Statin Use and Physical Activity: The Importance of Confounding
Editor's Note: Commentary based on Lee DSH, Markwardt S, Goeres L, et al. Statins and physical activity in older men: the Osteoporotic Fractures in Men Study. JAMA Intern Med 2014;174:1263-1270.
Myalgias, weakness, and fatigue are among the commonly reported adverse effects of statins. In this study, Lee et al. sought to determine whether statin use is associated with physical activity in older men.1
This was a multicenter prospective cohort study (N=5,994) of community-living men aged 65 years and older enrolled from 2000-2002. Statins were evaluated in cross-sectional (N=4,137) and longitudinal analyses (N=3,039). Outcomes included self-reported physical activity using the Physical Activity Scale for the Elderly (PASE) and accelerometer-measured metabolic equivalents (METS).
At baseline, 989 men (24%) were statin users and 3,148 (76%) were nonusers. In cross-sectional analysis, adjusted baseline PASE differed by -5.8 points (95% CI, -10.9 to -0.7) between users and nonusers. In longitudinal analysis, 727 (24%) patients were considered to be "prevalent users" who remained on statins throughout the study duration, 845 (28%) were "new users" initiated on statins during follow-up, and 1,467 (48%) were nonusers. Mean PASE score declined by a nonsignificant difference of 0.3 points per year (95% CI, -0.5 to 1.0) for nonusers compared to prevalent users. For new users, mean annual PASE declined by 0.9 points (95% CI, 0.1 to 1.7) faster than nonusers. Using accelerometry data, statin users were found to expend 0.03 less METS (95% CI, 0.02-0.04), engage in 5.4 fewer minutes (95% CI, 1.9-8.8) of moderate physical activity, and 0.6 fewer minutes (95% CI, 0.1-1.1) per day of vigorous activity.
Based on these results, the authors concluded that statin use was associated with modestly lower physical activity among community-living men.
In this investigation published by Lee et al., the authors sought to determine whether statin use was associated with physical activity in older men,1 and concluded from cross-sectional and longitudinal analyses that statins were associated with modestly lower physical activity among community-living men. Although this is indeed an important question that warrants investigation, we believe there are major epidemiological flaws in the authors' analyses that render the results inconclusive.
As noted in the accompanying editorial to the article,2 a major analytical concern in this study is confounding. The classical definition of confounding is when a variable is causally associated with the dependent variable (physical activity in this study) and causally or non-causally associated with the independent variable of interest (statins in this study). So the negative association of statin use with physical activity reported in this study could be present if a condition that is associated with less physical activity is more common in statin users, and these factors were not accounted for in multivariable analysis.
This is exactly the case in the report by Lee et al. In Table 1 of the authors' study, it is immediately evident that there are important and expected differences between statin users and nonusers. Strikingly, 30% of statin users had angina compared to only 7.5% of nonusers. Statin users were also twice as likely to have heart failure (6% versus 3%). Certainly having exertional angina and active heart failure symptoms would greatly limit one's physical activity irrespective of any mechanistic effects of HMG-CoA reductase inhibition! Furthermore, the authors do not directly adjust for these major differences among the two populations. In their "fully" adjusted models in Tables 2 and 3 of the study, they fail to include angina or active heart failure symptoms.
In the longitudinal sub-study, the PASE score declined at a comparable annual rate between "prevalent" statin users and nonusers with no statistical difference. Finally, using accelerometry data, the authors concluded that statin users expended 0.6 fewer minutes of vigorous physical activity per day (i.e., 36 less seconds), and 0.03 less METS than nonusers. Even if statistically significant, it is hard to believe that differences such as 0.03 less METS or 36 less seconds of daily vigorous activity is a clinically significant difference between users and nonusers.
In summary, based on cross-sectional data with inadequate adjustment for confounding, longitudinal data showing no difference in fitness decline, and accelerometry data showing statistical but likely not clinical differences between physical activity for statin users and nonusers, we cannot see how the authors came to the conclusions they did. Further investigation is needed to begin to answer this question more accurately.
- Lee DSH, Markwardt S, Goeres L, et al. Statins and physical activity in older men: the Osteoporotic Fractures in Men Study. JAMA Intern Med 2014;174:1263-1270.
- Golomb BA. Statins and activity: Proceed with caution. JAMA Intern Med 2014 Aug 1. [E-pub ahead of print].
Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Muscular Diseases, Myalgia, Motor Activity
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