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Impact of Statins on Physical Activity and Fitness: Ally or Adversary?

  • Barry A. Franklin
    Correspondence
    Correspondence: Address to Barry A. Franklin, PhD, Preventive Cardiology and Cardiac Rehabilitation, Beaumont Health Center, Area C, 4949 Coolidge Hwy, Royal Oak, MI 48073.
    Affiliations
    Preventive Cardiology and Cardiac Rehabilitation, William Beaumont Hospital, Royal Oak, MI
    Oakland University William Beaumont School of Medicine, Rochester, MI
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  • Carl J. Lavie
    Affiliations
    Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, LA
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      Statin drugs, in my view, are the best cardiovascular drugs ever created, in that they have the greatest potential to prevent atherosclerotic plaques and their complications, and they also have the greatest potential to arrest plaque formation, and therefore, to prevent additional atherosclerotic events. The statin drugs are to atherosclerosis what penicillin was to infectious diseases.—William C. Roberts
      • Roberts W.C.
      The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease.
      Since their introduction nearly 3 decades ago, statins (ie, 3-hydroxy-3-methylglutaryclo enzyme A reductase inhibitor drugs) have become widely prescribed in the primary and secondary prevention of cardiovascular (CV) disease (CVD) because of their favorable impact on lipid/lipoprotein metabolism and patient survival.
      • Gutierrez J.
      • Ramirez G.
      • Rundek T.
      • Sacco R.L.
      Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis.
      Recent randomized controlled trials and meta-analyses
      • Gutierrez J.
      • Ramirez G.
      • Rundek T.
      • Sacco R.L.
      Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis.
      • Kostis W.J.
      • Cheng J.Q.
      • Dobrzynski J.M.
      • Cabrera J.
      • Kostis J.B.
      Meta-analysis of statin effects in women versus men.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      JUPITER Study Group
      Rosuvastin to prevent vascular events in men and women with elevated C-reactive protein.
      have reported 20% to 44% reductions in cardiac events after the initiation of statin therapy, with comparable cardioprotective benefits for men and women. Despite the salutary effects, there are some unintended consequences of statins, including being linked to muscle pain, cramps, and fatigue, which may lead to reduced levels of physical activity (PA) and/or structured aerobic exercise. Moreover, statins have been associated with a higher incidence of diabetes mellitus (DM),
      • Stattar N.
      • Preiss D.
      • Murray H.M.
      • et al.
      Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials.
      elevation in serum creatine kinase concentrations (a widely used biomarker of muscle tissue injury), liver dysfunction, inflammation, and myopathy,
      • Stroes E.S.
      • Thompson P.D.
      • Corsini A.
      • et al.
      European Atherosclerosis Society Consensus Panel
      Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
      • Desai C.S.
      • Martin S.S.
      • Blumenthal R.S.
      Non-cardiovascular effects associated with statins.
      • Auer J.
      • Sinzinger H.
      • Franklin B.
      • Berent R.
      Muscle- and skeletal-related side-effects of statins: tip of the iceberg?.
      as well as attenuated training-induced increases in cardiorespiratory fitness (CRF) levels.
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      Reductions in PA and/or CRF levels—whether drug related or not—are particularly troubling, in view of their strong inverse relation with CV and all-cause mortality,
      • Franklin B.A.
      • Brinks J.
      • Sacks R.
      • Trivax J.
      • Friedman H.
      Reduced walking speed and distance as harbingers of the approaching Grim Reaper.
      and the fact that structured aerobic exercise and the positive aspects of drug therapy appear to offer similar mortality reductions in the secondary prevention of coronary heart disease (CHD).
      • Naci H.
      • Ioannidis J.P.
      Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study.
      In this issue of Mayo Clinic Proceedings, Williams and Thompson
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      provide an insightful epidemiological report on these aforementioned issues by evaluating a large cohort of physically active individuals who were diagnosed with hypercholesterolemia and whether a potential decrease in the level or intensity of exercise was greater in those treated with statins than in those who were not.
