September 14, 2022
The Lancet
TAKE-HOME MESSAGE
This large meta-analysis investigated the effects of statins on muscle symptoms over time based on data from 154,664 participants in 23 double-blind trials. The relative increase of muscle pain or weakness was <10% (1 in 15 patients), mainly during the first year of statin use. It also confirmed that high-intensity treatment was associated with an increased risk of muscle-related symptoms; however, these were mild and the patients could adhere to treatment.
Statin intolerance is infrequent, and the onset of muscle-related symptoms after the first year of therapy is unlikely to be caused by statins. Patient reassurance and encouragement to ensure treatment adherence are paramount given the compounding yearly benefits of statin therapy for cardiovascular prevention.
– Giselle A. Suero-Abreu, MD, PhD, MSc
Written by Paul D. Thompson MD
Were Clinicians Right All Along?
Whether or not statins can cause statin-associated muscle symptoms (SAMS) such as pain, weakness, and cramps without clinically important elevations in creatine kinase levels has been debated for years. Clinical trialists maintained that SAMS did not exist because there was no increase in SAMS in their best data — randomized controlled clinical trials (RCTs) — whereas clinicians maintained that SAMS did exist, at least in some of their individual patients. Well, here’s the news: the clinical trialists have just used individual patient data from their RCTs to suggest that the clinicians were right all along.
The Cholesterol Treatment Trialists’ Collaborative analyzed data from more than 150,000 patients enrolled in 23 RCTs to demonstrate that statins produced a 7% increase in SAMS (95% CI, 4%–10%) but an excess of only 11 complaints per 1000 patient years (95% CI, 6–16). This increase only occurred during year 1. More intensive statin treatment produced an 8% increase (95% CI, 4%–13%) in year 1, with a 5% statistically insignificant (95% CI, –1% to +12%) increase after year 1.
These small absolute increases in SAMS are trivial compared to statins’ ability to decrease cardiovascular risk, but this report probably underestimates the incidence of SAMS. Participants in RCTs are different from our usual patients in ways too numerous to enumerate. The present analysis included some RCTs that used a statin run-in period to eliminate nonadherent subjects who might also have been statin intolerant. The trialists’ data does not indicate that this affected the results, but one wonders. The methods used to detect SAMS varied among the studies, possibly leading to a “don’t ask and we won’t tell” underestimation of SAMS.
But this is an important report. It reaffirms that clinicians should encourage patients to remain on these life-saving drugs because true SAMS are rare, but it also confirms what clinicians have long suspected: some patients get SAMS. This report may also curtail the argument as to whether or not SAMS exist and encourage more research into what causes SAMS so that we can keep patients on these life-saving drugs.
Abstract
BACKGROUND
Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy.
METHODS
Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol.
FINDINGS
Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01-1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04-1·10), corresponding to an absolute excess rate of 11 (6-16) events per 1000 person-years, which indicates that only one in 15 ([1·07-1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96-1·02). For all years combined, more intensive statin regimens (ie, 40-80 mg atorvastatin or 20-40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04-1·13] vs 1·03 [1·00-1·05]) compared with placebo, and a small excess was present (1·05 [0·99-1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal.
INTERPRETATION
Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin.