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.


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?

8 Responses to “True or False: Fitness Program + Statin = No Fitness Program?”

  1. Enrique Guadiana, Cardiology says:

    Since the the study has a unblended design. I have a question. When you perform the CPX stress test, How do you decide the patient have reach the max oxigen uptake? Do you have similar RER CO2/vO2 at maximal oxigen uptake in the two grups? What happen with the anaerobic treshold? Physician and patient motivation is an important factor to take in acount in unblended designs.

    • Catherine R Mikus, PhD says:

      Thank you for your questions. As you mention, we use physiological measures (peak RER, peak HR, plateau in oxygen consumption despite increase in workload) to determine whether or not participants are giving their maximal effort during the treadmill test, and, thus, it is unlikely that the lack of change in cardiorespiratory fitness in the statins plus exercise group may be attributed to poor effort during the post-intervention test. Peak heart rate and peak RER were similar between the groups at baseline and following the intervention; again, indicating that a lack of motivation does not explain our findings. Finally, we know that changes in skeletal muscle mitochondrial content and function are closely related to changes in fitness in response to exercise training, and the lack of improvement in skeletal muscle mitochondrial content in the statins plus exercise group serves as basic science support of our clinical findings.

      As for your question about the lack of change in fat mass in the group taking statins, we can tell you that it is not uncommon for participants to unconsciously adjust their food intake to maintain weight balance when they initiate an exercise training program. There have been a few small studies which indicate that statins may interfere with lipid metabolism during exercise; however, our study was not designed to test this.

      What is clear is that this an area that warrants further study.

  2. Enrique Guadiana, Cardiology says:

    Maybe my question is not clear let me try again. VO2 peak was obtained when participants reached volitional exhaustion and met at least 3 of the following criteria: 1) respiratory exchange ratio 1 .10, 2) peak heart rate within 10 beats of age predicted maximum, 3) rating of perceived exertion  18, or 4) plateau in oxygen consumption despite increase in workload. The RER absolute measure in the two groups are comparable? Do you measure the anaerobic threshold? Do you measure the VO2/HR? I understand we have evidence of statin and deleterious muscular effect. In my cardiac rehab program I have observe blunt responses but no effect is extremely rare. So an analysis of max RER, anaerobic threshold and VO2/HR could bring more light.

  3. If this study is supported by more and larger investigations, the findings obviously represent a major problem. Millions of people are told to take statins and are advised to exercise. It may be that low doses of statins will not be a problem, but we need the data to show that. In addition, it may be possible use other approaches to prevent statins from interfering with exercise-induced gains. For example, the Deichman et al. study published last year suggests that adding CoQ10 may be helpful, but this also needs to be verified with further research. Another approach may be to determine whether or not there is a relative-time effect. For example, if the statin is taken many hours before or after exercise, perhaps it will not reduce the exercise effect? However, the first task is to determine the extent to which the current finding replicates, in what groups, and with which doses of the various statins.

  4. Enrique Guadiana, Cardiology says:

    In the study the patient has a 12 week supervised exercise training program. They reported a body weight and fat mass significant decrease only in the exercise no statin group. If you have a significant increase in energy expenditure for 12 weeks X 45 min X 5 days exercise. How do you explain the lack of change in body weight and fat mass in the statin group? Did they increased the food calories? Does the statin impairs the use of fat as energy source? Do the statins abolish the increase of energy expenditure during exercise so they didn’t require to use fat as energy source? Do the statins slow the metabolism? How do you explain these results?

  5. Regarding Dr. Guadiana question. Statins impair metabolism in various ways. There are data that increased quantities of fructose leads to rapid stimulation of lipogenesis and accumulation of triglycerides (Seneff S[Author] ). One may find some answers elsewhere: “… Muscle cell walls are more vulnerable to oxidation and glycation damage due to increased fructose concentrations in the blood, reduced cholesterol in their membranes, and reduced antioxidant supply” – see “How Statins Really Work Explains Why They Don’t Really Work” – by Stephanie Seneff – – or other Seneff´s papers.

  6. Regarding Dr. Guadiana question. Statins impair metabolism in various ways. There are data that increased quantities of fructose leads to rapid stimulation of lipogenesis and accumulation of triglycerides (Seneff S pubmed/22291727). Moreover with statins, muscle cell walls are more vulnerable to oxidation and glycation damage due to increased fructose concentrations in the blood, reduced cholesterol in their membranes, and reduced antioxidant supply.” See also Stephanie Seneff.

  7. Enrique Guadiana, Cardiology says:

    Thank you Dr. Kostek it’s an excellent point. This study is fascinating. They don’t mention in the conclusions that body weight and fat mass significant decrease only in the exercise no statin group. The authors didn’t discuss this result and this part also have significant relevance in clinical practice. I am aware the statins affect glucose and fructose metabolism, increases whole body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction, even though statins do not affect insulin resistance in adipose tissue, it has been demonstrated that lipophilic statins can indeed change the expression of adipokines. Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1 expression and Simvastatin induce changes in adipose tissue morphological properties causing adverse effects on adiponectin secretion from adipocytes. Statins also deplete coenzyme-Q bioavailability, which is responsible for H2S catabolism through mitochondrial oxidation. I believe all this information don’t completely explain the anthropometric results and I couldn’t find any reports, alerts or scientific studies regarding weight loss or weight gain as a side effect of statin use. In my practice, mostly secondary prevention, and I don’t use simvastatin, is very infrequent blunt responses to supervise exercise prescription especially in sedentary overweight / obese patients. If this prove to be truth it will have significant consequences in clinical practice. Further research is needed in this area. So it’s an excellent topic for discussion.