Commentary to Accompany
In patients with or at risk for atherosclerotic vascular disease, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are one of the most commonly prescribed medications; they significantly reduce serum cholesterol levels and the risk of future cardiovascular (CV) events. Statins are well tolerated by most patients; however, they can result in significant side effects involving skeletal muscle. Although the incidence of rhabdomyolysis is rare, the incidences of myalgias, myositis, and weakness are much more common, occurring with a frequency as low as 1% among patients in pharmaceutical trials but in as many as 25% of patients in clinical practice because many potential subjects are excluded from trials due to pretrial symptoms and medication intolerance (1). Statin-induced myopathies not only decrease patients’ quality of life but also limit their use of this powerful therapy for CV disease prevention. In this issue’s excellent review by Parker and Thompson (1), the best available evidence on statin-induced myopathy is summarized, highlighting many of the knowledge gaps in this field. Some of the key unanswered questions are related to the interaction between statins and exercise on skeletal muscle.
In healthy individuals, exercise can induce skeletal muscle injury under conditions in which the energy supply of skeletal muscle is insufficient to meet its metabolic demands. The susceptibility to exercise-induced skeletal muscle injury is increased in untrained individuals and by numerous factors, such as heat, humidity, intravascular volume depletion, and serum electrolyte disturbances. The risk of exercise-induced skeletal muscle injury may be increased by the use of statin therapy. The mechanism for this process is unclear, but it has been linked to coenzyme Q10 depletion, mitochondrial dysfunction, and alteration of the ubiquitin proteasome pathway (1). In a randomized controlled trial, lovastatin increased creatinine kinase levels compared with placebo after eccentric exercise via downhill treadmill exercise (3). However, as discussed in the accompanying review, several other potential factors, such as age, genetics, and vitamin D levels, may modify the relation between statins and exercise-induced myopathy (1). Because of these and many other unanswered questions, there is a strong need for more randomized placebo-controlled trials of statin therapy that evaluate the effects of statins on a range of skeletal muscle outcomes affected by both acute exercise and exercise training.
The need for greater understanding of the effects of the combined use of statins and exercise on skeletal muscle is underscored by new evidence demonstrating that statins increase the risk of incident diabetes mellitus (2). Because skeletal muscle is one the major tissue beds regulating whole-body insulin sensitivity, statin-induced diabetes may be mediated by statin-induced changes in the skeletal muscle. Furthermore, exercise is related intimately to insulin sensitivity, and this effect is mediated by biochemical changes in skeletal muscle, raising concern that the process of exercise-induced improvements in insulin sensitivity and other metabolic parameters may be unfavorably modified by statin therapy. Indeed, the accompanying review cites some evidence that statin therapy may unfavorably modulate whole-body lipid metabolism, thereby setting the stage for diabetes. Presumably, skeletal muscle would be a primary target for this effect because of its high metabolic capacity and large contribution to whole-body mass.
Despite each of their known effects on skeletal muscle, our understanding of the interactions between statins and exercise on the skeletal muscle is still in its infancy. Dyslipidemias and physical inactivity are both major global health challenges, so the need for combined therapy with statins and exercise training in CV disease prevention has become increasingly important. As a result, the scientific imperative for a more rigorous understanding of the interactions between statins and exercise is clear. Such an understanding will not only shed key insights into basic skeletal muscle and exercise physiology but also will inform treatment plans to optimize the effects of statins and exercise training in CV disease prevention.
William E. Kraus
Mahesh J. Patel
Department of Medicine, Division of Cardiology
Duke University School of Medicine
1. Parker BA, Thompson PD. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes. Exerc. Sport Sci. Rev
. 2012; 40: 118–24.
2. Sattar N, Preiss D, Murray HM, et al.
Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet
. 2010; 375: 735–42.
3. Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism
. 1997; 46: 1206–10.