      To clarify the impact of statin therapy on levels of habitual PA, the investigators used the well-established National Runners’ and Walkers’ Health Study database, the largest epidemiological cohort specifically created to assess the health outcomes associated with long-term participation in moderate-to-vigorous exercise regimens (ie, walking or running) in men and women with and without CVD, including CHD. The study population included 66,377 runners and 12,031 walkers not using cholesterol medications at baseline, who were initially surveyed and resurveyed over a mean follow-up of 7.2±1.7 years.
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      The standardized survey questionnaires included extensive queries on (1) exercise practices; (2) whether study participants used specific medications to treat high cholesterol levels, hypertension, or DM; and (3) whether they developed “incident hypercholesterolemia” during follow-up, defined as initiating drug therapy for the condition or self-reported physician diagnosis of high cholesterol levels. Additional questions included demographic information (eg, age, sex, height, and weight), smoking status, dietary practices, alcohol consumption, and comorbid conditions, including a history of CHD.
      The investigators found that statins per se were not associated with a reduced exercise level or intensity (which Williams and Thompson
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      suggest is good news for patients and the physicians who counsel them). Specifically, among individuals who were diagnosed with hypercholesterolemia, and with the passage of time, exercise levels decreased comparably in patients in whom statins were and were not used. These intriguing results raise the potential for reverse causality; that is, a decrease in exercise levels potentially resulted in adverse physiological and clinical responses, including hypercholesterolemia, which prompted the initiation of statin therapy, rather than statin therapy reducing the level of habitual PA.
      Limitations of the observational study included analyses that were based on self-reported survey data and the fact that most participants were taking low-dose statins, which may have been less likely to adversely impact their walking and running regimens. Other potential confounding variables include the adherence to, or the duration of statin use, and intercurrent illness or injury.

      Impact of Statins on PA and CRF

      Over the past decade, 11 relevant observational studies and randomized controlled trials
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      • Sinzinger H.
      • O’Grady J.
      Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems.
      • Traustadóttir T.
      • Stock A.A.
      • Harman S.M.
      High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults.
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      • Lee D.S.
      • Markwardt S.
      • Goeres L.
      • et al.
      Statins and physical activity in older men: the Osteoporotic Fractures in Men Study.
      • Rengo J.L.
      • Savage P.D.
      • Toth M.J.
      • Ades P.A.
      Statin therapy does not attenuate exercise training response in cardiac rehabilitation.
      • Terpak K.
      • Guthrie S.
      • Erickson S.
      Statin use and self-reported swimming performance in US masters swimmers.
      • Qureshi W.T.
      • Keteyian S.J.
      • Brawner C.A.
      • Dardari Z.
      • Blaha M.J.
      • Al-Mallah M.H.
      Impact of statin use on cardiorespiratory fitness in multi-racial men and women: the Henry Ford Exercise Testing (FIT) Project.
      • Panza G.A.
      • Taylor B.A.
      • Thompson P.D.
      • et al.
      The effect of atorvastatin on habitual physical activity among healthy adults.
      (as summarized in the Table ) evaluated the interactive effects of PA (including the types of training regimens, lifestyle activity, or both), CRF, and statin use in young, middle-aged, and older adults. According to one report,
      • Sinzinger H.
      • O’Grady J.
      Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems.
      only 20% of 22 highly trained athletes with familial hypercholesterolemia were able to tolerate any of the 5 statins then available. In another observational study, Lee et al
      • Lee D.S.
      • Markwardt S.
      • Goeres L.
      • et al.
      Statins and physical activity in older men: the Osteoporotic Fractures in Men Study.
      noted that PA declined more in older men (age, ≥65 years) who had recently initiated statin therapy than in statin nonusers. Over the follow-up period, older men receiving statins engaged in modestly less moderate and less vigorous PA and had more sedentary behavior. However, the generalizability of these population-specific observational findings—which were further limited by recall bias, short-duration accelerometer data collection, and the inability to account for numerous potential confounding variables—is tenuous at best.
