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. 

Abstract and Introduction

Objectives: To determine the relationship between hydroxymethyl glutaryl coenzyme A reductase inhibitor (statin) use and proximal muscle strength, cognition, and depression in older adults.
Design: Observational cohort study.
Setting: Outpatient primary care clinics.
Participants: Seven hundred fifty-six community-dwelling veterans aged 65 and older.
Measurements: Timed chair stands (a measure of proximal muscle strength), Trail Making Test Part B (a measure of cognition), and the Center for Epidemiologic Studies Depression Scale score were measured at baseline and 1-year follow-up. Participants were assessed for statin prescriptions (and indications for or contraindications to their use), concomitant medication use, comorbidities, and other potential confounders.
Results: Statin users (n=315) took a mean 6.6 medications, versus 4.6 for nonusers (n=441), and had a median duration of statin use of 727 days. Statin users were more likely to be white and had (as expected) more cardiac, cerebrovascular, and peripheral vascular disease. Based on multivariable models adjusting for pertinent covariates, statin users performed modestly better than nonusers for timed chair stands (−0.5 seconds; P=.04), Trail Making Test Part B (−7.7 seconds; P=.08), and depression scores (−0.2 points; P=.49) at follow-up. Of potentially high-risk participants (based on age, comorbidity, and number of medications), statin users also showed similar 1-year changes as nonusers, although worsened depression scores were found in those with greater comorbidity (+0.88 points; P=.10).
Conclusion: Older, community-dwelling male participants taking maintenance statin therapy had similar outcomes to those of nonusers in tests of muscle strength, cognition, and depression, but further examination of benefits and harms in different subgroups is warranted.

Hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) are among the most commonly prescribed classes of medications, with annual sales exceeding $12.5 billion.[1] Data showing benefits of these medications for primary and secondary prevention of cardiovascular events come mainly from adults younger than 80,[2] with scant information available about the safety and efficacy of statins in older adults, mainly because few clinical trials include large numbers of participants from this age group. The decision to prescribe a statin medication for older adults, therefore, relies heavily on extrapolating existing data from younger populations and on balancing potential benefits and harms.[3]

Clinical guidelines cite that older persons taking statins are the highest-risk group for experiencing an adverse event.[4] Several reasons may account for the potential for complications with their use. For example, more medical comorbidities, impaired kidney or liver function, aging-related pharmacokinetic changes, and multiple medication use each may contribute to greater risk of drug toxicity in older adults than in younger persons.[5-7] Several reports have questioned statin safety with regard to muscle function, cognition, and mood. The musculoskeletal risks of statins include myositis (occurring in 0.1–0.5% of users[8]) and subclinical muscle-related problems in older adults,[9,10] although the prevalence has not been quantified. There has been considerable interest in the protective effect of statin use on development of dementia, although evidence for cognitive changes is mixed. Study findings range from cognitive improvement[11] to declines in attention and working memory with statin use.[12-14] Finally, psychological changes (including depression and behavioral change) related to lower cholesterol levels have also been suggested.[15-18]

The possible adverse effects of statins in older adults, coupled with the dearth of evidence demonstrating their benefits in this age group,[3] supports the need for a rigorous evaluation of statin use. Clinical trials often focus on cardiac outcomes, including myocardial infarction and intermediate measures (e.g., cholesterol levels), but these trials may underestimate the potential for adverse effects because of short follow-up, a lack of information on outcomes of relevance to older patients (e.g., cognitive and physical functioning), and nonrepresentative samples of healthier persons with fewer comorbidities.[19] The potential for adverse cognitive, physical, and psychological outcomes, balanced against potential beneficial outcomes such as reduced stroke or myocardial infarction, may influence patient decision-making regarding initiating or continuing daily statin therapy. The compromise between these outcomes are largely unexplored in clinical trials of statins as well as in observational studies of patients in practice settings.

In this context, three outcome domains relevant to statin use were focused on, as reports from the medical literature suggest: proximal muscle strength, cognition, and depressive symptoms. The objective was to determine the relationship between statin use and these outcomes in a cohort of older community-dwelling adults in routine clinical practice.

Methods

The Connecticut Veterans Longitudinal Cohort (N=756) was a prospective cohort of patients receiving primary care at the Department of Veterans Affairs (VA) Connecticut. As previously described,[20] this project assessed a consecutive series of veterans attending VA primary care clinics from July 2000 to August 2001. Inclusion criteria were that subjects be aged 65 and older, English speaking, and ambulatory. Of 935 veterans screened, 767 (82%) agreed to participate. The final study sample included 756 participants who completed the baseline interview. Participants were interviewed and examined in person using standardized questionnaires and protocols at baseline and at 1-year follow-up. The institutional review boards of the VA Connecticut and Yale University School of Medicine approved the study.

