Simvastatin limits both biochemical and functional adaptations to exerciseLiterature - Mikus CR, Boyle LJ; Borengasser SJ et al. - J Am Coll Cardiol. 2013;62(8):709
Simvastatin Impairs Exercise Training Adaptations
Mikus CR, Boyle LJ; Borengasser SJ et al.
J Am Coll Cardiol. 2013;62(8):709 doi:10.1016/j.jacc.2013.02.074
BackgroundThe metabolic syndrome refers to several inter-related factors, including insulin resistance, central adiposity, hypertension and dyslipidemia, which are associated with increase cardiovascular risk [1,2]. Obesity and a sedentary lifestyle are closely linked to the metabolic syndrome. Improving cardiorespiratory fitness is the first choice of treatment for patients with metabolic syndrome [3-5].
Statins are commonly prescribed to patients with metabolic syndrome. Patients are advised to continue daily exercise during statin therapy.
Statins are also increasingly prescribed to low-risk patients, and to all patients over the age of 50 years for primary prevention of cardiovascular disease . However, statins have been linked to skeletal muscle cramping, pain, myalgia and in rare cases, rhabdomyolysis . Statins are not well-tolerated among top athletes  and may increase sensitivity to muscle damage during exercise [9,10]. Some statins have been shown to reduce skeletal muscle mitochondrial content and oxidative capacity in humans [11-14]. Nevertheless, studies and information on the benefits and risks of combining statins and exercise are limited.
This randomised controlled trial compared the effects of exercise training (n=21) to those of simvastatin plus exercise training (n=20) on changes in cardiorespiratory fitness and skeletal muscle citrate synthase activity, a marker of skeletal muscle mitochondrial content, in statin-naive, previously sedentary, overweight or obese patients with at least two metabolic syndrome risk factors.
- After 12 weeks, the exercise group had statistically significantly reduced body weight (97.9+18.4 to 96.23+18.3) as well as fat mass (38.0+8.5 to 36.6+8.0), while the exercise plus statin group did not lose weight (98.2+19.8 to 98.9+21.4), and fat mass was almost significantly reduced (39.7+11.6 to 39.4+11.9).
- Total cholesterol was reduced by 29% and LDL-c by 38% in the exercise plus statin group, while no significant changes were seen in de exercise group. No HDL-c changes were seen in either group.
- Increases in cardiorespiratory fitness (VO2 peak) in response to the exercise program were significantly attenuated by simvastatin. It increased by 10% after exercise alone, but no change was seen in the exercise plus statin group.
- Exercise-training-induced increases in skeletal muscle citrate synthase activity were prevented by simvastatin. An increase of activity of 13% was seen after exercise alone, and a decrease of 4.5% in the exercise plus statin group (not significant from baseline).
Click on the figures to enlarge or download
ConclusionAfter 12 weeks of aerobic exercise training, simvastatin attenuated improvements in cardiorespiratory fitness and skeletal muscle mitochondrial content, in overweight and obese volunteers at risk for metabolic syndrome. Statins are often prescribed in combination with exercise to lower risk of cardiovascular disease morbidity and mortality. Not all statins may have the same effect on skeletal muscle function. Further research should also focus on whether the effects may be prevented by supplementing for instance coenzyme Q10, or by starting exercise training before statin treatment.
Editorial comment The results in the study by Mikus et al add to existing evidence that statins affect the ability of skeletal muscle to adapt to the stress of exercise training. This is not good news for clinicians trying to convince physically active patients to stay on statins. However, it remains to be elucidated whether the same effect of statins is true for patients who are already physically active, and whether it only occurs after aerobic exercise training. This well-conducted study raises more questions than it answers, although the benefits of statins still clearly outweigh their risks,
1. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735–52.
2. Shaw DI, Hall WL, Williams CM. Metabolic syndrome: what is it and what are the implications? Proc Nutr Soc 2005;64:349–57.
3. Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346:793–801.
4. Kokkinos P, Myers J, Kokkinos JP, et al. Exercise capacity and mortality in black and white men. Circulation 2008;117:614–22.
5. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr., et al. Physical fitness and all-cause mortality: a prospective
study of healthy men and women. JAMA 1989;262:2395–401.
6. Lim GB. Vascular disease: even low-risk individuals can benefit from statin therapy. Nat Rev Cardiol 2012;9:371.
7. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002;40:163–71.
8. Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol 2004;57:525–8.
9. Kearns AK, Bilbie CL, Clarkson PM, et al. The creatine kinase response to eccentric exercise with atorvastatin 10 mg or 80 mg. Atherosclerosis 2008;200:121–5.
10. Parker BA,AugeriAL, Capizzi JA, et al. Effect of statins on creatine kinase levels before and after a marathon run. Am J Cardiol 2012;109:282–7.
11. Sirvent P, Mercier J, Vassort G, Lacampagne A. Simvastatin triggers mitochondria-induced Ca2þ signaling alteration in skeletal muscle. Biochem Biophys Res Commun 2005;329:1067–75.
12. Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 2006;291:C1208–12.
13. Sirvent P, Bordenave S, Vermaelen M, et al. Simvastatin induces impairment in skeletal muscle while heart is protected. Biochem Biophys Res Commun 2005;338:1426–34.
14. Wu JS, Buettner C, Smithline H et al. Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications. Muscle Nerve 2011;43:76–81.
15. Thompson PD, Parker B. Statins, exercise, and exercise training. J Am Coll Cardiol. 2013 Aug 20;62(8):715-16
Download Mikus jacc 2013 PACE.pptx