapy in a different study [44].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] WM Mampuya, 2013, Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience, Am Heart J source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThree studies reported the incidence of muscle symptoms, five studies provided data on treatment discontinuation due to muscle symptoms, and eight studies reported on effectiveness.
“Three studies reported the incidence of muscle symptoms [36–38], five studies provided data on treatment discontinuation due to muscle symptoms [36,37,39,42,45], and eight studies reported on effectiveness [35–37,39,41,44,45,50].”
Quote in the paperNot a substantial claim3 of 10 sources checked- cites [36] AFG Cicero, 2016, Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from an internal audit of a university lipid clinic, Curr Med Res Opin source
- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
- cites [38] EC Fung, 2012, Statin myopathy: a lipid clinic experience on the tolerability of statin rechallenge, Cardiovasc Ther source
- cites [39] CJ Glueck, 2006, Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther source
- cites [42] JH Kang, 2017, Rechallenging Statin Therapy in Veterans With Statin-Induced Myopathy Post Vitamin D Replenishment, J Pharm Pract source
- cites [45] C Meek, 2012, Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study, Curr Med Res Opin source
- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- cites [41] TN Harrison, 2018, Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management, Cardiovasc Drugs Ther source
- cites [44] WM Mampuya, 2013, Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience, Am Heart J source
The Results report myalgia as the most common intolerance complaint, statin discontinuation in 27.5% of patients, and LDL-C reductions and goal attainment, so this paper provides data relevant to muscle symptoms and effectiveness. It does not establish how many studies the citing review included, or specify that the reported discontinuations were due to muscle symptoms. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [50] K Williams, 2015, The Impact of Statin Intolerance in Lipid Clinic Patients, IJCM source
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationWith suggestion of a nocebo effect, trials started reporting the nocebo ratio.
“With suggestion of a nocebo effect, trials started reporting the nocebo ratio, e.g., the symptom intensity in placebo periods in relation to the symptom intensity when taking a statin [24,26].”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe higher discontinuation rate observed with statins may reflect challenges in patient adherence and could have implications for long-term cardiovascular risk prevention.
“The higher discontinuation rate observed with statins may reflect challenges in patient adherence and could have implications for long-term cardiovascular risk prevention [3].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] MF Piepoli, 2016, 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), Eur Heart J source
Section 3a.7.12 (p. 39) says statins reduce cardiovascular morbidity and mortality, supporting the concern that continued treatment matters for prevention. The passages found do not report a higher statin discontinuation rate or link such a rate specifically to patient-adherence challenges; the adherence-related material found is a reference list (p. 76). (LLM, conf=0.78)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSAMS usually occur 4-6 weeks after statin introduction and can last for up weeks to months after statin therapy discontinuation.
“SAMS usually occur 4–6 weeks after statin introduction and can last for up weeks to months after statin therapy discontinuation [14,54].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [14] ES Stroes, 2015, Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, Eur Heart J source
The Assessment and diagnosis section says discomfort and weakness typically begin within 4–6 weeks of starting statin therapy. It also says symptoms that regress markedly within a few weeks of stopping a statin are more likely to be statin-related, but does not establish that SAMS can last for months after discontinuation. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [54] KE Hansen, 2005, Outcomes in 45 patients with statin-associated myopathy, Arch Intern Med source
May combine two claims.
FindingcitationThe studies we analyzed utilized different definitions for SAMS, different comparators ranging from placebo to phytotherapeutics and newer lipid-lowering therapies such as PCSK-9 inhibitors.
“This variability is reflected in the studies we analyzed, which utilized different definitions for SAMS, different comparators ranging from placebo to phytotherapeutics and newer lipid-lowering therapies such as PCSK-9 inhibitors [20,40,46].”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationN-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].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
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 measured
May combine two claims.
InterpretationreasoningMany 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.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
May combine two claims.
InterpretationcitationThe heterogeneity is due to the wide variety of study designs, the wide confidence intervals of individual studies, and the inclusion of low-weight studies, which can have a disproportionate effect on heterogeneity, especially in random-effects models.
“This is due to the wide variety of study designs, the wide confidence intervals of individual studies, and the inclusion of low-weight studies, which can have a disproportionate effect on heterogeneity, especially in random-effects models [58].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] J IntHout, 2015, Small studies are more heterogeneous than large ones: a meta-meta-analysis, J Clin Epidemiol source
The Discussion (page unavailable) says differences in patient populations and study quality may increase between-study heterogeneity. The implications section says small studies can have major influence in random-effects meta-analyses, but it describes influence on the pooled result, not low-weight studies causing heterogeneity. The paper does not identify wide confidence intervals of individual studies as a cause of heterogeneity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
FindingcitationIn 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].”
