Statin therapy, while well-tolerated by the majority of patients, can be associated with muscle-related side effects and may exacerbate CK release and presumably the skeletal muscle damage associated with eccentric exercise. However, gaps in physiological, molecular, mechanistic and clinical knowledge regarding muscle effects of statin therapy remain substantial, with many unresolved issues and equivocal findings. Key questions include:
- Are statin-induced muscle side effects a continuum from myalgia to rhabdomyositis, and caused by similar mechanisms? This is an important question for clinicians who must decide whether or not continuing statin therapy in myalgic subjects increases the risk of life-threatening rhabdomyolysis.
- Should clinicians discontinue statin use for several days prior to endurance events, especially if heat stress or other potential exacerbators of rhabdomyolysis may occur? The latter could be particularly important for older runners who appear more likely from our 2011 Boston Marathon to experience muscle injury.
- Can we develop better, more consistent, screening and testing techniques to assess individuals who may be at risk for myalgia, decreases in muscle strength and aerobic performance, and increased muscle damage with statin treatment? This could include genetic profiles designed to identify genes associate with statin muscle complaints.
- Are statin-associated muscle complaints altered by acute and chronic physical activity, and what other factors contribute to the relationship between statins and skeletal muscle function? Discrepant results regarding the effects of statins on muscle strength, aerobic performance, and CK levels following exercise suggest that multiple additional factors influence the effects of statins on skeletal muscle at rest and during exercise. To date, although evidence supports the hypothesis that acute and chronic resistance and aerobic exercise may exacerbate statin-associated muscle complaints in some individuals, there are a paucity of carefully controlled, adequately powered, rigorously designed studies to fully document this.
- Finally, can increases in creatine kinase associated with exercise and statin therapy be confirmed with more direct measurements of muscle damage in human subjects that also provide important information about underlying mechanisms such as apoptosis, calcium handling, and oxidative stress? The majority of human studies on this topic have assessed noninvasive markers of muscle damage or assessed molecular and genetic pathways in resting skeletal muscle treated with statin therapy. There are also limited animal studies investigating statin-induced skeletal muscle damage with exercise.
A recent editorial in the New England Journal of Medicine emphasized the need for clinical trials in statin-intolerant patients (14). There is a similar need for large-scale trials investigating the effects of statins on skeletal muscle strength, aerobic performance, and exercise-induced muscle damage over a long-term duration of treatment, in individuals with and without statin myalgia. To this end, we have recently completed data collection of an NHBLI-funded (The Effect of STatins On Skeletal Muscle Function and Performance, or STOMP) study assessing creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo treatment for 6 months in 420 healthy, statin-naive subjects (30). We believe that these emerging results will address several of the inconsistencies in the literature to date regarding impacts of statin therapy on muscle and aerobic outcomes. Nonetheless, with an aging population, ever-lowering LDL cholesterol guidelines, and increasing numbers of statin prescriptions, research aimed at better elucidating the relationship between exercise, statin therapy and skeletal muscle will be critical for refining treatment guidelines.
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