Commentary based on Allard NAE, Janssen L, Aussieker T, et al. Moderate intensity exercise training improves skeletal muscle performance in symptomatic and asymptomatic statin users. J Am Coll Cardiol 2021;78:2023–37.¹

Rationale:

Does moderate-intensity exercise affect muscle and exercise performance in symptomatic and asymptomatic statin users and non-statin users?

Methods:

Baseline muscle biopsies were obtained from symptomatic (n=16; age 64±4 years) and asymptomatic statin-users (n=16; age 64±4 years) with non-statin users (n=20; age 63±5 years) used as control subjects. Statin users were considered symptomatic using the statin myalgia index score.² Peak oxygen consumption (VO2, maximal exercise performance), muscle performance and symptoms were determined. All participants completed a 12-week endurance and resistance training program. Repeat biopsies were then collected to assess various markers of muscle performance including citrate synthase activity, adenosine triphosphate (ATP) production capacity, muscle fiber type distribution (type 1 vs. type 2), fiber size, and capillarization. Exercise performance, muscle symptoms and quality-of-life were also re-evaluated.

Results:

Fifty-two participants (33 men and 19 women) completed the study. Most statin-users were taking simvastatin (n=17), with a minority taking atorvastatin (n=8) and rosuvastatin (n=5). At baseline, symptomatic statin users had higher pain-rating index than control subjects (P<0.01) and asymptomatic statin users (P<0.001), and higher fatigue scores than control subjects (P<0.05). Slow-twitch type I muscle fibers were less prevalent in symptomatic statin users than in control subjects (P=0.06). Following the 12-week program, muscle strength (P<0.001), resistance to fatigue (P=0.01), and muscle fiber capillarization (P<0.01) were significantly improved across all groups without differences between groups. Exercise training improved citrate synthase activity in the total group (P<0.01). Muscle fiber size, VO2, ATP production capacity, and muscle symptoms remained unchanged in all groups following training. Quality-of-life scores improved only in symptomatic statin users following the training program (P<0.01).

Conclusions:

Muscle performance, capillarization, and mitochondrial content in both asymptomatic and symptomatic statin users were improved by moderate-intensity endurance and resistance training without changing frequency or intensity of muscle complaints.

Perspective:

The prevention of primary and secondary atherosclerotic cardiovascular disease (ASCVD) relies on optimizing cardiovascular health metrics as well as appropriate pharmacotherapy, the mainstay of which is statin therapy.³ Statins reduce cardiovascular mortality and morbidity by multiple mechanisms including plaque stabilization, atherosclerosis regression, and reduction in inflammation.^4,5 However, statin use and dose optimization can be limited due to SAMS.⁶ For example, an estimated 60% of adults report muscle pain as the primary reason for discontinuation.⁷

SAMS encompass a spectrum of muscle symptoms ranging from aches and soreness to myopathy (weakness) or myositis, often considered to include several distinct entities that may overlap in presentation.² The mechanism by which statins cause muscle symptoms is not well understood and felt not always truly attributable to statin pharmacology.⁸ Posited factors include myocyte cellular membrane changes, impaired mitochondrial enzyme activity and genetic factors, electrolyte disturbances, and hypothyroidism.^9,10 Low vitamin D has been associated with higher rates of myalgia and myopathy, remediated by repletion.¹¹ Statins are also noted to cause SAMS at different frequencies related to liver CYP enzyme pharmacokinetics. For instance, SAMS were reported at a higher frequency in individuals who used simvastatin (18.2%) [metabolized by CYP3A4] compared with fluvastatin (5.1%) [metabolized by CYP2C9] in the PRIMO Study.^12,13

Appropriately, patients should be informed about the potential adverse effects that may occur when initiating statin therapy. Untowardly, this counselling may facilitate the nocebo effect, i.e., negative symptoms perceived in anticipation of a potentially harmful treatment.¹⁴ This phenomenon may help to explain the variation in reported rates of SAMS when comparing practice and observational studies with randomized trials.¹⁵ Indeed, as demonstrated in n-of-1 studies and cross-over randomized control trials, treatment cessation has been shown to be prompted by placebo at similar frequency to statin therapy.^16,17 Novel to the literature, Allard et al. provide evidence that regular exercise of at least moderate-intensity can be encouraged in statin-users with muscle-related symptoms without worsening of symptoms or performance and possible improvements in quality of life.