Quote in the paperNot a substantial claim5 of 10 sources checked- cites [17] AJ Keating, 2013, Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy, Ann Pharmacother source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [47] Pfizer, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
- cites [22] TR Joy, 2014, N-of-1 (single-patient) trials for statin-related myalgia, Ann Intern Med source
- cites [23] O Kristiansen, 2021, Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial, Eur Heart J Cardiovasc Pharmacother source
- cites [25] E Herrett, 2021, Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials, BMJ source
- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
The Methods passage (page unavailable) identifies incidence of withdrawal for intolerable muscle symptoms as the primary outcome and a daily pain-severity score as a co-primary outcome. It says the score came from a 0–10 question adapted from the Brief Pain Inventory, not a visual analogue scale (VAS). The Results passage (page unavailable) reports both incidence and pain scores, so the claim is supported except for its identification of the scale as VAS. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [49] N Wijekoon, 2020, Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial, Contemp Clin Trials Commun source
May combine two claims.
FindingcitationThe studies varied in minimum number of previously tried statin or various creatinine kinase thresholds.
“The studies varied in minimum number of previously tried statin [35,39,40,46] or various creatinine kinase thresholds [37,43].”
Quote in the paperSubstantial claim3 of 6 sources checked- cites [35] ET Brennan, 2017, Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?, Can J Cardiol source
- cites [39] CJ Glueck, 2006, Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther source
- cites [40] SC Halbert, 2010, Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance, Am J Cardiol source
- cites [46] PM Moriarty, 2015, Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial, J Clin Lipidol source
- cites [37] F Di Pierro, 2015, Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins, Diabetes Metab Syndr Obes source
- cites [43] SP Kennedy, 2011, Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance, J Clin Lipidol source
Classified as probably not a substantial claim.
Study design and conductcitationIn order to include cross-over trials using the method by Becker/Balagtas, OR was used to provide a stable effects measure.
“In order to include cross-over trials in our trials using the method by Becker/Balagtas, OR was used to provide a stable effects measure [34].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] DR Elbourne, 2002, Meta-analyses involving cross-over trials: methodological issues, Int J Epidemiol source
May combine two claims.
Interpretationown dataThe observed heterogeneity was mainly driven by two factors: the highly weighted study by Nissen et al. and the inclusion of a higher intensity statin in the Stein et al. trial.
“Overall, these findings suggest that the observed heterogeneity was mainly driven by two factors: the highly weighted study by Nissen et al. [20] and the inclusion of a higher intensity statin in the Stein et al. [48] trial.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [20] SE Nissen, 2016, Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial, JAMA source
- cites [48] EA Stein, 2008, Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins, Am J Cardiol source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were 47,628 participants in non-RCTs.
“In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFollow-up ranged from 12 weeks to 31 months.
“In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe review included 23 studies: 13 RCTs, 2 prospective studies, and 8 retrospective studies.
“In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataNo further studies were identified by hand search, but an unpublished trial was identified on clinicaltrials.gov and included in the analysis.
“No further studies were identified by hand search, however an unpublished trial was identified on clinicaltrials.gov and included in the analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were 1868 participants in RCTs.
“In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe number of participants ranged from 8 to 491 with a median of 101 participants.
“The number of participants ranged from 8 to 491 with a median of 101 participants.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe weighted mean age was 63.2 years.
“The weighted mean age was 63.2 years.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOne trial compared daily versus non-daily statin dosing.
“one trial daily versus non-daily statin dosing”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe exposure time ranged from 12 weeks to 12 months with a weighted mean exposure time of 22 weeks.
“The exposure time ranged from 12 weeks to 12 months with a weighted mean exposure time of 22 weeks.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe only trial comparing non-daily statin dosing to daily dosing found patterns of lower muscle symptoms incidence in daily dosing but with large confidence intervals.
“The only trial comparing non-daily statin dosing to daily dosing found patterns of lower muscle symptoms incidence in daily dosing but with large confidence intervals and did not report on discontinuation rate (OR 0.58 (0.23–1.43)).”
Quote in the paperNot a substantial claim- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe only trial comparing non-daily statin dosing to daily dosing did not report on discontinuation rate.
“The only trial comparing non-daily statin dosing to daily dosing found patterns of lower muscle symptoms incidence in daily dosing but with large confidence intervals and did not report on discontinuation rate (OR 0.58 (0.23–1.43)).”
Quote in the paperNot a substantial claim- Rests on an assumption: The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe weighted median age was 62.9 years and mean follow-up duration was 14.5 months.
