Musculoskeletal symptoms, including joint and muscle pain, are the most frequently reported statin-associated side effects. Although the incidence rate of muscle problems in statin randomized controlled trials (RCTs) is fairly low, and is similar between statin-treated patients and untreated controls, the reported frequency of muscle problems overall among people taking statins varies considerably. Muscle pain is reported in 5% to 29% of patients in clinical trials, registries, and observational studies.1 Levels of creatine kinase, an indicator of muscle damage, were elevated in some statin users compared to controls.2 In addition, a possible biological basis of muscle toxicity is supported by evidence that statins in some studies decrease mitochondrial function and affect muscle protein degradation in the laboratory.3 Further study is needed to quantify the actual frequency of statin-associated muscle symptoms (SAMS), as well as their biological basis and clinical significance.
The rates of muscle or joint pain that were reported in pre-market trials according to statin package inserts vary considerably from statin to statin and when compared to placebo (Table 1).4–10 While rates of musculoskeletal symptoms in these trials were consistently higher in treated individuals compared to placebo, it is not evident from this data if the differences were clinically or statistically significant. Also, more recent guidelines focus on muscle-specific problems associated with statins and exclude joint symptoms that are more likely attributable to arthritis and other pain syndromes.11,12
Diagnosing SAMS can be challenging because it is difficult to distinguish between self-reported symptoms that are truly caused by the use of a statin and symptoms that are caused by other common sources of musculoskeletal pain such as overuse and chronic pain disorders. The reported incidence of muscle symptoms is often similar among patients taking statins and those taking placebo, as several crossover studies have illustrated. For example, Taylor et al. conducted a double-blind, placebo-controlled crossover study of 120 patients with a history of SAMS. Among the study participants, 35.8% reported muscle symptoms only when taking simvastatin, 17.5% had no symptoms on simvastatin or placebo, 29.2% reported muscle pain when taking placebo but not when they were taking simvastatin, and 17.5% reported pain when taking both simvastatin and placebo.13
The variation in reported muscle adverse events may also be explained by differences in definition used by different study authors.2 The 2014 National Lipid Association’s Muscle Safety Expert Panel examined the definitions used for muscle problems associated with statin use.12 In an attempt to lessen the ambiguity of terminology in clinical trials, they described the spectrum of muscle toxicity as including myalgia (muscle discomfort), myopathy (muscle weakness), myositis (tenderness to palpation or muscle inflammation determined by biopsy or imaging), myonecrosis (mild to severe muscle enzyme elevations), and clinical rhabdomyolysis (myonecrosis with myoglobinuria or acute renal failure). After a review of the relevant literature, they reported the incidence of myalgia to be from 1% to 5% in clinical trials and between 11% and 29% in observational cohorts.
Another estimate of potential statin-associated muscle toxicity is a patient’s decision to discontinue a statin because of patient-perceived muscle problems.1,14 In one survey of 1220 people who had discontinued a statin prescription, 62% gave the main reason for discontinuation to be side effects, predominantly muscle-related symptoms.15 Discontinuation of a statin can increase the risk of cardiovascular events and should be avoided whenever possible.16
Many patients who have side effects respond to a statin re-challenge with an alternate statin or revised dosing of the same statin.12,14,17,18 In the Reasons for Geographic and Racial Differences in Stroke study, 1081 (15%) discontinued treatment, and of those, 593 cited muscle problems from the statins as the cause.19 Of note, 28% of those who discontinued their statin due to SAMS were willing to re-initiate use of a statin, with guidance by their physician.
Two other possible measures of muscle-related effects of statin use are the level of creatine kinase in the blood and exercise performance. Creatine kinase is elevated in the blood after exercise but can also be a measure of muscle damage in the absence of exercise. Parker et al. assessed the effect of atorvastatin 80 mg on 420 statin-naive healthy patients’ muscle function and performance.20 Objective measures of strength and exercise performance did not differ between those on atorvastatin and controls, but muscle complaints and average creatine kinase levels differed significantly between the two groups. Average creatine kinase increased 20.8 ± 14.1 U/L (p<0.0001) with atorvastatin, suggesting that further study is needed to evaluate prolonged use of high-dose statin therapy on muscle function.
Severe muscle damage, necrosis, and rhabdomyolysis can occur in patients taking statins, but this is rare.21 Graham et al. identified a cohort of statin users (n=252,460) from a large health insurance data base from 11 managed care plans in the US to estimate the risk of rhabdomyolysis. The number needed to treat to observe one case of rhabdomyolysis was 22,727 people per year of statin monotherapy.
- Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Hear J 2015; 36: 1012-1022.
- Ganga H V, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Hear J 2014; 168 (1): 6-15.
- Apostolopoulou M, Corsini A, Roden M. The role of mitochondria in statin-induced myopathy. Eur J Clin Invest 2015; 45 (7): 745-754.
- Pravastatin [package insert]. Princeton, NJ: Bristol Myers Squib.
- Pitavastatin [package insert]. Tokyo, Japan: Kowa Pharmaceuticals; 2012.
- Fluvastatin [package insert]. East Hanover NJ: Novartis Pharmaceuticals; 2012.
- Lovastatin [package insert]. Morgantown WV: Mylan Pharmaceuticals.
- Simvastatin [package insert]. Cramlington UK: Merck, Sharpe & Dohne, LTD; 2010.
- Atorvastatin [package insert]. Dublin Ireland: Pfizer Parke-Davis; 2009.
- Rosuvastatin [package insert]. Wilmington DE: AstraZeneca Pharmaceticals; 2010.
- Backes JM, Ruisinger JF, Gibson CA, Moriarty PM. Statin-associated muscle symptoms — managing the highly intolerant. J Clin Lipidol 2019; 11 (1): 24-33.
- Rosenson RS, Baker SK, Frcp C, Jacobson TA, Kopecky SL, Parker BA. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014; 8 (3): S58-S71.
- Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with con firmed statin myopathy. Atherosclerosis 2015; 238 (2): 329-335.
- Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M. Discontinuation of statins in routine care settings. Ann Intern Med 2013; 158 (7): 526-534.
- Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 2012; 6 (3): 208-215.
- Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Hear J 2013; 34 (38): 2940-2948.
- Grundy S, Stone N, Beam C, Birtcher KK, Harm PD. 2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood vholesterol. J Am Coll Cardiol 2019; 73 (24): e285-e350.
- Booth JN 3rd, Colantonio LD, Chen L, et al. Statin discontinuation, reinitiation, and persistence patterns among Medicare beneficiaries after myocardial infarction: a cohort study. Circulation 2017; 10 (10).
- Mefford M, Tajeu S, Tanner M et al. Willingness to be reinitiated on a statin (from the Reasons for Geographic and Racial Differences in Stroke Study). Am J Cardiol 2018; 122 (5): 768-774.
- Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013; 127: 96-103.
- Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2019; 292 (21): 2585-2590.