May 23rd, 2013

Small Study Suggests Statins May Blunt Benefits of Exercise

A small study is raising big questions about whether statins may blunt the beneficial effects of exercise. The study has been published online in the Journal of the American College of Cardiology and is the subject of a New York Times blog.

Some 37 previously sedentary, overweight or obese adults with at least two other risk factors underwent 12 weeks of aerobic exercising training; 19 were randomized to also receive a statin (simvastatin 40 mg/day). At the end of the study, cardiorespiratory fitness, as measured by maximal oxygen uptake, had increased significantly by 10% in the control group but only by 1.5% in the simvastatin group. The control group also had 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, led by John Thyfault at the University of Missouri, say their results “suggest that simvastatin may mitigate improvements in fitness in response to exercise training by impairing increases in skeletal muscle mitochondrial content and function.”

The authors conclude: “Given the strong independent cardio-protective effects of increasing cardiorespiratory fitness or lowering LDL, the benefits and risks of each should be carefully considered when choosing treatment modalities.”

The study raises troubling questions about the interactions of statins and exercise, but its small size, along with other limitations, may hinder its immediate impact. In an accompanying editorial, Paul Thompson and Beth Parker take note of several of these limitations. For one, because the control group did not take a placebo pill, participants were not blinded to their treatment. They cite evidence that people on statins are likely to overestimate the skeletal muscle side effects of statins.

They also note that the researchers did not report whether the two groups achieved similar levels of exercise intensity:

We have observed a reduction in spontaneous physical activity levels in individuals over age 55 years treated with atorvastatin. Knowing whether or not the statin-treated subjects exercise-trained less intensely…would indicate if statins reduced the training stimulus itself or if they reduced the physiological response to a similar training stimulus.

Thompson and Parker also cite a recent analysis published in the Lancet that found that both statins and increased physical fitness were independently associated with low mortality but that “the combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone.” This suggests that the short-term changes in surrogate endpoints seen in the JACC study, even if found to be true, may not result in important long-term differences in health.

Robert Eckel, speaking on behalf of the American Heart Association, raised several other questions about the study. “The bottom line,” he said, is that the simvastatin 40 mg regimen used in the study “may impact on your training,” but that the results would need to be validated for lower doses of simvastatin and for other statins. In addition, he said, the results of a study in a population that does not have established cardiovascular disease should not be extrapolated to people with established disease, in whom  the benefits of statins have been conclusively demonstrated.

4 Responses to “Small Study Suggests Statins May Blunt Benefits of Exercise”

  1. Update–I asked Thyfault to respond to some of Thompson’s points in the editorial, including his concerns about any possible difference between the groups in training intensity and the possible limitations caused by the lack of double blinding. Thyfault responded:

    “We actually first started the study to determine whether the exercise or exercise statins groups would have more powerful effects for lowering metabolic syndrome risk factors, so in essence the subjects were blinded to the fitness/mitochondria side of the story. i.e. they didn’t sign up for a study where they thought the statins would impact their fitness one way or the other.”

    “We monitored all exercise sessions and recorded heart rate, and treadmill speed/intensity every 5 minutes. There was no difference in training intensity between the exercise and exercise+statin groups. I guess we should have more clearly pointed this out in the paper.”

    I also asked Thyfault about his current recommendations regarding exercise and statins:

    “I am a PhD, not a MD so I of course do not make those sort of decisions. But my inclination would be that statins should be reserved for those with very high cholesterol, or previous cardiovascular disease. Prescribing statins to borderline high cholesterol patients or just providing to everyone above a certain age should likely go by the wayside, or at the very least, be cautiously done with the patient and physician knowing there are risks.”

    Finally, I received a comment from Michael Blaha, a cardiology fellow at Johns Hopkins:

    “Indeed statins probably have some mild effects on skeletal muscle. But they clearly prevent heart attacks and are probably life saving in people at increased cardiovascular risk. This article reaffirms the importance of accurate risk prediction, which is the backbone of any approach to preventive medicine. Doctors should continue to selectively prescribe statins to those determined to be at increased cardiovascular risk.”

  2. Leon Hyman, Ms M.D. says:

    The lack of blinding and a placebo significantly lowers the quality of this study. I assume the statin group were told of the muscle risk of simvastatin and probably over reacted to any type of muscle discomfort and held back on their conditioning.

  3. Uffe Ravnskov, MD, PhD says:

    The effect of statins on muscular function may surprise many readers, because according to the statin trials muscular problems occur in less than one percent of the patients. However, muscular problems have been recorded in the trials only if creatine kinase is high, and high CK is defined as a value that is ten times higher than the normal upper limit at two successive determinations, Independent researchers have reported that muscular problems occur in up to 20% of statin-treated patients, at least among patients who are physically active (1). Most interesting is that seventeen out of twenty-two professional athletes with familial hypercholesterolemia treated with statins, stopped because of muscular problems; probably because their results deteriorated (2).

    The habit of recording muscle damage only if CK is elevated is also questionable by another reason. Even in people on statins with normal CK and without any symptoms, the muscle cells may have microscopic signs of damage (3).

    It is not a minor problem because the cheapest and the least risky way to prevent heart disease is regular exercise.

    1. Sinzinger H and others. J Cardiovasc Pharm 40, 163-71, 2002. 46
    2. Sinzinger H, O’Grady J. Br J Clin Pharmacol 57: 525-8, 2004
    3. Phillips PS and others. Ann Intern Med 2002;137:581-5.

  4. Uffe Ravnskov, MD, PhD says:

    There is yet another problem. Whereas adverse effects from other drugs usually occur immediately after the start of the treatment, it may take many months before muscular problems due to statin treatment occur. Both doctor and patient may therefore consider them as a sign of age and continue the treatment.