“The weighted median age was 62.9 years and mean follow-up duration was 14.5 months.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataExposures and comparators were highly variable, with different non-statin lowering agents as comparators and various dosing strategies.
“Exposures and comparators were highly variable, with different non-statin lowering agents as comparators and various dosing strategies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe number of participants ranged from 27 to 45,037 with a median of 113 participants.
“The number of participants ranged from 27 to 45’037 with a median of 113 participants.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOverall, the odds ratio for treatment discontinuation due to muscle symptoms was 1.48 (95% CI 1.03-2.12), indicating higher treatment discontinuation in statin-based treatment strategies.
“Overall, the OR for treatment discontinuation due to muscle symptoms was 1.48 (95% CI 1.03–2.12), indicating higher treatment discontinuation in the statin-based treatment strategies (Fig 3).”
- Also stated in: § Discussion · plain
“More patients discontinued statin therapies over the trial duration compared to non-statin therapies (OR 1.48, 95% CI 1.03–2.12).”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataReporting of outcomes of interest was diverse.
“Reporting of outcomes of interest was diverse.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSensitivity analysis excluding Nissen et al. led to a marked drop in overall heterogeneity and a corresponding narrowing of confidence intervals, without a meaningful shift in the direction of the effect estimate.
“Sensitivity analysis excluding Nissen et al. led to a marked drop in overall heterogeneity and a corresponding narrowing of confidence intervals, without a meaningful shift in the direction of the effect estimate. (S5 File)”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningOur GRADE assessment indicates that the overall certainty of evidence was moderate for incident muscle symptoms and low to moderate for discontinuation of statin treatment.
“Our GRADE assessment indicates that the overall certainty of evidence was moderate for incident muscle symptoms and low to moderate for discontinuation of statin treatment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataA higher discontinuation rate was observed with statins in our analysis.
“If future research confirms the higher discontinuation rate observed with statins in our analysis”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe prevalence of SAMS varies across populations and is influenced by female sex, older age, obesity, and statin intensity.
“However the prevalence of statin-associated muscle symptoms varies across populations and is influenced by factors such as female sex, older age, obesity, and statin intensity [6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] I Bytyci, 2021, The prevalence of statin intolerance worldwide: a systematic review and meta-analysis with 4,143,517 patients, European Heart Journal source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSAMS is a common adverse effect occurring in approximately 10% (95% CI 8.1-10%) of patients taking a statin.
“Nevertheless SAMS is a common adverse effect occurring in approximately 10% (95% CI: 8.1–10%) of patients taking a statin.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] I Bytyci, 2021, The prevalence of statin intolerance worldwide: a systematic review and meta-analysis with 4,143,517 patients, European Heart Journal source
May combine two claims.
PremisecitationTo date, the results of systematic reviews and meta-analysis are limited and focused on statin-naïve patients.
“To date, the results of systematic reviews and meta-analysis are limited and focused on statin-naïve patients [16–18].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] K Awad, 2017, 81Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis, European Heart Journal source
- cites [17] AJ Keating, 2013, Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy, Ann Pharmacother source
- cites [18] ZA Muhammad, 2019, Can alternate-day Statin regimen minimize its adverse effects on muscle and tendon? A systematic review, J Pak Med Assoc
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDiscrepancies between reviewers were solved by consensus or by a third person.
“Discrepancies between reviewers were solved by consensus or by a third person.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDisagreements were resolved through discussion with senior investigators and consensus.
“Disagreements were resolved by through discussion with senior investigators (MB, NR) and consensus.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThree trained researchers evaluated eligibility independently based on titles and abstracts and then by full-text screening.
“Three trained researchers evaluated (FV, CL, PA) independently eligibility based on titles and abstracts and then by full-text screening.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe review followed the PRISMA reporting guideline for meta-analysis.
“We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for meta-analysis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenTrials were separated into subgroups according to control treatment to reduce overall heterogeneity.
“We separated trials in subgroups according to their control treatment to reduce overall heterogeneity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe overall quality of evidence was assessed using GRADE.
“The overall quality of evidence was assessed by using GRADE (Grading of Recommendations Assessment, Development and Evaluation working group methodology) [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] D Atkins, 2004, Grading quality of evidence and strength of recommendations, BMJ source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThree authors independently performed study selection, review, and data extraction.
“Three authors (FV, CL, PA) independently performed study selection, review, and data extraction.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThree reviewers independently evaluated risk of bias of each study using the Risk-of-Bias 2 tool for RCTs, the ROBINS-I tool for prospective cohort studies, and the Newcastle-Ottawa scale for retrospective cohort studies converted per AHRQ criteria.
“Three reviewers evaluated (FV, CL, PA) independently the risk of bias of each study using the Risk-of-Bias 2 tool for RCTs, the ROBINS-I tool from the Cochrane Collaboration tools for prospective cohort studies [29] and the Newcastle-Ottawa scale for retrospective cohort studies, which was converted to per AHRQ criteria into a summary quality rating [30].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] JP Higgins, 2019, Assessing risk of bias in a randomized trial, Cochrane Handbook for Systematic Reviews of Interventions source
- cites [30] GA Wells, 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe search was performed in the different databases from inception until February 2025.
“We performed the search in the different databases from inception until February 2025.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe inter-rater reliability for the initial title and abstract screening phase in Cohen's kappa was 0.58.
“The inter-rater reliability for the initial title and abstract screening phase in Cohen’s kappa was 0.58.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenWhere needed, authors were contacted to obtain exact data for within-individual comparison of treatments.
“Where needed, we contacted authors to obtain exact data for within-individual comparison of treatments.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAll three prior studies applied differing definitions of SAMS, contributing to variability in outcome assessment and limiting comparability across findings.
“All three studies [16–18] applied differing definitions of statin-associated muscle symptoms (SAMS), contributing to variability in outcome assessment and limiting comparability across findings.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] K Awad, 2017, 81Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis, European Heart Journal source
- cites [17] AJ Keating, 2013, Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy, Ann Pharmacother source
- cites [18] ZA Muhammad, 2019, Can alternate-day Statin regimen minimize its adverse effects on muscle and tendon? A systematic review, J Pak Med Assoc
Not checked in the free run.
May combine two claims.
Study design and conductcitationConfidence in the body of evidence was estimated using GRADE as moderate for incident muscle symptoms and low to moderate for discontinuation of statin treatment.
“We estimated our confidence in the resulting body of evidence using GRADE as moderate for the outcome of incident muscle symptoms and low to moderate for the outcome of discontinuation of statin treatment [31] (S3 File).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] D Atkins, 2004, Grading quality of evidence and strength of recommendations, BMJ source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn all trials, with the exception of one, both patients and investigators were blinded to the treatment allocation.
“In all trials, with the exception of one, both patients and investigators were blinded to the treatment allocation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA small retrospective cohort study found non-statin lipid-lowering monotherapy (including ezetimibe, fibrate, bile acid sequestrant, or omega-3 fatty acids) to be ineffective in patients with statin intolerance in comparison to statin-based treatments.
“A small retrospective cohort study found non-statin lipid-lowering monotherapy (including ezetimibe, fibrate, bile acid sequestrant, or omega-3 fatty acids) to be ineffective in patients with statin intolerance in comparison to statin-based treatments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe first prospective cohort study compared 5 mg rosuvastatin to 10 mg rosuvastatin and found similar muscle symptoms, discontinuation rate and effectiveness.
“The first prospective cohort study compared 5 mg rosuvastatin to 10 mg rosuvastatin and found similar muscle symptoms, discontinuation rate and effectiveness [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] CJ Glueck, 2006, Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies, Clin Ther source
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningThis review helps to strengthen recommendations on the management of SAMS in clinical practice and guide future research.
“As SAMS remain a major obstacle in lipid-lowering treatment, this review helps to strengthen recommendations on the management of SAMS in clinical practice and guide future research.”
Quote in the paperNot a substantial claim- Rests on an assumption: SAMS remain a major obstacle in lipid-lowering treatment.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationcitationThis review did not focus exclusively on patients with prior statin-associated muscle symptoms (SAMS), limiting the applicability of its findings to this high-risk population.
“Importantly, this review did not focus exclusively on patients with prior statin-associated muscle symptoms (SAMS), limiting the applicability of its findings to this high-risk population.”
Quote in the paperNot a substantial claim- Rests on an assumption: A recent systematic review and meta-analysis evaluated intermittent non-daily versus daily statin administration and included a broad range of study designs—three case reports, five retrospective cohort studies, one prospective cohort, and one randomized trial.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningAnalyzing the discontinuation rate provides insights into the real-world effectiveness of the therapy.
“Analyzing the discontinuation rate provides insights into the real-world effectiveness of the therapy, thereby informing daily clinical practice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenThrough this thorough literature search, we were able to also include data from unpublished trials.
“Through this thorough literature search, we were able to also include data from unpublished trials.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningA challenge was the inconsistent definition of SAMS in inclusion criteria as well as in the outcome measurements.