Basic demographic data (age, sex, race/ethnicity, and education level) were obtained from patients. Data on medical conditions and other health status variables that might confound the relationship between statin use and the primary outcomes were analyzed as part of the current study. The 19 diseases included in the Charlson Comorbidity Index[21] were used as a summary comorbidity measure and were recorded from diagnoses made by clinicians in the medical record during patient visits or hospitalizations during the year before enrollment, including up to (but not after) the time of the baseline assessment. Evidence of dementia (a potential confounder not assessed in the Charlson index) was recorded in a similar manner. Health behaviors, including alcohol use in the previous month and a history of tobacco use, were documented from patient interviews. The number of primary care visits recorded in the electronic record in the previous year was collected as a severity-of-illness measure. Seven instrumental activities of daily living (IADLs), representing higher-level tasks necessary for independent living (e.g., shopping, bill paying, and meal preparation), were documented from patient self-report during the baseline medical interview.[22] Information was obtained from participants by asking, "Can you (take your own medicine, handle your own money, etc.) without help/with some help/not at all?" Total number of IADL impairments was defined as the number of tasks for which participants required help or were dependent. Baseline cholesterol and transaminase levels were recorded from the medical record on the nearest date before enrollment.

Participants' medications (prescription and over-the-counter) were recorded at baseline and at 1 year using information from patient self-report, inspection of medication bottles during interviews, and verification with electronic pharmacy records. Most participants brought in their medication bottles. To minimize misclassification, the electronic record was reviewed, and any self-reported drugs not recorded in the electronic record during the baseline interview were added. Statin name, dosage, and time since earliest medication use was obtained from electronic records, supplemented by self-report, inspection of medication bottles, and a recently filled prescription. Medication discrepancies were resolved using clinical consensus. The four statins available at the time of the study (atorvastatin, lovastatin, pravastatin, and simvastatin) were treated in the dataset as physiologically equivalent. The preferred medication on the hospital formulary during the study period was lovastatin; if adequate lipid profiles were not achieved, then simvastatin or atorvastatin was prescribed. The number of other (nonstatin) medications at baseline was defined as the sum of active prescriptions and regularly consumed over-the-counter medications, counted by product and not by the number of unique ingredients.

The primary outcomes were chosen, because they are measures that assess three important domains potentially affected by statin use: muscle strength, cognition, and depressive symptoms. Timed chair stands, a measure of proximal muscle strength associated with functional decline and disability,[23,24] was defined as the amount of time needed to complete three sit-to-stand maneuvers from a chair. The Trail Making Test Part B (Trail Making B) is a measure of cognitive flexibility that requires attention, visuospatial ability, and immediate memory skills.[25] The 11-item Center for Epidemiologic Studies Depression Scale (CES-D) [26] is a self-reported measure of depressive symptoms, which was transformed to the 20-item score.[27] Each primary outcome was measured at baseline in a face-to-face interview and again at follow-up after 1 year; they were coded as continuous variables in the analyses.

A sequence of linear regression models was constructed to analyze the association between statin use and each of the three outcome variables (chair stands, Trail Making B, and CES-D scores). Model 1 included statin exposure (use vs nonuse) as a predictor and adjusted for the baseline score for the corresponding outcome measure, sociodemographic factors (age, race, education level), and other health behaviors (alcohol and tobacco use). Model 2 included Model 1 variables plus comorbidity (Charlson comorbidities, dementia) and other health factors (number of medications taken at baseline, primary care visits in the previous year, and IADL impairments). The fully adjusted Model 3 included Model 2 variables plus accepted clinical indications for statin use (baseline cholesterol level, history of myocardial infarction or peripheral vascular disease) and common clinical contraindications to statin use (moderate or severe liver disease according to history and abnormal liver transaminase levels (alanine transaminase or aspartate transaminase)). In secondary analyses, the use of a cutpoint for each outcome (versus coding as continuous variables) was explored to determine whether an association existed for a threshold of "poor" performance. In this context, the worst quartile of performance was used as the outcome of interest, largely because no criterion-standard cutpoint exists for these factors.

To identify other potential subgroups at higher risk from adverse effects of statin use, the final models were rerun stratified by age (≥80 vs <80), number of comorbidities (stratified by highest quartile, >3 vs ≤3), and the number of medications taken (stratified by highest quartile of use, >7 vs ≤7). These subgroups were chosen, because older and less-healthy participants could be more susceptible to adverse medication effects.