      TableInteractive Effects of Physical Activity, Cardiorespiratory Fitness, and Statin Treatment in Young, Middle-Aged, and Older Adults
      Reference, yearPopulationAge (y)Study designMajor findings
      Sinzinger and O’Grady,
      • Sinzinger H.
      • O’Grady J.
      Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems.
      2004
      22 highly trained athletes with FH13-35Descriptive/observational∼20% of professional athletes with FH tolerate statin treatment without adverse effects.
      Traustadóttir et al,
      • Traustadóttir T.
      • Stock A.A.
      • Harman S.M.
      High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults.
      2008
      9 men, 1 woman with LDL-C levels >3.3 mmol/L (130 mg/dL)55-76Descriptive/observationalAfter 12 wk of simvastatin treatment (80 mg/d), no significant changes were observed in V˙o2max, endurance, or measures of muscle function.
      Parker et al,
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      2013
      420 healthy, statin-naive men and women41-47RCT; atorvastatin (80 mg/d) vs placeboAfter 6 mo, there was no adverse effect of atorvastatin on muscle strength or exercise capacity; however, increased myalgia and CK levels were noted.
      Mikus et al,
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      2013
      37 inactive, overweight/obese adults with ≥2 MS risk factors25-59RCT; exercise vs exercise plus statinsV˙o2max increased 10% in the exercise-only group, but only 1.5% in the exercise-plus-simvastatin group. Similarly, SMCSA increased, respectively, by 13% and decreased by 4.5% in these groups.
      Kokkinos et al,
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      2013
      10,043 veterans with dyslipidemia59±11Descriptive/observationalStatin treatment and increased CRF are independently associated with lower mortality in veterans with dyslipidemia (see Figure 2).
      Lee et al,
      • Lee D.S.
      • Markwardt S.
      • Goeres L.
      • et al.
      Statins and physical activity in older men: the Osteoporotic Fractures in Men Study.
      2014
      5994 participants in the Osteoporotic Fractures in Men Study≥65Descriptive/observationalOver a 6.9-y follow-up, men receiving statins engaged in modestly less moderate and vigorous physical activity (∼10%) and more sedentary behavior.
      Rengo et al,
      • Rengo J.L.
      • Savage P.D.
      • Toth M.J.
      • Ades P.A.
      Statin therapy does not attenuate exercise training response in cardiac rehabilitation.
      2014
      1201 patients undergoing exercise-based cardiac rehabilitation65±11Descriptive/observationalImprovements in V˙o2peak were 3.2 and 3.1 mL/kg per minute for statin users and nonusers, respectively. Long-term statin use does not attenuate aerobic training effects.
      Terpak et al,
      • Terpak K.
      • Guthrie S.
      • Erickson S.
      Statin use and self-reported swimming performance in US masters swimmers.
      2015
      749 adult masters swimmers and 558 controls≥35Descriptive/observational (survey, self-reported)Statin use was not associated with decreased self-reported swimming performance, considering the frequency, duration, or intensity of workouts.
      Qureshi et al,
      • Qureshi W.T.
      • Keteyian S.J.
      • Brawner C.A.
      • Dardari Z.
      • Blaha M.J.
      • Al-Mallah M.H.
      Impact of statin use on cardiorespiratory fitness in multi-racial men and women: the Henry Ford Exercise Testing (FIT) Project.
      2015
      17,264 participants in the FIT Project59±8Descriptive/observationalStatin use was not significantly associated with lower peak METs in this large multiracial cohort of men and women.
      Panza et al,
      • Panza G.A.
      • Taylor B.A.
      • Thompson P.D.
      • et al.
      The effect of atorvastatin on habitual physical activity among healthy adults.
      2015
      418 statin-naive adults44±16RCT; atorvastatin vs placeboSedentary time increased and physical activity decreased in the total study population during 6 mo of drug treatment, independent of group assignment.
      Williams and Thompson,
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      2015
      66,377 runners and 12,031 walkers in the NRWHS∼21-82Descriptive/observational (survey, self-reported)Decreased exercise activity occurred similarly in runners and walkers who developed hypercholesterolemia, irrespective of statin treatment.