Importantly, this study adds to the limited armamentarium of approaches for the management of SAMS. In addition to statin re-challenge (lower dose or alternative), and evaluation and management of alternative causes of muscle-related symptoms, clinicians may now suggest the addition of exercise in appropriate patients. It remains to be determined if exercise-related increases in the proportion of type I muscle fibers (typically used for endurance exercises) is an effective strategy to improve muscle performance in symptomatic statin users. Parallel to n-of-1 trials to assess statin drug effect, exercise therapy may be considered to individualize treatment.¹⁸

This study may also serve to argue against the value of CoQ10 supplementation among those with SAMS. Mitochondrial dysfunction resulting from a reduction in circulating/intramuscular CoQ10 has served as an attractively plausible explanation for muscle-related symptoms.¹⁹ In the current study, ATP production (for which CoQ10 is a precursor) was unchanged before and after activity.¹ This is aided by evidence from the LIFESTAT (Living with Statins) Study which demonstrated that simvastatin-treated patients with muscle symptoms had decreased levels of mitochondrial respiration by muscle biopsy, but comparable CoQ10 levels to the control group.²⁰

Potential limitations of the study include its small cohort size, limiting the generalizability of the findings. The lack of change in peak exercise performance over the 12-weeks raises the concern as to whether the exercise regimen was sufficient to result in adaptations necessary to reveal differences among the groups which may eventually manifest under more intense exercise regimens.

Ultimately, this study advocates for exercise of moderate intensity, as an adjunct to statin therapy, even in the presence of SAMS. Future studies of higher-intensity and/or longer-duration exercise regimens would be welcome to provide clinicians further guidance on statin prescribing for those with muscle symptoms. Nonetheless, clinicians may feel more assured to provide encouragement and reassurance in terms of statin and exercise initiation/continuation in select patients with SAMS.

References

1. Allard NAE, Janssen L, Aussieker T, et al. Moderate intensity exercise training improves skeletal muscle performance in symptomatic and asymptomatic statin users. J Am Coll Cardiol 2021;78:2023–37.
2. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA, 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:S58-71.
3. Physical Activity Guidelines for Americans, 2nd edition (health.gov). 2018. Available at: https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf. Accessed 01/20/2022.
4. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.
5. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207-13.
6. 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 Heart J 2015;36:1012-22.
7. Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol 2013;7:472–83.
8. Taylor BA, Sanchez RJ, Jacobson TA, et al. Application of the statin-associated muscle symptoms-clinical index to a randomized trial on statin myopathy. J Am Coll Cardiol 2017;70:1680–81.
9. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res 2019;124:328–50.
10. Patel J, Martin SS, Banach M. Expert opinion: the therapeutic challenges faced by statin intolerance. Expert Opin Pharmacother 2016;17:1497-507.
11. Michalska-Kasiczak, M., Sahebkar, A., Mikhailidis, DP, et al. Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol 2015;178:111–16.
12. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med 2005;165:2671–76.
13. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 2005;19:403–14.
14. Colloca L, Miller FG. The nocebo effect and its relevance for clinical practice. Psychosom Med 2011;73:598-603.
15. Tobert JA, Newman CB. The nocebo effect in the context of statin intolerance. J Clin Lipidol 2016;10:739-47.
16. Wood FA, Howard JP, Finegold JA, et al. N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med 2020;383:2182–84.
17. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90.
18. Herrett E, Williamson E, Brack K, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlledn-of-1 trials. BMJ 2021;372:n135.
19. Qu H, Guo M, Chai H, Wang W-T, Gao Z-Y, Shi D-Z. Effects of coenzyme Q10 on statin-induced myopathy: an updated meta-analysis of randomized controlled trials. J Am Heart Assoc 2018;7:e009835.
20. Dohlmann TL, Morville T, Kuhlman AB, et al. Statin treatment decreases mitochondrial respiration but muscle coenzyme Q10 levels are unaltered: the LIFESTAT study. J Clin Endocrinol Metab 2019;104:2501-08.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Sports and Exercise Cardiology, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet, Exercise

Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quality of Life, Myalgia, Atorvastatin, Citrate (si)-Synthase, Cytochrome P-450 CYP2C9, Cytochrome P-450 CYP3A, Fluvastatin, Rosuvastatin Calcium, Cardiovascular Diseases, Control Groups, Nocebo Effect, Quality Indicators, Health Care, Resistance Training, Simvastatin, Oxygen Consumption, Vitamin D, Muscle Strength, Dietary Supplements, Mitochondria, Withholding Treatment, Adenosine Triphosphate, Atherosclerosis, Hypothyroidism, Inflammation, Muscle Fibers, Skeletal, Electrolytes, Counseling, Respiration, Morbidity, Biopsy, Myositis, Fatigue, Pharmaceutical Preparations

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