ACCEL | Statins are highly effective drugs used to reduce LDL cholesterol levels in high-risk patients, particularly for secondary prevention. In recent years, there has been a growing movement to begin prescribing statins to low-risk patients and all patients older than 50 years for the primary prevention of cardiovascular disease. This concept is gaining momentum with the availability of inexpensive, generic statins.

Take-aways Mikus et al. sought to determine if simvastatin impairs exercise training adaptations. Simvastatin was found to attenuate the beneficial increases in cardiorespiratory fitness and skeletal muscle mitochondrial content seen with exercise training. However, a larger study, done in direct response to the results reported by Mikus et al., showed no evidence of such an effect specifically in CHD patients undergoing cardiac rehabilitation.

However, both in research models and clinically, it's clear that statins can have deleterious effects on skeletal muscle. The most serious side effects are myositis and rhabdomyolysis manifested by marked elevations in creatine kinase. Much more common, however, are milder muscle complaints including myalgia, muscle cramps, and weakness. The incidence of such muscle effects in statin studies has been about 10%, although in some studies there has been myalgia reported in the placebo arms, too, leaving about a 6% rate of statin-related myalgia.

Mikus et al. and associates examined the effects of simvastatin on cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training.1 Sedentary overweight or obese adults were randomized to 12 weeks of aerobic exercise training (n = 19) or to exercise in combination with simvastatin (n = 18; 40 mg/day).

Cardiorespiratory fitness increased by 10% in response to exercise training alone, but was blunted by the addition of simvastatin, resulting in only a 1.5% increase. Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group, but decreased by 4.5% in the simvastatin-plus-exercise group.

But Wait, There's More

Given the results reported by Mikus et al., Philip A. Ades, MD, medical director of cardiac rehabilitation (CR) for Fletcher Allen Health Care in Vermont, and colleagues assessed whether statin use blunts exercise training in individuals with coronary heart disease (CHD) participating in CR.² Dr. Ades' team analyzed data prospectively collected on 1,201 patients during the review period, including 968 (81%) in the statin group and 233 (19%) in the non-statin group. (Each completed an exercise program of three sessions per week for 36 sessions.)

In contrast to the study reviewed above, their larger analysis showed no effect of statins on the exercise-induced improvement in VO2 peak during CR. Furthermore, the study by Ades et al. suggested an improved VO2 peak in the range of previously reported values.

Because the exercise training response to CR is linked to improvements in prognosis, Dr. Ades and his coauthors wrote that their findings have relevance to >250,000 individuals participating in CR annually in the United States. "The study by Mikus et al. was limited by not performing a pre-training, on-statin exercise test compared to pre-statin status to assess the acute effect of statins on exercise performance prior to training," they wrote. "Therefore, their results may be explained by an acute reduction in VO2 peak whereas both groups could have trained similarly."

Additionally, Mikus et al. did not include a placebo group. The goal of the study by Ades and colleagues was to investigate training-induced improvements in fitness on or off statin and they said their results suggest "the training response between groups was identical."

Clinical Ramifications

At the time of the original publication in JACC, Mikus et al. and his team noted that their results have direct clinical ramifications as patients at risk for metabolic syndrome are commonly prescribed statins to lower blood lipids and at the same time advised to exercise to improve fitness, both of which are independently proven to lower cardiovascular disease risk. They said simvastatin may mitigate improvements in fitness in response to exercise training by impairing increases in skeletal muscle mitochondrial content and function. Given the strong independent cardioprotective effects of increasing cardiorespiratory fitness or lowering LDL cholesterol, the benefits and risks of each should be carefully considered when choosing treatment modalities.

In an accompanying commentary, Paul D. Thompson, MD, and Beth Parker, PhD, noted that the results by Mikus et al. are not good news for clinicians trying to convince physically active patients to stay on statins,³ and that other studies have suggested that statins affect the skeletal muscle response to exercise and exercise training. For example, only 20% of 22 professional soccer players with familial hypercholesterolemia were able to tolerate any of the five statins available a decade ago.⁴

However, in concluding their paper, Dr. Ades and his group wrote, "our results clearly demonstrate that chronic statin use does not attenuate aerobic training effects in CR patients and the expected survival benefits of CR should, indeed, persist."

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References

1. Mikus CR, Boyle LJ, Borengasser SJ, et al. J Am Coll Cardiol. 2013;62:709-14.
2. Rengo JL, Savage PD, Toth MJ, Ades PA. J Am Coll Cardiol. 2014 March 19. [Epub ahead of print]
3. Thompson PD, Parker B. J Am Coll Cardiol. 2013;62:715-6.
4. Sinzinger H, O'Grady J. Br J Clin Pharmacol. 2004;57:525-8.

To listen to an interview with John Thyfault, PhD, about statins and exercise training, visit youtube.cswnews.org. The interview was conducted by Anthony N. DeMaria, MD.

Keywords: Incidence, Prognosis, Secondary Prevention, Muscle, Skeletal, Cholesterol, LDL, Soccer, Cardiovascular Diseases, Risk Assessment, Simvastatin, Primary Prevention, Exercise Test, CardioSource WorldNews, ACC Publications

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