Because the outcome measures were missing in fewer than 2% of patients at baseline and 6% to 10% at Year 1, multiple imputation (SAS PROC MI and PROC MIanalyze, SAS version 9.1, SAS Institute, Inc., Cary, NC) was used to evaluate the potential effect of the missing data on the results. This technique was used to replace the missing values and refit the fully adjusted models.[28] No substantive differences were found after imputation in population models or in models stratified by high-risk groups.

All statistical tests were two-tailed, and P<.05 was considered to indicate statistical significance. All analyses were performed using SAS Version 9.1 (SAS Institute, Inc.).

Results

shows the baseline characteristics of the 756 participants in the cohort. The mean age of participants was 74.5, 10% were nonwhite (primarily African American), 17% reported depressive symptoms, and 24% required help with at least one IADL. At baseline, 315 participants were statin users. Statin users were more likely to be white and had (as expected) more cardiac, cerebrovascular, and peripheral vascular disease. Median duration of statin use before enrollment was 726.5 days (range 30 to >1,599 days). Statin users took a mean 6.6 medications, versus 4.6 for nonusers. One hundred fifty-six 156 (56%) statin users took lovastatin, 98 (31%) simvastatin, and 38 (12%) atorvastatin, with mean baseline dosages±standard deviation of 25±13 mg, 27±22 mg, and 34±19 mg, respectively.

  Baseline Characteristics for Participants (N=756)

Characteristic Statin Nonuser (n=441) Statin User (n=315) P-value*
Demographic
Age, mean ± SD 74.7 ± 5.4 74.2 ± 5.1 .16
Male, n (%) 437 (99.1) 312 (99.1) 1.00
Nonwhite, n (%) 53 (12.0) 21 (6.7) .01
Education, years, mean ± SD 11.8 ± 2.8 12.1 ± 2.7 .26
Health factor
Number of instrumental activity of daily living impairments, mean ± SD 0.6 ± 1.0 0.5 ± 1.0 .31
Alcohol use in previous 30 days, n (%) 208 (47.2) 164 (52.1) .18
Ever smoked, n (%) 360 (81.6) 260 (82.5) .75
Primary care visits in previous year, mean ± SD 5.5 ± 4.2 6.0 ± 4.8 .20
Cholesterol level, mg/dL, mean ± SD 187.3 ± 36.5 174.3 ± 33.5 <.001
Number of medications taken, mean ± SD 4.6 ± 3.0 6.6 ± 2.6 <.001
Outcome measure, baseline, mean ± SD
Timed chair stands, seconds 7.4 ± 2.8 7.6 ± 2.7 .46
Trail Making Test Part B, seconds 159.6 ± 75.6 151.1 ± 76.1 .15
Center for Epidemiologic Studies Depression Scale score 4.0 ± 3.8 3.8 ± 3.6 .48
Charlson Comorbidity Index, mean ± SD
Total score 1.4 ± 1.5 1.6 ± 1.4 .07
Mean number of diagnoses 1.1 ± 1.0 1.3 ± 1.1 <.001

*Derived fromttests for continuous variables and chi-square or Fisher exact tests for categorical variables.

SD=standard deviation.

The unadjusted analyses of statin exposure status and each of the three outcomes in the domains of muscle strength, cognition, and depressive symptoms are shown in . Statin nonusers tended to perform worse on each outcome measure, but the difference in performance reached statistical significance only for the Trail Making B outcome (11.0 seconds; P=.05).

  Unadjusted Analysis for Statin Exposure and Outcomes at Year 1

Statin Exposure Timed Chair Stands, Seconds Trail Making Test Part B, Seconds Center for Epidemiological Studies Depression Scale Score
Statin nonusers (n=441), mean ± SD 8.0 ± 3.6 151.1 ± 71.6 3.9 ± 3.9
Statin users (n=315), mean ± SD 7.8 ± 2.9 140.1 ± 72.6 3.6 ± 3.8
Difference in outcome* −0.2 −11.0 −0.3
P-value .37 .05 .44

*Positive difference in outcome indicates worse performance in statin users.

Studentttest comparing group means between statin users and nonusers.

shows adjusted results from linear regression modeling. In the fully adjusted Model 3, statin users were slightly better than nonusers in their performance on timed chair stands (−0.5 seconds; P=.04). Differences between statin users and nonusers were also minimal for Trail Making B (−7.7 seconds; P=.08) and CES-D depression scores (−0.2 points; P=.49). Results were similar (data not shown) when analyses were based on the worst quartile of performance.

