May 30th, 2013
True or False: Fitness Program + Statin = No Fitness Program?
Catherine Mikus and John Thyfault discuss their study group’s small randomized trial, published in JACC, suggesting that statin use may blunt the benefits of exercise. CardioExchange’s Payal Kohli conducted the interview.
Thirty-seven previously sedentary, overweight, or obese adults with at least two other risk factors for metabolic syndrome were randomized to 12 weeks of aerobic exercising training plus 40 mg/day of simvastatin or to the exercise training alone (control). At the end of the study, cardiorespiratory fitness, as measured by maximal oxygen uptake, had increased by a significant 10% in the control group but by only 1.5% in the simvastatin group. The control group also showed a significant 13% increase in skeletal-muscle citrate synthase activity, a measure of mitochondrial activity in muscles, compared with a 4.5% decrease in the simvastatin group.
THE AUTHORS RESPOND
Kohli: What is the physiological mechanism for the observed results? May there be some heterogeneity between high- and low-potency statins?
Mikus and Thyfault: The precise mechanisms underlying our findings have yet to be elucidated. Some reports have shown that physiologic doses of simvastatin disrupt mitochondrial respiration, increase oxidative stress, and activate mitochondrial apoptotic pathways in skeletal muscle. Therefore, we suspect that statins may induce mitochondrial oxidative stress, thereby activating pathways of apoptosis or autophagy and mitigating increases in mitochondrial content and oxidative capacity in response to exercise training.
Although some statins (simvastatin, cerivastatin, fluvastatin, and atorvastatin) have been shown to induce cell death and impair mitochondrial respiration and beta-oxidation in rodent skeletal-muscle cell lines, others (such as pravastatin) do not exhibit those toxic effects, suggesting that individual statins may differentially affect skeletal-muscle mitochondrial content and function in the absence of exercise. Further studies must evaluate and compare how different classes of statins affect adaptations to exercise training.
Kohli: Statin users often report myalgias that may be exacerbated by aerobic exercise. Were there more patients in the statin group who reported myalgias than in the control group? And did the unblended design influence this issue?
Mikus and Thyfault: Initially, our primary aim was to study the effects of combining exercise and statin use on traditional cardiometabolic risk factors. It was not until the initial cohorts completed the trial that we noticed the conspicuous lack of improvement in cardiorespiratory fitness among participants in the statin-plus-exercise group. So the participants were not aware that we were studying the effects of statin use on changes in cardiorespiratory fitness or markers of skeletal-muscle mitochondrial content in response to exercise training. Thus, although we cannot exclude the possibility that the unblended design may have influenced our findings, it is unlikely that our results are attributable to a placebo effect, especially when the data are considered in light of accumulating evidence of the undesirable effects of statins on skeletal-muscle mitochondrial function.
Our data indicate that statins interfere with specific adaptations to exercise training in skeletal muscle, even among patients whose creatine kinase levels do not change with statin use, suggesting a physiological basis for complaints of muscle fatigue or discomfort that is not captured by current methods for screening and monitoring patients with sensitivities to statins. In our study, two participants in the statin group and none in the control group complained of muscle fatigue and mild myalgia. However, because the study was not designed a priori to evaluate the effects of statins on muscle or joint pain, we had no formal mechanism (e.g., a questionnaire) for systematically evaluating these endpoints; therefore, these data should be interpreted with caution.
Kohli: What are your study’s implications for clinical practice?
Mikus and Thyfault: We are excited that our study is stimulating discussions about pharmaco-lifestyle interactions. Unfortunately, we have much yet to learn. Although the data are not conclusive, some evidence suggests that coenzyme Q10 supplementation or initiating statin therapy and exercise training at different times may protect against some of the potentially unfavorable effects of statins. Alternatively, some statins (e.g., pravastatin) may be less likely to disturb skeletal-muscle mitochondrial content and function.
Our groups and others are working to identify therapeutic options that minimize the adverse effects of LDL-lowering therapies on adaptions to exercise training, but it may be years or even decades before we have sufficient evidence for consensus recommendations. If anything, our data highlight the need for further research into pharmaco-lifestyle interactions. For now, physicians and patients must bear the burden of carefully weighing the risks and benefits of statin use in the clinical setting.
How does this study’s findings affect your thinking about statin use in relation to exercise training?