Abstract
Statins are highly effective medications that reduce risk of atherosclerotic cardiovascular disease, but are very commonly discontinued by patients because of muscle symptoms. The risk factors for statin-associated muscle symptoms (SAMS) are not well understood, so in this study we examined the predictors of SAMS in a well-studied cohort of patients in the VITAL trial. We found that female sex and younger age (50–64 years) were significant, independent predictors of higher rates of SAMS.
Background
Statins significantly reduce the risk of developing atherosclerotic cardiovascular disease. While statins were well tolerated in placebo-controlled trials, observational studies of real world populations suggest a higher rate of adverse effects,1 especially statin-associated muscle symptoms (SAMS) that lead to statin discontinuation,2–4 which is associated with worse cardiovascular outcomes. 5 The relation of patient characteristics to SAMS has been inconsistent in previous studies.1–4 We sought to define the frequency and predictors of SAMS among new initiators of statins during follow up in the VITAL trial,6 a primary prevention trial of vitamin D and omega-3 fatty acids that documented use of medications at baseline and during follow-up among 25,871 participants.
Methods
We identified VITAL participants who were not taking a statin at baseline and were started on a statin by their personal physicians during follow-up. In the Spring of 2016 we mailed these presumed statin initiators a survey that asked:
“Have you started any of the statin medications listed below since you joined VITAL?”
“Did you ever experience musculoskeletal aches or discomfort while on a statin that persisted more than a few days?”
“Was the discomfort concerning enough for either you or your clinician to stop the statin medication?”
We compared frequencies of responses using chi-square testing, and used multivariable logistic regression to assess independent predictors of SAMS and statin discontinuation (SAS 9.4, SAS Institute Inc, Cary, NC).
This study was supported by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants (R01 AT011729, U01 CA138962, and R01 CA138962) from the National Institutes of Health. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. The authors have no relationships with industry to declare.
Results
Over 4.8 years of follow-up, 2835 VITAL participants who were not taking a statin at baseline initiated statin treatment; 2486 of 2799 (89%) surviving participants responded to the survey, and 2083 confirmed taking a statin, mostly atorvastatin (49%) and simvastatin (21%). SAMS were reported by 648 (31%) of statin initiators (Table), and led to statin discontinuation in 270 (13%). Most participants who switched statins because of SAMS did not tolerate the second statin (71% = 82 of 115).
Table.
Incidence of muscle symptoms while taking a statin
| Factor | Total N | Muscle symptoms N (%) | Adjusted odds ratio (95% confidence limits) | P-value in multivariable model |
|---|---|---|---|---|
|
| ||||
| Overall | 2083 | 648 (31%) | ||
| Age at baseline | .025 | |||
| 50–64 yrs | 806 | 282 (35%) | Reference | |
| 65–74 yrs | 1092 | 316 (29%) | 0.74 (0.59–0.93) | |
| >=75 yrs | 185 | 50 (27%) | 0.74 (0.50–1.08) | |
| Sex | <.0001 | |||
| Male | 1068 | 293 (27%) | Reference | |
| Female | 1015 | 355 (35%) | 1.55 (1.26–1.92) | |
| Race/ethnicity | .97 | |||
| White (Non-Hispanic) | 1456 | 434 (30%) | Reference | |
| African-American | 389 | 135 (35%) | 0.93 (0.70–1.24) | |
| Hispanic | 92 | 30 (33%) | 1.08 (0.66–1.75) | |
| Asian/Pacific Islander | 38 | 11 (29%) | 0.96 (0.45–2.02) | |
| Other or Unknown | 61 | 21 (34%) | 1.09 (0.61–1.94) | |
| Body mass index | .24 | |||
| <25 | 562 | 151 (27%) | Reference | |
| 25 to <30 | 797 | 242 (30%) | 1.14 (0.88–1.47) | |
| >=30 | 673 | 235 (35%) | 1.27 (0.96–1.68) | |
| Exercise (met-hours/week) | .56 | |||
| <6.7 | 682 | 236 (35%) | Reference | |
| 6.7 to <24.92 | 698 | 206 (30%) | 0.88 (0.69–1.12) | |
| >=24.93 | 656 | 195 (30%) | 0.97 (0.75–1.25) | |
| Education | .15 | |||
| <High school | 27 | 10 (37%) | Reference | |
| High school graduate | 232 | 66 (28%) | 0.70 (0.29–1.69) | |
| College | 844 | 287 (34%) | 1.06 (0.46–2.47) | |
| Post-college | 976 | 282 (29%) | 0.99 (0.42–2.31) | |
| Hypertension | .11 | |||
| Absent | 911 | 262 (29%) | Reference | |
| Present | 1165 | 383 (33%) | 1.18 (0.96–1.46) | |
| Diabetes | .83 | |||
| Absent | 1736 | 531 (31%) | Reference | |
| Present | 342 | 116 (34%) | 1.03 (0.78–1.37) | |
| Smoking | .28 | |||
| Never | 1029 | 316 (31%) | Reference | |
| Past | 827 | 257 (31%) | 1.03 (0.84–1.27) | |
| Current | 166 | 61 (37%) | 1.35 (0.93–1.96) | |
In univariable analyses, the incidence of SAMS was significantly higher in women (P = .0002), participants 50 to 64 years old (P = .009), and obese participants (P = .009). In the multivariable analysis (Table), the independent predictors of developing SAMS were female sex (P < .0001), and age (P = .025). Among participants who reported SAMS, no baseline factor was a significant independent predictor of statin discontinuation.
Discussion
This study confirms the high frequency of SAMS, even among volunteers in a randomized trial, and that individuals who report SAMS frequently discontinue taking a statin. The frequency of SAMS in our study was similar to that among 7924 French patients, where 10% discontinued taking a statin due to muscle symptoms.2 While randomized challenge studies suggest that most muscle symptoms are non-specific,7,8 significantly more participants developed myalgias while taking a statin than taking placebo.7 The rate of statin discontinuation in real world populations approaches 50%,1 and indicates a large gap in preventive care.
We found that women were significantly more likely to report SAMS, confirming the results of prior studies.2–4,9 Because women are less likely to receive statin therapy, the gaps in preventive care appear to be especially high for women.
We also found that younger participants (50–64 years) were significantly more likely to report muscle symptoms, even after adjustment for physical activity levels and other baseline factors. The effect of age on SAMS has been inconsistent in prior studies, with most suggesting that SAMS are more common in older patients4, but others reported SAMS to be more common in younger patients.3 While obese participants were more likely to report SAMS in this study, the effect of obesity on SAMS was no longer significant after adjustment for other baseline factors.
The main limitation of this study was its cross-sectional design among recent initiators of statins, and the selected nature of the population, who were participants in the VITAL randomized trial. Statin treatment in this study was not blinded, so some of the reported SAMS may have been due to the “nocebo” effect.7,8 The study’s strength is its very high survey response rate (93%), and the well characterized, closely followed study population.
In summary, this study confirms the high frequency of SAMS in a large primary prevention population, and suggests that women and younger patients are at higher risk of reporting SAMS.
References
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