By Seema Gupta, MD, MSPH
Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV
SYNOPSIS: A review of large-scale, randomized, double-blind trials of statin therapy suggested statins are responsible for only a small excess of muscle pain symptoms in patients taking these drugs.
SOURCE: Cholesterol Treatment Trialists’ Collaboration. Effect of statin therapy on muscle symptoms: An individual participant data meta-analysis of large-scale, randomised, double-blind trials. Lancet 2022;400:832-845.
From 1990 to 2019, the prevalent cases of total cardiovascular disease (CVD) across the world nearly doubled from 271 million to 523 million. The number of CVD deaths steadily increased from 12.1 million to 18.6 million.1 Evidence from randomized trials indicates statin therapy lowers the risk of major CV events by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) the drug continues to be taken.2
In terms of adverse events from statins used for primary prevention of CVD, the risk of adverse events attributable to statins has been demonstrated to be low in a large scale meta-analysis.3 Such adverse events do not outweigh statin’s efficacy in preventing CVD, suggesting the benefit-to-harm balance of statins generally is favorable. Although all statins have been associated with muscle pain, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Thus, there is a need for better understanding related to statin-associated muscle symptoms (SAMS).4
The Cholesterol Treatment Trialists’ Collaboration used individual-level patient data from long-term, randomized, double-blind trials to evaluate the effects of statin therapy on muscle events. They studied every adverse event, including the timing of such events, the reasons for stopping statins, use of other medication, and comorbidities, to investigate whether statins cause muscle weakness or pain. Nineteen placebo-controlled trials were included in the meta-analysis, with 123,940 participants at a mean age of 63 years; approximately 28% of subjects were women. The authors sought to examine how any additional risks changed over time among various types of patients and for distinct statin regimens, along with the effect of statin medication on muscle impacts of varying severity.
Researchers found among the entire cohort, 27.1% of patients assigned to statins and 26.6% taking placebo reported at least one episode of muscle pain or weakness during a median of 4.3 years. This represented a 3% relative increase (relative risk [RR] = 1.03; 95% CI, 1.01-1.06). In addition, the higher risk was similar for the different muscular symptoms (e.g., myalgia, cramp or spasm, muscle fatigue, or weakness). During the first year of therapy, statins produced a 7% relative increase in muscle pain or weakness (RR = 1.07; 95% CI, 1.04-1.10), although there was no significant increase thereafter. Researchers calculated that only one in 15 of the muscle-related effects participants reported were caused by the drug. Additionally, they found more than 90% of all reports of muscle symptoms in patients allocated to statins were not caused by the drug. The authors concluded statin therapy caused a small excess of mostly mild muscle pain. They suggested that when a patient reports muscle symptoms while taking a statin, the probability that it is caused by the statin is quite low (less than 10%).
COMMENTARY
Although statin therapy is prescribed widely and successfully across the globe and works well to prevent atherosclerotic CVD, clinicians often remain concerned that it frequently could result in muscle pain or weakness. Statin intolerance caused by SAMS is low in randomized, controlled trials, but much higher in clinical observation studies. Recent evidence has validated SAMS for some patients likely experiencing true intolerance, but for others, has suggested a psychosomatic component or misattribution of the source of pain. This highlights the importance of differentiating from the musculoskeletal symptoms caused by concomitant factors.5
The Cholesterol Treatment Trialists’ Collaboration provided reliable data on the infrequent prevalence of truly statin-intolerant patients. Experts have suggested managing such patients may require candid patient counseling, shared decision-making, treating contributing factors (e.g., osteoarthritis), as well as stopping and reintroducing a statin after a minimum two-week statin-free period, which may help identify the truly statin-intolerant patients. Perhaps it is time clinicians take another look at the management of patients reporting muscle symptoms while on statin therapy. It also may be beneficial to look at the drug labeling, which often leads to negative expectations from patients. In practice, it may be important to consider continuing treatment with statins for most patients until a cause of muscle symptoms can be evaluated rather than impulsively discontinuing statins.
REFERENCES
1. Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 Study. J Am Coll Cardiol 2020;76:2982-3021.
2. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-2561.
3. Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: Systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021;374:n1537.
4. Taylor BA, Thompson PD. Muscle-related side-effects of statins: From mechanisms to evidence-based solutions. Curr Opin Lipidol 2015;26:221-227.
5. Backes JM, Ruisinger JF, Gibson CA, Moriarty PM. Statin-associated muscle symptoms-Managing the highly intolerant. J Clin Lipidol 2017;11:24-33.
A review of large-scale, randomized, double-blind trials of statin therapy suggested statins are responsible for only a small excess of muscle pain symptoms in patients taking these drugs.
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