https://orcid.org/0000-0002-5714-0907
-
PDF
- Split View
-
Views
-
Cite
Cite
Giovanna Liuzzo, Carlo Patrono, Solid evidence that very few muscle symptoms are due to statin therapy, European Heart Journal, Volume 44, Issue 1, 1 January 2023, Pages 12–13, https://doi.org/10.1093/eurheartj/ehac620
Close - Share Icon Share
Comment on the article ‘Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials’, presented at the European Society of Cardiology Congress 2022 and simultaneously published in the Lancethttps://doi.org/10.1016/S0140-6736(22)01545-8.
To estimate the risk of muscle symptoms (pain or weakness) with the use of statins, the Cholesterol Treatment Trialists’ Collaboration (CTTC) analyzed individual participant data from 19 large-scale, long-term, randomized, double-blind, clinical trials (RCTs) of statin vs. placebo (n = 123 940) and four RCTs of a more intensive vs. a less intensive statin regimen (n = 30 724).1
In trials comparing statin use against placebo [mean age 63 ± 8 years, 28% women, 48% with cardiovascular disease (CVD), 19% with diabetes] during a weighted average median follow-up of 4.3 years, 27.1% of the statin group and 26.6% of the placebo group reported muscle pain or weakness [rate ratio (RR), 1.03; 95% confidence interval (CI), 1.01–1.06]. The RRs were similar for each term used to categorize muscle symptoms. Statin therapy produced a 7% relative increase in muscle pain or weakness during the first year (RR 1·07; 95% CI 1·04–1·10) corresponding to an absolute excess of 11 (95% CI, 6–16) per 1000 person-years, but no significant increase thereafter. Although the rate of reporting of any muscle pain or weakness varied substantially by trial, there was no evidence that the RR for the comparison of statin vs. placebo depended on the absolute reporting rate. Approximately 1 in 15 reports of muscle symptoms (<10% of reports) during the first year were attributable to statin therapy.
In trials comparing a more intensive vs. a less intensive statin regimen (mean age 62 ± 9 years, 26% women, 100% with known CVD, median duration of follow-up 4.9 years), more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once daily) were associated with a larger relative increase in the rate of muscle pain or weakness [RR, 1.08 (95% CI, 1.04–1.13)] compared with low-intensity or moderate intensity regimens [RR, 1.03 (95% CI, 1.00–1.05)], for all years combined. Additionally, a modest RR excess was observed for more intense regimens after the initial year.
There was no conclusive proof that the RR varied for various statin preparations (including hydrophilic vs. lipophilic groups) or under different clinical conditions. Besides, the median creatine kinase (CK) levels increased by a negligible amount (around 0.02 times the higher limit of normal) following statin medication.
Comment
European and North-American Societies of Atherosclerosis recognized that there is evidence for causality for three statin-related adverse effects: statin-associated muscle side effects, new-onset diabetes, and transient elevations of liver enzymes, with muscle symptoms being the most common complaint during statin treatment.2 Systematic reviews and meta-analyses of RCTs, as well as the results of N-of-1 studies, have confirmed the safety of statins, reporting that the risk of myopathy and its progression to severe rhabdomyolysis are rare and suggesting that symptomatic adverse events may be misattributed to statins.3–7 Indeed, the association between muscle symptoms and statins have suffered the bias of observational unblinded studies, reinforced by drug labelling and misleading sources of information, contributing to the so-called ‘nocebo’ or ‘drucebo’ effect, whereby negative expectations can lead to perceived adverse effects. This phenomenon often leads to patients discontinuing or being hesitant to start treatment with statins. Nonadherence to statin therapy might be as high as 60% after 24 months of treatment, and it is associated with a 70% increase in the risk of cardiovascular disease events.8
The CTTC meta-analysis1 confirmed that statin intolerance is over-diagnosed. The small excess in risk observed was related to events that did not lead to treatment discontinuation, confirming previous observation,3 and did not result in a clinically significant increase in CK. Thus, most episodes of muscle pain or weakness caused by statins were clinically mild. Moreover, no new risk of statin-associated muscle symptoms after a year was found, apart from a small effect associated with high-intensity therapy. As participants with muscle symptoms generally continued treatment, the absence of any significantly increased risk after the first year is not explained by statin discontinuation.
The availability of individual participant data was the main strengths of the CTTC meta-analysis, allowing for more detailed risk analyses for each statin than have previously been possible, including analyses examining the effects on particular symptoms, the timing of any excess risk, and the variation in treatment effects in different types of patients. Indeed, there was no evidence that risk estimates were biased by excluding patients with comorbidities, as relative risks were similar in studies that recruited patients with diabetes, heart failure, or chronic kidney disease.
However, the results of this meta-analysis should be interpreted with caution. The patients enrolled in the trials included in the meta-analysis were highly selected, and optimally monitored; most trials excluded patients with a history of statin-associated muscle symptoms, or who developed symptoms in the run-in period; the exclusion criteria of trials listed risk factors (alcoholism) and conditions (drug-drug interactions) that increase the risk of statin intolerance. Given the strict exclusion criteria, the finding that no clinical circumstances increased the risk of statin-associated muscle symptoms needs to be assessed carefully. However, this finding might suggest that if the management of diabetes, chronic kidney disease, and chronic liver disease is optimized (as it was in the patients included in these trials), these conditions would not increase the risk of statin intolerance.
Other potential limitations are recognized by the authors. First, there was considerable heterogeneity in the methods used to ascertain muscle symptoms and definitions varied from trial to trial. Second, not all adverse event data were available (missing data represented < 1%); in addition, data on discontinuation of treatment, on some relevant comorbid conditions (such as hypothyroidism) or on concomitant medications that could affect the risk of having symptoms, were not consistently available. Third, CK levels were not measured every time muscle pain or weakness occurred, so the authors were unable to assess whether some of the symptoms were associated with large increases in CK. However, among the cases for which data on CK concentrations were available, > 96% were less than three times the ULN. The exclusion of patients with previous statin sensitivity or hypersensitivity might explain the non-significant increase in CK in the statin group, and myopathy being observed in 13 patients (0.08%).
Nevertheless, the known protective effects of statins against CVD greatly exceed the slightly increased risk of muscle symptoms. For example, for every 1000 people taking a moderate intensity statin, treatment would cause 11 generally mild episodes of muscle pain or weakness in the first year with no significant excess in subsequent years. Over a 5-year period, statins typically prevent 50 major vascular events in every 1000 people with pre-existing CVD and 25 major events in those with no pre-existing CVD, with longer treatment yielding larger benefits.8
These results suggest that if the diagnosis of statin intolerance is approached using the available algorithms and if reversible risk factors for statin intolerance are addressed (nocebo or drucebo effects, drug–drug interactions, or conditions associated with increased risk of statin intolerance, e.g. hypothyroidism or renal impairment),9,10 then statin intolerance might be expected in only one in 100 patients.1 Effective lipid-lowering therapies are therefore possible in the vast majority of patients.
The data of the current meta-analysis do not imply that the genuine concerns of people who do experience muscle symptoms should be dismissed, but there is a clear need to both review the clinical management of muscle symptoms in patients taking statins and to revise drug label information.
References
Author notes
Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programmes of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.