“A challenge was the inconsistent definition of SAMS in inclusion criteria as well as in the outcome measurements.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe inclusion of observational studies was necessary to enhance the comprehensiveness of our review.
“The inclusion of observational studies was necessary to enhance the comprehensiveness of our review.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe timing of the measurement of muscle symptoms is important.
“Furthermore, the timing of the measurement of muscle symptoms is important.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningThe strength of our meta-analysis lies in the broad selection criteria used for the included studies.
“Given the significant variability in current clinical practices regarding the management of SAMS, the strength of our meta-analysis lies in the broad selection criteria used for the included studies.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductcitationOur analysis specifically targets patients with documented SAMS allowing all clinically relevant evaluation of treatment strategies in this population.
“In 14, our analysis specifically targets patients with documented SAMS allowing all clinically relevant evaluation of treatment strategies in this population [16].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] K Awad, 2017, 81Efficacy and safety of alternate-day versus daily dosing of statins: a systematic review and meta-analysis, European Heart Journal source
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningCreating a universal recommendation for clinicians remains challenging.
“Therefore, creating a universal recommendation for clinicians remains challenging, underscoring the importance of individualized patient assessment and management.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningThe resulting recommendation from the evidence is weak for both outcomes.
“As a result, while our findings provide important insights, the resulting recommendation from the evidence is weak for both outcomes.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningWe did not have a pre-specified plan in the protocol for dealing with non-randomized trials, but we ultimately decided not to include them in the quantitative analysis due to their low quality.
“We did not have a pre-specified plan in the protocol for dealing with non-randomized trials, but we ultimately decided not to include them in the quantitative analysis due to their low quality.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe GRADE assessment reflects limitations in trial methodology, heterogeneity across outcome definitions, and concerns regarding residual confounding in observational studies.
“This reflects limitations in trial methodology, heterogeneity across outcome definitions, and concerns regarding residual confounding in observational studies.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The definitions of prior SAMS used in the included studies validly identify patients with a history of SAMS.
“History of SAMS was defined according to the respective study protocol.”
The paper relies on this without support.
The definitions of muscle symptoms used by the individual included studies are sufficiently comparable to be pooled in a meta-analysis.
“The primary outcome was incidence of muscle symptoms as defined by the individual studies.”
The paper relies on this without support.
The unpublished trial identified on clinicaltrials.gov is eligible and its data are reliable.
“No further studies were identified by hand search, however an unpublished trial was identified on clinicaltrials.gov and included in the analysis.”
The paper relies on this without support.
The diverse control interventions used in the included trials are appropriate comparators for evaluating the safety of statin-based therapy.
“Interventions and comparators were diverse: nine trials assessed statin against placebo [20–26,43], two trials statin against PCSK9 inhibitors [46,47], one trial statin against red yeast rice [40], one trial daily versus non-daily statin dosing and two trials statin with ezetimibe against ezetimibe alone [46,48].”
The paper relies on this without support.
A recent systematic review and meta-analysis evaluated intermittent non-daily versus daily statin administration and included a broad range of study designs—three case reports, five retrospective cohort studies, one prospective cohort, and one randomized trial.
“A recent systematic review and meta-analysis evaluated intermittent non-daily versus daily statin administration and included a broad range of study designs—three case reports, five retrospective cohort studies, one prospective cohort, and one randomized trial.”
The paper relies on this without support.
Intermittent dosing is only one possible approach to manage SAMS.
“Additionaly intermittent dosing is only one possible approach to manage SAMS.”
The paper relies on this without support.
SAMS remain a major obstacle in lipid-lowering treatment.
“As SAMS remain a major obstacle in lipid-lowering treatment, this review helps to strengthen recommendations on the management of SAMS in clinical practice and guide future research.”
The paper relies on this without support.
N-of-1 trials produce intrapersonal evidence that gains perspective into an individual patient’s care.
“They produce intrapersonal evidence gaining perspective into an individual patient’s care.”
The paper relies on this without support.
OR have the tendency of overestimating effects especially in common events.
“OR have the tendency of overestimating effects especially in common events.”
The paper relies on this without support.
The original main outcome definitions for SAMS used across the included studies are sufficiently comparable to pool in a meta-analysis.
“In our review, we used the original main outcome definitions as reported in each study without further harmonization across trials.”
The paper relies on this without support.
The patients included in the reviewed studies are representative of the broader population with prior SAMS.
“This suggests that in patients with prior SAMS, a re-challenge with statin therapy should be aimed for in clinical practice, implemented alongside shared decision-making and close clinical monitoring, to achieve LDL-C reduction and cardiovascular risk prevention.”
The paper relies on this without support.
The comparator groups in the included studies represent appropriate alternative treatment options for patients with prior SAMS.
“the incidence of muscle-related symptoms and treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Discontinuation described as comparable despite a higher pooled rate
MajorThe clinical-impact section describes treatment discontinuation as comparable between therapies, but the reported pooled estimate shows significantly higher discontinuation with statin-based treatment (OR 1.48, 95% CI 1.03-2.12).
“the incidence of muscle-related symptoms and treatment discontinuation appears comparable between statin-based therapies and alternative treatment options.”
“Overall, the OR for treatment discontinuation due to muscle symptoms was 1.48 (95% CI 1.03–2.12), indicating higher treatment discontinuation in the statin-based treatment strategies (Fig 3).”
Stein trial called the only moderate-to-high-intensity study
MajorThe discussion says the moderate-to-high-intensity subgroup contained only Stein et al., yet the characteristics identify trial 47 as using a high-intensity statin, and the incidence analysis includes trial 47.
“the moderate- to high-intensity subgroup comprised only the single study by Stein et al.”
“two trials used high-intensity statins [23,47].”
Search end date differs between abstract and methods
MinorThe abstract says the databases were searched through February 2024, while the methods say the search was extended through February 2025.
“databases were searched from inception up to February 2024.”
“We performed the search in the different databases from inception until February 2025.”
Discussion reverses the observational study counts
MinorThe discussion says there were two retrospective and eight prospective studies; the results consistently give eight retrospective and two prospective studies.
“The present review extends these findings through including a broader array of studies, including 13 RCTs, two retrospective studies, and eight prospective studies.”
“We included eight retrospective cohort studies [35,38,39,41,42,44,45,50] and two cohort prospective studies [36,37] (S4 File, Table 2).”
Prospective and retrospective cohort classifications conflict
MinorThe quality assessment classifies studies 37 and 39 as prospective, whereas the study characteristics classify 36 and 37 as prospective and 39 as retrospective.
“The two prospective cohort studies were both of low quality, mainly due to concerns regarding residual confounding and ascertainment of outcomes (S2 File) [37,39].”
“We included eight retrospective cohort studies [35,38,39,41,42,44,45,50] and two cohort prospective studies [36,37] (S4 File, Table 2).”
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“However, the effectiveness of red-yeast rice in LDL-C reduction was similar compared to pravastatin [40].”
InfluentialThe role of mitochondria in statin‐induced myopathy
Apostolopoulou, M., Corsini, A., & Roden, M. (2015) · European Journal of Clinical Investigation · doi:10.1111/eci.12461 · Cited by 142 · see citing works
Rosenson, R. S., Miller, K., Bayliss, M. S., Sanchez, R. J., Baccara‐Dinet, M. T., Chibedi-De-Roche, D., Taylor, B. A., Khan, I., Manvelian, G. Z., White, M. K., et al. (2017) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-017-6723-4 · Cited by 142 · cited 1× · see citing works
“Several non-invasive diagnostic tools have been evaluated [55,56], we propose the use of the SAMS-CI Score [57] due to its feasibility for both clinical and research purposes.”
<i>N</i>-of-1 (Single-Patient) Trials for Statin-Related Myalgia
Joy, T. R., Monjed, A., Zou, G. Y., Hegele, R. A., McDonald, C. G., & Mahon, J. L. (2014) · Annals of Internal Medicine · doi:10.7326/m13-1921 · Cited by 130 · cited 7× · see citing works
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
InfluentialMallinson, J. E., Constantin‐Teodosiu, D., Sidaway, J. E., Westwood, F. R., & Greenhaff, P. L. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.164699 · Cited by 119 · cited 1× · see citing works
“Additionally, statins can interfere with calcium signaling and activate muscle atrophy pathways [13].”
Warden, B. A., Guyton, J. R., Kovacs, A. C., Durham, J. A., Jones, L. K., Dixon, D. L., Jacobson, T. A., & Duell, P. B. (2023) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2022.09.001 · Cited by 111 · cited 1× · see citing works
“Recent narrative reviews on the management of SAMS found that further research is needed to close the knowledge gap [19].”
Design, Analysis, and Reporting of Crossover Trials for Inclusion in a Meta-Analysis
Li, T., Yu, T., Hawkins, B. S., & Dickersin, K. (2015) · PLOS ONE · doi:10.1371/journal.pone.0133023 · Cited by 107 · cited 1× · see citing works
“[34,51,52].”
