Abstract
Background:
HMG-CoA reductase inhibitors (statins) are among the most commonly prescribed classes of medications. Although their cardiovascular benefits and myalgia risks are well documented, their effects on older adults initiating an exercise training program are less understood.
Methods:
1,635 sedentary men and women aged 70–89 years with Short Physical Performance Battery (SPPB) score of 9 or below and were able to walk 400 m were randomized to a structured, moderate-intensity physical activity (PA) program consisting of both center-based (twice/wk) and home-based (3–4 times/wk) aerobic, resistance, and flexibility training or to a health education (HE) program combined with upper extremity stretching.
Results:
Overall, the PA intervention was associated with lower risk of major mobility disability (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.69–0.98). The effect was similar (p value for interaction = .62) in both statin users (PA n = 415, HE n = 412; HR = 0.86, 95% CI = 0.67–1.1) and nonusers (PA n = 402, HE n = 404; HR = 0.78, 95% CI = 0.61–1.01). Attendance was similar for statin users (65%) and nonusers (63%). SPPB at 12 months was slightly greater for PA (8.35±0.10) than for HE (7.94±0.10) in statin users but not in nonusers (PA 8.25±0.10, HE 8.16±0.10), though the interaction effect was not statistically significant. Self-reported PA levels were not different between statin users and nonusers.
Conclusions:
Although statins have been associated with adverse effects on muscle, data from the LIFE Study show that statin users and nonusers both benefit from PA interventions. Older adults who require statin medications to manage chronic medical conditions and are sedentary will be able to benefit from interventions to increase PA.
Keywords: Physical activity, Physical function, Functional performance, Exercise
HMG CoA reductase inhibitors (statins) are widely prescribed medications. Currently greater than 40% of older adults take these medications to manage and prevent cardiovascular conditions (1). Under the most recent guidelines, three quarters of older adults are eligible for statin use (2). Statins can also cause adverse muscular effects ranging from mild myalgias to rhabdomyolysis. Several smaller studies suggest that these adverse effects can be worsened by physical activity (PA) or exercise training (3–5). Adverse muscle effects are more common in older adults and are often unrecognized (6,7). If these adverse effects hinder older adults’ ability to participate in PA or exercise training, they could limit numerous exercise-associated metabolic and functional benefits (8,9).
Several large observational studies have investigated the effect of statins on PA and function with inconsistent results. The Osteoporotic Fractures in Men (MrOS) Study found that statin use, especially initiation of a statin, led to decreased PA and increased sedentary behavior (10). The Women’s Health Initiative (WHI) found no association between statin use and the rate of functional decline (11); and, Dumurgier and colleagues found a 25% slower decline in walking speed among older adults taking statins in the functional substudy of the Three City (3C) cohort (12). The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study found no difference in muscle strength or exercise capacity after 6 months of high-dose statin treatment versus placebo (13).
Several studies have evaluated the interaction of statin use with exercise training also with inconsistent results. Among elite athletes with familial hypercholesterolemia, about 25% (6 of 22) were able to tolerate statin therapy, whereas the remainder discontinued statin use due to myalgias (3). Statin users had greater elevations of creatine kinase, a marker of muscle injury, after participating in a marathon (4). However, Panayiotou and colleagues saw that statin use did not increase muscle damage following exercise in older men (14) and Riechman and colleagues found that older adults using statins had a greater response to resistance training (15).
Given that greater than 40% of older adults in the United States use statins (1), the importance of PA to disability prevention, and the current lack of consistency in the literature, we addressed this issue using data from the Lifestyle Interventions and Independence for Elders (LIFE) study. The LIFE study was a large randomized single-blinded controlled trial of PA for the prevention of major mobility disability (MMD). We sought to test two related hypotheses: (i) statin users in each group would have a higher rate of onset of mobility disability than nonusers in the same group and (ii) statin users would respond less robustly to the exercise intervention compared with nonusers. Analyses contained herein of mobility disability represent a post hoc, subgroup analysis of the LIFE study, which concluded that the structured PA program reduced MMD over 2.6 years compared with a health education (HE) program among older adults at risk for disability (9).
Methods
Trial Design and Participants
The study methods, recruitment, intervention, and primary outcome are detailed elsewhere (9,16,17). Briefly, this was a 1,635-person multicenter single-blind randomized trial conducted between February 2010 and December 2013 (for a period of 46 months with a mean follow-up of 2.6 years) at eight centers across the United States (University of Florida, Gainesville and Jacksonville, Florida; Northwestern University, Chicago, Illinois; Pennington Biomedical Research Center, Baton Rouge, Louisiana; University of Pittsburgh, Pittsburgh, Pennsylvania; Stanford University, Stanford, California; Tufts University, Boston, Massachusetts; Wake Forest School of Medicine, Winston-Salem, North Carolina; and Yale University, New Haven, Connecticut). The study protocol was approved by the institutional review board at all participating centers. The centers included rural, suburban, and urban communities. (clinicaltrials.gov Identifier: NCT01072500)
Eligible participants were men and women aged 70–89 years who were sedentary (self-reported <20min/wk of regular physical exercise in the past month and reporting <125min/wk of moderate-intensity PA) and at high risk of mobility disability (Short Physical Performance Battery [SPBB] score ≤ 9). Participants had to be able to walk 400 m in less than 15 minutes without sitting, leaning, or the help of another person or walker; had to be cognitively intact (Modified Mini-Mental State Examination score ≤ 1.5 SD below education- and race-specific norms); and could safely participate in the intervention. The 1,633 participants who had medication data were included in the analysis.
Intervention
Participants were randomized to either a PA intervention or a HE program. The PA intervention involved endurance, strength, flexibility, and balance training. Participants attended two center-based sessions per week and were encouraged to perform home-based activity 3–4 times per week throughout the study. PA sessions progressed to a goal of 30 minutes of walking at a moderate intensity, 10 minutes of lower extremity strength training (with ankle weights), and 10 minutes of balance training and large muscle flexibility exercises.
The HE program involved meeting weekly for the first 26 weeks and monthly (with optional bimonthly sessions) thereafter and discussed a variety of topics of interest to older adults, including travel safety, age-appropriate preventive services, legal and financial issues, and nutrition. Each session included 5–10 minutes of instructor-led gentle upper extremity stretching exercises.
Medical Screening and Medication Assessment
Baseline demographics and medical history were obtained by self-report. Baseline medication use was assessed by visual inspection of all prescription and nonprescription medications taken in the previous 2 weeks. Drug names and whether the medication was prescribed were recorded. Medications were later coded to reflect their function and drug class. Baseline biometrics and functional data obtained by study staff included body mass index, Short Physical Performance Battery (SPPB), and PA assessed with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire (18). The SPPB is a three-part measure of lower extremity function including a 4-m walk at usual speed, five timed repeated chair stands and static balance testing, each scored 0–4 and totaled with 0 indicating the worst performance and 12 the best (19). CHAMPS is a 41-item questionnaire of self-reported PA specifically designed for older adults, which is measured in minutes per week (18). This analysis used the values for moderate-intensity activities, referred to as CHAMPS-18.
Outcomes
Participants were evaluated at baseline and every 6 months throughout the study. The main study outcome, MMD, was based on the ability to walk 400 m in 15 minutes (approximately 1 mile per hour). Participants who were unable to complete the walk within 15 minutes without sitting, using a walker, or requiring assistance by another individual were classified as having MMD. Participants were allowed to use a cane and rest for up to 1 minute due to fatigue. When the 400-m walk test could not be administered, alternative assessments, such as inability to walk 4 m in less than 10 seconds, or self-, proxy-, or medical record–reported inability to walk across the room, were done to measure MMD (9). If participants meet these criteria, they would not be able to complete the 400-m walk within 15 minutes and were classified as having MMD. The SPPB was also assessed at each clinic visit.
Statistical Considerations
Baseline characteristics of participants whose baseline statin use was known were compared across treatment arms and statin use status (users vs nonusers) using means and standard deviations for continuous variables or percentages for categorical variables. Statistical tests were done comparing baseline statin users versus nonusers regardless of treatment arm, using t tests (for continuous variables) or chi-squared tests (for categorical variables). Intervention adherence was calculated as the percentage of scheduled sessions attended by participants, overall and separately by study arm. Differences in intervention adherence in the baseline statin users versus nonusers were assessed using quasi-likelihood estimation for proportions.
The effect of the intervention on the primary outcome, time until the first occurrence of MMD, was tested using a Cox proportional hazard regression model, stratified by field center and sex. Failure time was measured from the time of randomization; follow-up was censored at the last successfully completed 400-m walk test. For participants who did not have any postrandomization assessments, 1 hour of follow-up time was assigned. An interaction term between treatment arm and baseline statin use group was included in the model, and likelihood ratio tests were used to assess the consistency of the intervention effect across levels of baseline statin use. Sensitivity analyses were performed by adjusting each model for prespecified baseline variables: number of chronic conditions (hypertension, diabetes, arthritis, pulmonary disease, heart attack, stroke, heart failure, cancer, broken hip, or liver disease). Body mass index, peripheral arterial disease (ankle brachial index < 1.0), and 400-m walk time were also added as adjustment factors after analyses were underway.
SPPB and CHAMPS-18 scores were analyzed using mixed-effects analysis of covariance models for repeated-measures outcomes with unstructured covariance. These models contained field center and sex, baseline value of SPPB, study arm, clinic visit, and visit by study arm interaction. Least squares means were obtained, and contrasts were used to estimate the average effects over the follow-up period.
Results
The baseline characteristics of statin users and nonusers were similar with some exceptions (Table 1). Half of the participants used statins (51% of PA [415 of 817], 50% of HE [412 of 816]). Statin users included a higher prevalence of males and had a higher weight and body mass index. Statin users also had more comorbidities, particularly diabetes, prior myocardial infarction, hypertension, stroke, and peripheral arterial disease and were more likely to have a pacemaker. Statin users had a lower educational level. Despite these baseline differences, both groups had similar function based on SPPB scores, though nonusers had a faster baseline 400-m walk time. Both groups had a similar level of PA based on CHAMPS-18 scores.
Table 1.
Baseline Characteristics of the LIFE Study Cohort by Baseline Statin Use and Treatment Arm
| Statin Use | No Statin Use | p Value | |||
|---|---|---|---|---|---|
| Physical Activity (n = 415) | Health Education (n = 412) | Physical Activity (n = 402) | Health Education (n = 404) | All Users Vs Nonusers | |
| Age (y) | 78.7±5.1 | 79.0±5.2 | 78.6±5.3 | 79.2±5.3 | .9323 |
| Female | 270 (65.1%) | 247 (60.0%) | 276 (68.7%) | 303 (75.0%) | <.0001 |
| Race/ethnicity | .8369 | ||||
| Black | 83 (20.0%) | 58 (14.1%) | 79 (19.7%) | 67 (16.6%) | |
| White | 307 (74.0%) | 323 (78.4%) | 297 (73.9%) | 311 (77.0%) | |
| Other | 25 (6.0%) | 31 (7.5%) | 26 (6.5%) | 26 (6.4%) | |
| Education | .0111 | ||||
| ≤High school/equivalent | 152 (36.6%) | 142 (34.7%) | 117 (29.2%) | 116 (28.8%) | |
| College or technical degree | 173 (41.7%) | 170 (41.6%) | 180 (44.9%) | 176 (43.7%) | |
| Post graduate | 90 (21.7%) | 97 (23.7%) | 104 (25.9%) | 111 (27.5%) | |
| CHAMPS-18 (min/wk) | 16.7±33.2 | 18.6±33.7 | 15.0±30.8 | 18.2±34.3 | .5292 |
| Weight (kg) | 83.2±18.6 | 84.2±19.0 | 80.5±18.1 | 79.7±19.4 | <.0001 |
| BMI (kg/m2) | 30.6±5.8 | 30.8±6.0 | 29.7±5.6 | 29.9±6.5 | .0022 |
| SPPB | 7.4±1.6 | 7.4±1.6 | 7.5±1.5a | 7.2±1.6a | .9230 |
| 400-m Walk time (s) | 515.7±117.7 | 516.9±117.5 | 495.8±107.6 | 507.0±112.3 | .0085 |
| Diabetes | 147 (35.5%) | 147 (35.8%) | 52 (13.0%) | 68 (17.0%) | <.0001 |
| Heart attack | 52 (12.6%) | 52 (12.7%) | 8 (2.0%) | 17 (4.2%) | <.0001 |
| Chronic lung disease | 69 (16.6%) | 58 (14.1%) | 61 (15.3%) | 65 (16.2%) | .8431 |
| High blood pressure | 323 (78.0%) | 328 (80.6%) | 249 (62.6%) | 249 (62.3%) | <.0001 |
| Stroke | 42 (10.1%) | 32 (7.8%) | 15 (3.8%) | 20 (5.0%) | .0002 |
| Pacemaker | 23 (5.7%) | 21 (5.2%) | 10 (2.5%) | 12 (3.0%) | .0079 |
| Peripheral artery disease (ABI < 1.0) | 126 (31.7%) | 137 (35.2%) | 110 (28.1%) | 99 (25.6%) | .0047 |
Note: ABI = Ankle Brachial Index; BMI = body mass index; CHAMPS = Community Healthy Activities Model Program for Seniors; LIFE = Lifestyle Interventions and Independence for Elders; SPPB = Short Physical Performance Battery; Bold values indicate significant p values.
a p Value less than .05 testing difference between randomized groups within statin use category
The distribution of statin use by type was examined. Of those who reported taking statins, 52% took simvastatin, 22% took atorvastatin, and 10% each took pravastatin or rosuvastatin.
The main finding of the LIFE study was that PA decreased the onset of MMD in at-risk older adults. When stratified by statin use, the intervention effect was similar in both users and nonusers (statin users hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.67–1.10; nonusers HR = 0.78, 95% CI = 0.61–1.01, p value for interaction = .62) (Figure 1). This was consistent after adjustment for baseline peripheral arterial disease, 400-m walk time, number of chronic conditions, and body mass index (statin users HR = 0.86; 95% CI = 0.67–1.11; nonusers HR = 0.83; 95% CI = 0.64–1.08, p value for interaction = .84).
Figure 1.
Kaplan–Meier plot for major mobility disability for physical activity and health education groups by statin use status and rate of major mobility disability onset for physical activity and health education groups by statin use status (inset): The Lifestyle Interventions and Independence for Elders Study.
The rate of MMD was also compared for participants according to baseline statin use. For the HE group, the rate of MMD was 16.7 events per 100 person-years for statin users and 16.0 for nonusers. In the PA group, the rate was 14.0 events per 100 person-years for statin users and 12.6 for nonusers, but no interaction between statin use and intervention was seen (p value = .49), as noted earlier (Figure 1 inset).
We then evaluated whether baseline statin use was associated with differences in attendance rates for the study intervention. Statin use had similar study attendance overall (65% for users vs 63% for nonusers) or by intervention (Table 2).
Table 2.
Intervention Session Attendance by Baseline Statin Use: The LIFE Study (mean and 95% CI)
| Overall | Statin Use | No Statin Use | |
|---|---|---|---|
| All participants | N = 1,623 | n = 821 | n = 802 |
| Percent sessions attended | 0.64 (0.62–0.66) | 0.65 (0.63–0.68) | 0.63 (0.60–0.65) |
| Physical activity intervention | N = 811 | n = 412 | n = 399 |
| Percent sessions attended | 0.55 (0.53–0.58) | 0.57 (0.53–0.60) | 0.54 (0.51–0.57) |
| Health education intervention | N = 812 | n = 409 | n = 403 |
| Percent sessions attended | 0.73 (0.70–0.75) | 0.74 (0.71–0.77) | 0.71 (0.68–0.74) |
Note: CI = confidence interval; LIFE = Lifestyle Interventions and Independence for Elders. Attendance data are missing for 10 participants.
MMD is influenced by many factors including the level of physical function. To better compare our findings with those that examined physical performance measures, we evaluated SPPB, a measure of lower extremity function (Figure 2). PA improved the SPPB score compared with HE in the LIFE trial overall (PA to HE for follow-up across all visits = 0.20 [95% CI = 0.01–0.39], p value = .04) (9). The average effect of the intervention across all follow-up visits was statistically significant for statin users (0.29 [95% CI = 0.03–0.54], p value = .03) and not for nonusers (0.10 [95% CI = −0.17 to 0.37], p value = .46). However, there was no evidence that the average effect of the intervention was different between statin groups (p value for test of equality of average intervention effect across statin groups = .30). Average SPPB scores in each of the intervention by statin use groups are shown in Table 3. When the SPPB scores were assessed separately by component (gait speed, chair rise, or balance), a slightly larger intervention effect was observed in chair rise between statin users (0.20 [95% CI = 0.06–0.34], p value = .005) and nonusers (0.14 [95% CI = 0.002 to 0.29], p value = .06; test for equality of average intervention effect across statin groups p value = .50), but not gait speed or balance. Finally, we compared the CHAMPS-18 scores throughout the intervention for each group. Those in the PA group had higher self-reported PA than the HE group (131.8±4.9 vs 64.8±4.9 at 6 months, all participants) (Supplementary Figure 1) There was no association between self-reported PA and statin use (123.8±6.8 in statin users vs 139.9±7.2 in nonusers in the PA group at 6 months; 62.2±6.8 in statin users vs 67.7±7.0 in nonusers in the HE group at 6 months (p value for test of equality of average intervention effect across statin groups = .44) (Supplementary Table 1).
Figure 2.
Short Physical Performance Battery score by treatment arm and baseline statin use: The Lifestyle Interventions and Independence for Elders Study.
Table 3.
Short Physical Performance Battery Score by Intervention and Statin Use: The LIFE Study
| Overalla | Statin Useb | No Statin Usec | ||||
|---|---|---|---|---|---|---|
| Physical Activity | Health Education | Physical Activity | Health Education | Physical Activity | Health Education | |
| Baseline (raw statistics) | 7.43±0.06 (N = 818) | 7.30±0.06 (n = 817) | 7.36±0.08 (n = 415) | 7.38±0.08 (n = 412) | 7.50±0.08 (n = 402) | 7.23±0.08 (n = 404) |
| 6 Months | 8.46±0.07 (N = 770) | 8.16±0.07 (n = 787) | 8.41±0.09 (n = 394) | 8.12±0.09 (n = 396) | 8.52±0.10 (n = 375) | 8.21±0.09 (n = 390) |
| 12 Months | 8.31±0.07 (N = 747) | 8.05±0.07 (n = 766) | 8.35±0.10 (n = 383) | 7.94±0.10 (n = 387) | 8.25±0.10 (n = 363) | 8.16±0.10 (n = 378) |
| 24 Months | 7.89±0.08 (N = 700) | 7.73±0.08 (n = 711) | 7.98±0.11 (n = 358) | 7.62±0.11 (n = 358) | 7.79±0.12 (n = 341) | 7.86±0.12 (n = 352) |
| 36 Months | 7.65±0.12 (N = 279) | 7.57±0.11 (n = 283) | 7.61±0.16 (n = 148) | 7.53±0.17 (n = 141) | 7.69±0.16 (n = 131) | 7.60±0.16 (n = 141) |
Note: Least squares means ± SE (n).
ap Value for test of equality of average intervention effect across statin groups (interaction test) is .30.
bp Value for average intervention effect across all follow-up visits in statin users is .03.
cp Value for average intervention effect across all follow-up visits in non-statin users is .46.
Discussion
We found that older adults at risk for mobility disability who use statins did not differ from nonusers in response to an exercise intervention to delay the onset of mobility disability. To our knowledge, this is the first study to evaluate the effect of statin use in older adults at high risk for disability who are initiating an exercise program. In addition, we found that statin use was not associated with risk of MMD. Nor is it associated with lower participation rates in an exercise intervention or lower PA levels.
Our findings are consistent with several other studies. Health ABC investigators evaluated the gait speed of older adults (aged 70–79 years) over a 3-year period and found that statin users were no more likely to have a decline in gait speed than nonusers. Additionally, STOMP investigators found that 6 months of statin therapy did not decrease muscle strength or exercise performance in healthy individuals (13).
Several studies have shown a decrease in PA after initiation of statins or lower spontaneous PA in statin users. In STOMP, although exercise performance was unaffected, at 6 months statin users had decreased their PA, and this was more pronounced in the older age group (55+) (13). Similarly in MrOS, older men on statins at baseline had lower self-reported PA and those who started statins had greater declines in PA (10). We, however, found that statin users had a similar level of baseline PA. Additionally, throughout the study, statin users had similar adherence to the exercise intervention and similar levels of self-reported PA as nonusers. Our study population did differ from that of STOMP and MrOS by being specifically recruited to be sedentary at baseline. This lower baseline PA may have obscured differences that would be evident in a more active population.
Improvements or slowed decline in measures of physical function have been observed in several other studies of older populations using statins. In the 3C study, Dumurgier and colleagues found that fast walking speed declined more slowly in older adults (aged 65 years and older) who took lipid lowering drugs (statins or fibrates). This effect was seen more robustly in those on statins and those who took the medications continuously over the 10 years of follow-up (12). McDermott and colleagues reported that statin users older than 55 years, mean age between 68 and 72 years, had better SPPB, 6-minute walk performance, and 4-m walk gait speeds than nonusers at baseline. However, only statin users with peripheral arterial disease had a slower rate of decline of these measures over 3 years of follow-up (20,21). The WHI found no effects of statin use on functional parameters overall, but did see a slowed rate of decline in timed chair stands for the oldest women who used statins (11). These observations are consistent with our SPPB data in which the improvement in statin users in the PA group, driven mainly by improvements in timed chair stands, declined more slowly than for those in the HE group. This difference was somewhat attenuated in statin nonusers. It is possible that statin users may have had a longer lasting functional response to PA than nonusers; however, our data do not support this because the p value for a test of equality of the average effect of intervention for the statin group was .30. Also of note, all participants had substantial improvements in SPPB scores at 6 months, though larger in the PA group. Although both groups may have benefited from a learning effect, as is often seen with functional testing, this is also potentially explained by the increase in PA at 6 months seen in all groups from baseline (18.4±1.2 to 64.8±4.9 HE; 15.8±1.1 to 131.8±4.9 PA). The increased PA in the HE group may be at least partially explained by greater social interaction associated with the weekly center- and group-based HE sessions. The gradual decline in all groups may also be partially explained by the gradual decline in PA seen after 6 months (Supplementary Table 1).
This study has several strengths including large sample size (827 statin users, 806 nonusers), a geographically diverse community-dwelling sedentary population at high risk of disability with homogeneous baseline activity, and a clinically relevant outcome (prevention of mobility disability). Previous evaluations of statin users were smaller and shorter (STOMP) and did not include an exercise intervention or measure the onset of mobility disability (WHI, 3C, MrOS). However, our study has limitations. The participants were not randomized to statin use, so there is potential for confounding by indication, as seen by the greater burden of comorbidities in the baseline statin users. Although we controlled for indications for use, we cannot rule out residual confounding related to reasons for statin prescription or adherence. The effect of statins in this population was not an a priori hypothesis, so was not a prespecified subgroup of the primary outcome. As an interaction hypothesis within a study powered to test a main effect of the intervention on MMD, our ability to detect heterogeneity of intervention effects within statin groups would be limited to large effects. Additionally, our study does not address statin intolerance nor the initiation or discontinuation of statin use. Animal studies indicate that the timing of statin initiation will alter the response to exercise (22).
In summary, older adults at high risk for mobility disability who use statins do not differ appreciably in the benefit achieved from a PA intervention to prevent mobility disability.
Supplementary Material
Please visit the article online at http://gerontologist.oxfordjournals.org/ to view supplementary material.
Funding
This work was supported by the National Institutes of Health, National Institute on Aging (UO1AG22376), the National Heart, Lung, and Blood Institute (3U01AG022376-05A2S), the Intramural Research Program, and the Claude D. Pepper Older Americans Independence Centers (1P30AG031679, 1P30AG028740, P30AG024827, 1P30AG21332, and P30AG021342).
Supplementary Material
Acknowledgments
Disclosure: Several of the authors are members of the editorial board of the Journal.
Stephen B. Kritchevsky, Editor-in-Chief
Roger A. Fielding and Anne B. Newman, Associate Editors
Mary M. McDermott and Marco Pahor, Editorial Board
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