      CK = creatine kinase; CRF = cardiorespiratory fitness; FH = familial hypercholesterolemia; FIT = Henry Ford Exercise Testing Project; LDL-C = low-density lipoprotein cholesterol; MET = metabolic equivalent (1 MET = 3.5 mL/kg per minute); MS = metabolic syndrome; NRWHS = National Runners’ and Walkers’ Health Study; RCT = randomized controlled trial; SMCSA = skeletal muscle citrate synthase activity; V˙o2max = maximal oxygen consumption; V˙o2peak = peak oxygen consumption.
      Of the remaining 9 studies reviewed, 3 reported that statin use per se was unrelated to habitual PA
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      • Terpak K.
      • Guthrie S.
      • Erickson S.
      Statin use and self-reported swimming performance in US masters swimmers.
      • Panza G.A.
      • Taylor B.A.
      • Thompson P.D.
      • et al.
      The effect of atorvastatin on habitual physical activity among healthy adults.
      ; 2 found that statins were not associated with lower exercise capacity, expressed as peak metabolic equivalents (METs), or impaired exercise trainability
      • Rengo J.L.
      • Savage P.D.
      • Toth M.J.
      • Ades P.A.
      Statin therapy does not attenuate exercise training response in cardiac rehabilitation.
      • Qureshi W.T.
      • Keteyian S.J.
      • Brawner C.A.
      • Dardari Z.
      • Blaha M.J.
      • Al-Mallah M.H.
      Impact of statin use on cardiorespiratory fitness in multi-racial men and women: the Henry Ford Exercise Testing (FIT) Project.
      ; and an additional 2 noted that statins were unrelated to changes in muscle strength or exercise capacity.
      • Traustadóttir T.
      • Stock A.A.
      • Harman S.M.
      High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults.
      • Parker B.A.
      • Capizzi J.A.
      • Grimaldi A.S.
      • et al.
      Effect of statins on skeletal muscle function.
      In contrast, Mikus et al
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      randomized sedentary overweight or obese adults (n=37) with 2 or more metabolic syndrome risk factors to 12 weeks of supervised aerobic exercise training alone (n=19) or in combination with 40 mg/d of simvastatin (n=18). CRF levels increased by 10% (P<.05) with training in the exercise-only group, but only 1.5% in the exercise-plus-simvastatin group (P<.005 for group-by-time interaction). Citrate synthase activity, a measure of skeletal muscle mitochondrial content, increased by 13% in the exercise-only group (P<.05), but decreased by 4.5% in the exercise-plus-statin group (P<.05 for group-by-time interaction). The investigators concluded that statins (or at least simvastatin, which potentially has the propensity for more muscle adverse effects than do other statins) attenuate exercise training–associated adaptations in patients at risk for the metabolic syndrome, signified by reduced improvement in CRF levels and contrasting citrate synthase responses. Elsewhere, Kokkinos et al
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      reported that statin treatment and increased CRF levels, when combined, provided independent and additive survival benefits in military veterans with dyslipidemia. The discrepancy between clinical trial evidence and selected epidemiological associations may have been due to the lack of a placebo-treated or control group in some studies.
      • Panza G.A.
      • Taylor B.A.
      • Thompson P.D.
      • et al.
      The effect of atorvastatin on habitual physical activity among healthy adults.

      Exercise Plus Statins: A Synergistic Combination?

      If the current mantra “exercise is medicine” is embraced, the mortality benefits of prescribed PA should be comparable to those of commonly prescribed cardioprotective medications, and under- and overdosing are possible.
      • O’Keefe J.H.
      • Franklin B.
      • Lavie C.J.
      Exercising for health and longevity vs peak performance: different regimens for different goals.
      In men and women with and without CHD, each 1-MET increase in CRF levels is associated with an approximately 15% reduction in CV mortality, which, in the post–myocardial infarction population, compares favorably with the survival benefit conferred by low-dose aspirin, statins, β-adrenergic blockers, and angiotensin-converting enzyme inhibitors.
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis.
      • Boden W.E.
