Effects of Statin Use on Muscle Strength, Cognition, and Depressive Symptoms in Older Adults

Joseph V. Agostini, MD; Mary E. Tinetti, MD; Ling Han, MD, MS; Gail McAvay, PhD, MS; JoAnne M. Foody, MD; John Concato, MD, MS


J Am Geriatr Soc. 2007;55(3):420-425. 

In This Article


This study examined statin use in a representative sample of older male veterans who had been taking statins for an average of 2 years before enrollment. These analyses took advantage of longitudinal data on outcomes not routinely evaluated in clinical trials and provided an opportunity to try to address postmarketing surveillance concerns about adverse medication effects. Evidence was not found to suggest that continued statin use adversely affects muscle strength, cognition, or depressive symptoms. Although minimal changes were noted across these domains when chronic statin users were compared with nonusers in subgroups at higher potential risk from statin effects, a trend toward greater depressive symptoms was found in patients with greater comorbidity.

These findings are important, because previous randomized clinical trials of statin use have enrolled selected (generally younger) patients with few comorbidities. In addition, important endpoints reported in those clinical trials—such as risk of myocardial infarction, stroke, and death—did not capture other outcomes that are important to older patients, including risks of physical, social, and psychological decline. In particular, when medication effectiveness has not been clearly established, older patients may place a lower priority on the potential for long-term benefits than on the risk for harms that could lead to functional decline.

The strength of the evidence concerning the effect of statins on noncardiac outcomes is important to consider; few of the associations reported herein have been studied in large clinical trials. Forexample, two randomized, controlled trials of cognitive outcomes in middle-aged adults taking simvastatin or lovastatin showed evidence of declines in some, but not all, tests of neuropsychological performance,[12,14] although the clinical significance and generalizability of these findings to older adults is unclear.

One study demonstrated that lovastatin users experienced modest adverse changes in four of 17 neuropsychological tests of cognitive performance: attention,psychomotor speed, working memory, and overall cognitive functioning.[14] In a subsequent study focused on simvastatin use, similar small decrements in performance were noted.[12] As in the current study, performance on the Trail Making Test B was not affected, although the difference in times between Trail Making Test Parts A and B (or the ratio of B:A) has been reported to be a better indicator of the executive component of cognition.[29] Although the relationship between statin exposure and myopathic changes is well documented, data on its effect on basic daily functioning in older adults are scant.

Finally, in contrast to previous observational cohort and case-control studies,[15,17,18] the evidence from a recent nested case-control study of lipid-lowering drugs[30] and a randomized, controlled trial of simvastatin[31] does not support an association with development of depression, although the data from the current study suggest that additional studies in older, high-risk subgroups may be indicated, because these groups have not been well represented in studies. A planned randomized, controlled trial focusing on statin exposure and several noncardiac outcomes (e.g., changes in cognition and depression symptoms) may yield further insights.[32]

Statins lead to lower circulating lipid levels, which are associated with altered neurochemical changes at the cellular level.[33] In particular, mitochondrial dysfunction after statin use has been postulated as a mechanism for muscle-related effects.[10] The potential for more-extensive physiological changes supports examining cognitive and mood-related measurements in older adults taking these drugs.[34] One-year outcomes were examined, and it was hypothesized that changes with medication use would be detectable after 12 months of use, but this study was not designed to establish the definitive time course of potential adverse effects. Future studies could ascertain outcomes at other time intervals to clarify the findings reported here.

Several aspects of this study deserve comment. Residual confounding related to participants with better health being more likely to receive statin therapy cannot be completely excluded. In addition, because patients receiving VA health care who were mainly male and white were enrolled, these findings may not be generalizable to women or minorities. Although it is possible that some veterans received statins from outside the VA system, recruitment from patients in primary care clinics and the strong financial incentive for patients to obtain these drugs more inexpensively inside the VA would tend to minimize this occurrence. Also, the population was not an inception cohort of patients taking newly prescribed statins. The vast majority of statin users had been taking the medications available on the VA pharmacy's formulary for at least 1 year before enrollment, suggesting that they had tolerated the medications. It was also assumed that participants remained on the same statin regimen throughout the follow-up period. Medication refill histories and examination of serial cholesterol levels could have provided additional data regarding interim adherence to a statin regimen.

This study addresses the effects of long-term statin use on measures of muscle strength, cognition, and depression. The risk of adverse effects cannot be estimated for users who discontinued treatment soon after initiation and thus were not taking statins at the time of the current study. Accordingly, the frequency of "early" adverse effects may have been underestimated. (In the statin nonusers group, only six (1.4%) were found who had past statin use in their electronic records from 1996 forward.) Finally, statin use could deleteriously affect more-discriminating tests that measure muscle strength, cognition, and depressive symptoms (other than the tests reported here), and certain individuals might still be at high risk, but their effects could be obscured within a larger population's "average" observed changes over time. Because statins share a similar pharmacological mechanism of action, statins were grouped together; larger studies may have adequate statistical power to discern whether there are differences in outcomes for particular statins.

Despite the overall safety record of statin medications, it is important to examine the full spectrum of possible adverse effects of drugs in older adults. Because a suggestion of potential harm was found in some subgroups in this study, further investigation of the benefit-risk ratio of statin use in different subgroups is warranted. Investigators should consider assessing medications' benefits and harms in a broader range of persons than typically enrolled in randomized clinical trials, particularly in older adults with multiple comorbidities and in other high-risk subgroups.

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