Statin-associated muscle symptoms (SAMS) are defined as a wide spectrum of muscle symptoms, including muscle aches, weakness, soreness, stiffness, cramping, tenderness, or general fatigue, associated with statin initiation. SAMS adverse events reports vary from blinded randomized control trials (1%–5%) to observational studies (7%–29%).1,2 A recent metanalysis reported that during the first year, statin therapy produced a 7% relative increase in SAMS, also highlighting that only 1 of 15 SAMS adverse event patient reports were actually the result of the statin3. These may be also be due to the so-called nocebo effect. In fact, Gupta et l,1 in a randomized, double-blind, placebo-controlled trial and its nonrandomized nonblind extension phase, described an increased rate of adverse events reports only when both patients and their doctors were aware of statin therapy use and not when they were blinded. Therefore, it is possible that there is adverse event overreporting. Because statins play a major role in cardiovascular disease prevention, it is crucial for physician to partner with the patient to gain a thorough symptom history and determine if he or she is truly statin intolerant.2–5

SAMS usually involve both sides of large muscle groups (eg, buttocks, calves, shoulder girdle, thighs) and mostly develop between 4 and 6 weeks from statin initiation or increase.6 Several risk factors have also emerged from several studies that may help to stratify patients at an increased risk of SAMS development, including medicine or food interactions (eg, CYP3A4A inhibitors), high-dose statin therapy, history of myopathy with other lipid-modifying medicines, regular vigorous physical activity, impaired hepatic or renal function, substance abuse (eg, alcohol, opioids, cocaine), female gender, and low body mass index.6 However, further studies are needed to better clarify the association between risk factors and SAMS. In fact, Al-Makhamreh et al,7 in their observational retrospective cohort study, did not confirm gender, and both kidney and hepatic impairment association with an increased risk of SAMS onset, giving more prominence instead to the presence of autoimmune diseases. Moreover, a recent metanalysis pointed out that statin therapy causes approximately 11 additional reports of any muscle pain or weakness per 1000 patients during the first year, with only a little increase thereafter, with some evidence of persistent risk for more intensive regimens.3

A better detection and definition of SAMS has been addressed in the past as a crucial point to improve patient treatment adherence.6 Moreover, in a systematic review, it was reported that 5%–15% of the patients ceased the medication due to adverse events onset. Of these, some patients complained that they were not properly informed about side effects before starting statin treatment.8 Al-Makhamreh et al,7 in their recent article, have reported a non–statistically significant difference between patients experiencing SAMS and the control group. This finding might be due to the improvement in doctor–patient relationship, to patient involvement in assessing and managing adverse effects, which rarely represent a life-threatening condition (myopathy incidence is ∼1 in 10,000 per year; rhabdomyolysis incidence ∼1 in 100,000 per year), and to the increase in patient knowledge about the risk–benefit ratio of statin therapy use and discontinuation.6,7

However, although on the one hand, Al-Makhamreh et al reported encouraging data about SAMS, on the other hand, they have given an alert to the scientific community for the urgency of improving drug adherence. In fact, lack of adherence among statin and control groups were 28.9% and 28.0%, respectively.7 In this scenario, it becomes clear that clinicians can still do a lot to improve patient adherence. It has been pointed out that inquiring about medication-taking behavior, developing a trusting relationship, improving continuity of care, understanding the role of family support, identifying nonsupportive family member behaviors, understanding patient's financial situation, and suggesting the best treatment for all budgets could represent a good path on the way to patient adherence improvement.9,10

1. Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389:2473–2481. 2. Rosenson RS, Baker SK, Jacobson TA, et al., The national lipid association's muscle safety expert panel. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8:S58–S71. 3. 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. 4. Gentile S, Turco S, Guarino G, et al. Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia. Diabetes Obes Metab. 2000;2:355–362. 5. Sasso FC, Pafundi PC, Gelso A, et al.; NO BLIND Study Group. High HDL cholesterol: a risk factor for diabetic retinopathy? Findings from NO BLIND study. Diabetes Res Clin Pract. 2019;150:236–244. 6. Stroes ES, Thompson PD, Corsini A, et al.; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36:1012–1022. 7. Al-Makhamreh HK, Toubasi AA, Obaid YY, et al. The significance of statin associated muscle symptoms and its impact on patients adherence and outcomes. J Cardiovasc Pharmacol. 2022. 8. Ingersgaard MV, Helms Andersen T, Norgaard O, et al. Reasons for nonadherence to statins - a systematic review of reviews. Patient Prefer Adherence. 2020;14:675–691. 9. Caturano A, Brunelli V, Galiero R, et al. Comment on: warfarin adherence and anticoagulation control in atrial fibrillation patients-a systematic review. Eur Rev Med Pharmacol Sci. 2022;26:1068–1069. 10. Brown MT, Bussell J, Dutta S, et al. Medication adherence: truth and consequences. Am J Med Sci. 2016; 351, 387–399.