      • Franklin B.A.
      • Wenger N.K.
      Physical activity and structured exercise for patients with stable ischemic heart disease.
      Another review of prospective cohort studies and randomized controlled trials in patients with established CHD sought to provide evidence for a prognostic benefit of lifestyle modification, including structured exercise. Effect estimates for higher levels of PA approximated a 25% lower risk of all-cause mortality.
      • Iestra J.A.
      • Kromhout D.
      • van der Schouw Y.T.
      • Grobbee D.E.
      • Boshuizen H.C.
      • van Staveren W.A.
      Effect size estimates of lifestyle and dietary changes on all-cause mortality in coronary artery disease patients: a systematic review.
      Moreover, a recent meta-analysis
      • Naci H.
      • Ioannidis J.P.
      Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study.
      that included 305 randomized controlled trials and 339,274 participants reported comparable survival benefits of exercise treatment vs drug interventions in the secondary prevention of CHD. In patients with stroke, exercise interventions were more effective than drug treatment.
      As compared with the Adult Treatment Panel III guidelines,
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
      implementation of the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of blood cholesterol
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      would increase the number of US adults who would be eligible for statin treatment by 12.8 million, with the greatest increase in adults between the ages of 60 and 75 years without CVD.
      • Pencina M.J.
      • Navar-Boggan A.M.
      • D’Agostino Sr., R.B.
      • et al.
      Application of new cholesterol guidelines to a population-based sample.
      These new guidelines
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      make recommendations about the appropriate statin therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels in the following patient subsets:
      • 1.
        patients with clinical CHD;
      • 2.
        patients with LDL-C level of greater than 190 mg/dL (to convert mg/dL values to mmol/L, multiply by 0.0259), such as those with familial hypercholesterolemia;
      • 3.
        patients with DM who are 40 to 75 years of age with LDL-C levels between 70 and 189 mg/dL and without evidence of CHD; and
      • 4.
        patients without evidence of CHD or DM who are 40 and 75 years of age with LDL-C levels between 70 and 190 mg/dL and a 10-year CHD risk of more than 7.5%.
      Exercising regularly appears to have CV mortality benefits that are similar to those of statin therapy, but with other salutary effects (Figure 1).
      • Myers J.
      • Kokkinos P.
      • de Araüjo C.G.
      Coronary artery disease prevention: Should exercise, statins, or both, be prescribed?.
      For example, statins tend to increase the incidence of DM,
      • Stattar N.
      • Preiss D.
      • Murray H.M.
      • et al.
      Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials.
      whereas regular moderate-to-vigorous exercise appears to reduce the incidence of DM by a similar magnitude. An increase in PA levels also improves insulin action in obesity, with or without a concomitant reduction in body weight and fat stores.
      • Kelley D.E.
      • Goodpaster B.H.
      Effects of physical activity on insulin action and glucose tolerance in obesity.
      This is an important (and often overlooked) salutary effect, suggesting that PA is as efficacious in preventing insulin resistance as losing body weight. In addition, long-term exercise has been shown to improve CRF levels or exercise capacity; enhance cognition; reduce fall risk, body weight, and fat stores; and improve quality of life—all of which have relevance to improved health outcomes.
      • Myers J.
      • Kokkinos P.
      • de Araüjo C.G.
      Coronary artery disease prevention: Should exercise, statins, or both, be prescribed?.
      In contrast, statins have little or no effect on these variables.
      • Myers J.
      • Kokkinos P.
      • de Araüjo C.G.
      Coronary artery disease prevention: Should exercise, statins, or both, be prescribed?.
      Figure thumbnail gr1
      Figure 1Comparison of the effects of exercise training and statins on varied risk factors and health outcome modulators in the prevention of initial and recurrent cardiovascular events. Although both regular exercise and statins appear to confer substantial reductions in cardiovascular mortality, there are numerous independent and additive benefits of exercise over statins when other variables are considered.
      • Myers J.
      • Kokkinos P.
      • de Araüjo C.G.
      Coronary artery disease prevention: Should exercise, statins, or both, be prescribed?.