Stein, E. A., Ballantyne, C. M., Windler, E., Sirnes, P. A., Sussekov, A., Yigit, Z., Seper, C., & Gimpelewicz, C. R. (2008) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2007.09.099 · Cited by 102 · cited 7× · see citing works
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
InfluentialStatin-Associated Muscle Disease: Advances in Diagnosis and Management
Taylor, B. A., & Thompson, P. D. (2018) · Neurotherapeutics · doi:10.1007/s13311-018-0670-z · Cited by 85 · cited 1× · see citing works
“Several non-invasive diagnostic tools have been evaluated [55,56], we propose the use of the SAMS-CI Score [57] due to its feasibility for both clinical and research purposes.”
Hunninghake, D. B., Stein, E. A., Bays, H. E., Rader, D. J., Chitra, R., Simonson, S. G., & Schneck, D. W. (2004) · Coronary Artery Disease · doi:10.1097/00019501-200403000-00008 · Cited by 77 · see citing works
Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy
Keating, A. J., Campbell, K. B., & Guyton, J. R. (2013) · Annals of Pharmacotherapy · doi:10.1345/aph.1r509 · Cited by 74 · cited 1× · see citing works
“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].”
Glueck, C. J., Aregawi, D., Agloria, M., Khalil, Q., Winiarska, M., Munjal, J., Gogineni, S., & Wang, P. (2006) · Clinical Therapeutics · doi:10.1016/j.clinthera.2006.06.004 · Cited by 73 · cited 5× · see citing works
“…studies reported the incidence of muscle symptoms [36–38], five studies provided data on treatment discontinuation due to muscle symptoms [36,37,39,42,45], and eight studies reported on effectiveness [35–37, The first prospective cohort study compared 5 mg rosuvastatin to 10 mg rosuvastatin…”
InfluentialEfficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance
Kennedy, S. P., Barnas, G. P., Schmidt, M. J., Glisczinski, M. S., & Paniagua, A. C. (2011) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2011.03.454 · Cited by 53 · cited 9× · see citing works
“Three trials showed some concern on the randomization process [43,46,47].”
InfluentialMeek, C., Wierzbicki, A. S., Jewkes, C., Twomey, P. J., Crook, M. A., Jones, A., & Viljoen, A. (2012) · Current Medical Research and Opinion · doi:10.1185/03007995.2012.657302 · Cited by 52 · cited 4× · see citing works
“Notably all 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment (S2 File) [35,36,38,41,42,44,45,50].”
InfluentialBosco, G., Di Giacomo Barbagallo, F., Spampinato, S., Lanzafame, L., Di Pino, A., Piro, S., Purrello, F., & Scicali, R. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12062444 · Cited by 50 · cited 1× · see citing works
“The 2015 European Atherosclerosis Society Consensus Panel Statement recommended multiple strategies to optimize statin tolerance in patients with previous SAMS based on expert opinion due to lack of sufficient data [14,15].”
Di Pierro, F., Bellone, I., Rapacioli, G., & Putignano, P. (2015) · Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy · doi:10.2147/dmso.s78877 · Cited by 48 · cited 6× · see citing works
“…five studies provided data on treatment discontinuation due to muscle symptoms [36,37,39,42,45], and eight studies reported on effectiveness [35–37, The first prospective cohort study compared 5 mg rosuvastatin to 10 mg rosuvastatin and found similar muscle symptoms, discontinuation rate and…”
InfluentialTice, J. A., Kazi, D. S., & Pearson, S. D. (2015) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2015.7248 · Cited by 46 · cited 1× · see citing works
“Meanwhile, the non-statin alternative medications such as PCSK9 inhibitors suffer from substantial costs [7] and have been mainly studied in large RCTs as add-on treatments on top of statins [8].”
Statin Myopathy: A Lipid Clinic Experience on the Tolerability of Statin Rechallenge
Fung, E. C., & Crook, M. A. (2012) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2011.00267.x · Cited by 34 · cited 4× · see citing works
“Notably all 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment (S2 File) [35,36,38,41,42,44,45,50].”
InfluentialPCSK9 inhibition: from effectiveness to cost-effectiveness
Mercep, I., Strikic, D., Hrabac, P., Pecin, I., & Reiner, Ž. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1339487 · Cited by 31 · see citing works
Rechallenging Statin Therapy in Veterans With Statin-Induced Myopathy Post Vitamin D Replenishment
Kang, J. H., Nguyen, Q.-N., Mutka, J., & Le, Q. A. (2017) · Journal of Pharmacy Practice · doi:10.1177/0897190016674407 · Cited by 28 · cited 4× · see citing works
“When comparing effectiveness and discontinuation rates of different statin-based therapy intensities found that the discontinuation rate was similar across intensities [41,42].”
InfluentialKristiansen, O., Vethe, N. T., Peersen, K., Wang Fagerland, M., Sverre, E., Prunés Jensen, E., Lindberg, M., Gjertsen, E., Gullestad, L., Perk, J., et al. (2021) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvaa076 · Cited by 27 · see citing works
Cicero, A. F. G., Morbini, M., Bove, M., D’Addato, S., Fogacci, F., Rosticci, M., & Borghi, C. (2016) · Current Medical Research and Opinion · doi:10.1080/03007995.2016.1190326 · Cited by 23 · cited 3× · see citing works
“Notably all 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment (S2 File) [35,36,38,41,42,44,45,50].”
Lancet, T. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60240-3 · Cited by 23 · see citing works
Unmet Patient Need in Statin Intolerance: the Clinical Characteristics and Management
Harrison, T. N., Hsu, J.-W. Y., Rosenson, R. S., Levitan, E. B., Muntner, P., Cheetham, T. C., Wei, R., Scott, R. D., & Reynolds, K. (2018) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-018-6775-0 · Cited by 10 · cited 3× · see citing works
“When comparing effectiveness and discontinuation rates of different statin-based therapy intensities found that the discontinuation rate was similar across intensities [41,42].”
Muhammad, Z. A., Ahmad, T., & Baloch, N. (2019) · PubMed · Cited by 8 · see citing works
Bytyci, I., Bajraktari, G., Sahebkar, A., Penson, P. E., Rysz, R., & Banach, M. Y. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab724.2943 · Cited by 5 · see citing works
Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?
Brennan, E. T., & Joy, T. R. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2017.02.013 · Cited by 5 · cited 5× · see citing works
“We included eight retrospective cohort studies [35,38,39,41,42,44,45,50] and two cohort prospective studies [36,37] (S4 File, Table 2).”
InfluentialWijekoon, N., Wijekoon, S., Bulugahapitiya, U., Pathirana, N., Wickramasinghe, M., Paranavitane, S., Kottage, A., Wijayawardena, S., Karunarathne, M., Samarasinghe, M., et al. (2020) · Contemporary Clinical Trials Communications · doi:10.1016/j.conctc.2020.100685 · Cited by 4 · cited 8× · see citing works
“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.”
InfluentialAwad, K., Mikhailidis, D. P., Toth, P. P., Jones, S. R., Moriarty, P., Lip, G. Y. H., Muntner, P., Catapano, A. L., Pencina, M. J., Rosenson, R. S., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx501.81 · Cited by 2 · see citing works
The Impact of Statin Intolerance in Lipid Clinic Patients
Williams, K., & Mishra, V. (2015) · International Journal of Clinical Medicine · doi:10.4236/ijcm.2015.65040 · Cited by 1 · cited 2× · see citing works
“Notably all 8 identified retrospective studies were of low quality, mainly due to concerns regarding residual confounding because of lack of adjustment (S2 File) [35,36,38,41,42,44,45,50].”
Villoz, F., Lyko, C., Del Giovane, C., Rodondi, N., & Blum, M. R. (2021) · BMJ Open · doi:10.1136/bmjopen-2021-052341 · Cited by 1 · cited 3× · see citing works
“To avoid missing relevant data, we set no restriction on the type of comparator [27].”
InfluentialSelf-citation
Flagged first, then by citations
Research works printed but not linked: 2
- CGJ Lefebvre, 2021, Cochrane Handbook for Systematic Reviews of Interventions, version 6.2
- GA Wells, 2000, The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses
- Authors
- Aebi, P. S., Villoz, F., Bührer, J., Lyko, C., Abolhassani, N., Del Giovane, C., Gencer, B., Rodondi, N., & Blum, M. R.
- Affiliations
- University of Bern (CH)
- Hôpital Riviera-Chablais (CH)
- Corresponding author
- Blum, Manuel R.
- Venue
- PLOS One
- Publisher
- Public Library of Science (PLoS)
- Published
- 2025-12-11
- Volume
- 20
- Issue
- 12
- Pages
- e0338575
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC12698018
- OpenAlex
- W4417248158
- Semantic Scholar
- 5481642cff4face41df753ad758df81809379aab
- Cited by
- 0
- References
- 48
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- The Swiss National Science Foundation (33IC30_193052, 32003B_205067)
- 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
- statin-associated muscle symptoms, statin rechallenge, statin discontinuation, lipid-lowering therapy, ezetimibe, PCSK9 inhibitors, statin safety, cardiovascular risk prevention
- MeSH terms
- Hypolipidemic Agents, Cardiovascular Diseases, Humans, Muscular Diseases, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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