  Adjusted Risk of Impairment Across Outcome Measures for Statin Users Relative to Nonusers

Model Timed Chair Stands Trail Making Test Part B Center for Epidemiological Studies Depression Scale Score
Beta*(95% Confidence Interval)P-value
1 −0.23 (0.60–0.15) .23 −4.33 (−11.4–2.73) .23 −0.06 (−0.47–0.35) .78
2 −0.40 (−0.81–0.002) .05 −4.81 (–12.34–2.72) .21 −0.19 (−0.64–0.26) .40
3§ −0.50 (−0.96 to –0.03) .04 −7.66 (−16.30–0.98) .08 −0.18 (−0.69–0.33) .49
3||
Age
≥80 −0.22 (−1.18–0.74) .66 −9.41 (−32.37–13.56) .42 0.88 (−0.38–2.14) .18
<80 −0.59 (−1.09 to –0.09) .02 −7.39 (−16.51–1.73) .11 −0.29 (−0.82–0.24) .28
Number of comorbidities
>3 −0.85 (−2.01–0.31) .15 −11.1 (−28.72–6.57) .22 0.88 (−0.15–1.90) .10
≤3 −0.47 (−0.94–0.002) .05 −5.35 (−14.84–4.14) .27 −0.34 (−0.89–0.22) .24
Medications taken
>7 −0.26 (−1.31–0.80) .63 −9.41 (−24.10–5.28) .21 0.12 (−0.96–1.20) .83
≤7 −0.51 (−0.98 to –0.05) .03 −6.42 (−15.96–3.12) .19 −0.19 (−0.71–0.34) .48

*Beta represents the difference between statin use and nonuser groups in the changes of each outcome measure, with negative sign indicating statin users doing better.

Statin use (vs non-use)+baseline outcome measure+sociodemographic factors (age, race, education, alcohol use, tobacco use).

Model 1+comorbidity and other health factors (number of medications, primary care visits, and instrumental activity of daily living impairments).

§Model 2+indications and contraindications (see Methods section for details).

||Model 3 stratified into risk groups.

Because the primary analyses considered average risk and might have obscure results for participants at high or low risk, whether trends existed in older patients or those with poorer health were also examined. Multiple linear regression models, stratified by age, number of comorbidities, or number of medications, showed that statin use was not associated with significant adverse effects in both low-risk or high-risk groups ( ), although the relationship between CES-D depressive symptoms and statin use was reversed in those in the higher-risk subgroups, suggesting possible adverse effects in those with more than three comorbidities (difference of +0.88 points; P=.10).

  Adjusted Risk of Impairment Across Outcome Measures for Statin Users Relative to Nonusers

Model Timed Chair Stands Trail Making Test Part B Center for Epidemiological Studies Depression Scale Score
Beta*(95% Confidence Interval)P-value
1 −0.23 (0.60–0.15) .23 −4.33 (−11.4–2.73) .23 −0.06 (−0.47–0.35) .78
2 −0.40 (−0.81–0.002) .05 −4.81 (–12.34–2.72) .21 −0.19 (−0.64–0.26) .40
3§ −0.50 (−0.96 to –0.03) .04 −7.66 (−16.30–0.98) .08 −0.18 (−0.69–0.33) .49
3||
Age
≥80 −0.22 (−1.18–0.74) .66 −9.41 (−32.37–13.56) .42 0.88 (−0.38–2.14) .18
<80 −0.59 (−1.09 to –0.09) .02 −7.39 (−16.51–1.73) .11 −0.29 (−0.82–0.24) .28
Number of comorbidities
>3 −0.85 (−2.01–0.31) .15 −11.1 (−28.72–6.57) .22 0.88 (−0.15–1.90) .10
≤3 −0.47 (−0.94–0.002) .05 −5.35 (−14.84–4.14) .27 −0.34 (−0.89–0.22) .24
Medications taken
>7 −0.26 (−1.31–0.80) .63 −9.41 (−24.10–5.28) .21 0.12 (−0.96–1.20) .83
≤7 −0.51 (−0.98 to –0.05) .03 −6.42 (−15.96–3.12) .19 −0.19 (−0.71–0.34) .48

*Beta represents the difference between statin use and nonuser groups in the changes of each outcome measure, with negative sign indicating statin users doing better.

Statin use (vs non-use)+baseline outcome measure+sociodemographic factors (age, race, education, alcohol use, tobacco use).

Model 1+comorbidity and other health factors (number of medications, primary care visits, and instrumental activity of daily living impairments).

§Model 2+indications and contraindications (see Methods section for details).

||Model 3 stratified into risk groups.

Discussion

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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