      Although both higher CRF levels and statin use are effective in reducing CVD risk, until recently few data were available on the impact of these combined interventions on all-cause mortality. To address this question, Kokkinos et al
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      studied 10,043 veterans who had hypercholesterolemia (mean age, 59±11 years) and who underwent exercise testing to determine CRF levels. During a mean follow-up of 10 years, 2318 patients died. Mortality risk was higher in those veterans not taking statins (28% vs 19%). In patients who took statins, mortality risk decreased as CRF levels increased: that is, highly fit individuals (>9 METs) who were taking statins had a 70% lower mortality rate than did the least fit cohort (≤5 METs) who were taking statins. For those not taking statins, the hazard ratio for the least fit participants was 1.35 (95%CI, 1.17-1.54) and it progressively decreased to 0.53 (95%CI, 0.44-0.65) for those in the highest CRF quartile (Figure 2). In a recent subgroup analysis of these data,
      • Myers J.
      • Kokkinos P.
      • de Araüjo C.G.
      Coronary artery disease prevention: Should exercise, statins, or both, be prescribed?.
      researchers found that among veterans in the highest quintile of CRF (>10 METs), the marked reduction in mortality (when compared to unfit individuals) was similar regardless of whether statins were taken or not. These findings suggest that middle-aged and older adults who can achieve more than 10 METs during exercise testing (implying the partial or complete attainment of stage IV [or higher] on the Bruce treadmill protocol or the ability to run at a 6 mph pace or faster) receive little or no additional benefit from taking statins for CHD prevention.
      Figure thumbnail gr2
      Figure 2Mortality risk, expressed as fully adjusted hazard ratios and 95% CIs, for combined cardiorespiratory fitness and statin categories. Patients with a peak MET value of 5.0 or less were classified as “least fit”; those with a peak MET value of 5.1 to 7.0 were classified as “moderately fit”; those with a peak MET value of 7.1 to 9.0 were classified as “fit”; and those with a peak MET value greater than 9.0 were classified as “highly fit.”
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      In summary, the report by Williams and Thompson
      • Williams P.T.
      • Thompson P.D.
      Effects of statin therapy on exercise levels in participants in the national runners' and walkers' health study.
      in this issue of Mayo Clinic Proceedings extends previous studies suggesting that prescribed statins, especially in low-to-moderate doses, do not reduce habitual PA or exercise intensities, at least in any meaningful, clinically important way. With 2 exceptions (see the Table),
      • Mikus C.R.
      • Boyle L.J.
      • Borengasser S.J.
      • et al.
      Simvastatin impairs exercise training adaptations.
      • Lee D.S.
      • Markwardt S.
      • Goeres L.
      • et al.
      Statins and physical activity in older men: the Osteoporotic Fractures in Men Study.
      statins were not associated with reduced PA levels, peak METs, or measures of muscular strength, nor were they associated with impaired exercise trainability. These data and other recent reports
      • Franklin B.A.
      • Brinks J.
      • Sacks R.
      • Trivax J.
      • Friedman H.
      Reduced walking speed and distance as harbingers of the approaching Grim Reaper.
      strongly support the independent and additive benefits of both improved CRF levels and statin therapy on reducing all-cause mortality.
      • Kokkinos P.F.
      • Faselis C.
      • Myers J.
      • Panagiotakos D.
      • Doumas M.
      Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.
      The high prevalence of statin use in the United States and the new guidelines
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      emphasizing more aggressive treatment for more people with higher doses of statins suggest the need for closer monitoring of their potential adverse effects.
      “We doctors can now state from our experience with people, both sick and well, and from a growing series of scientific researches that ‘keeping fit’ does pay richly in dividends of health and longevity.” Like all statements of wisdom, this observation, by the late Dr Paul Dudley White,
      • Franklin B.A.
      Memorable cardiology quotes.
      ,p429 is both elegant and reasoned, and so clearly evident and acceptable today that we feel we should have known it all along. When combined with statin therapy, CRF can provide a powerful survival advantage to the patients we counsel.

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