Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women’s Health Initiative
JAMA Internal Medicine
Annie L. Culver, BPharm; Ira S. Ockene, MD; Raji Balasubramanian, ScD; Barbara C. Olendzki, RD, MPH; Deidre M. Sepavich, MBA; Jean Wactawski-Wende, PhD; JoAnn E. Manson, MD, DrPH; Yongxia Qiao, MD; Simin Liu, MD, ScD; Philip A. Merriam, MSPH; Catherine Rahilly-Tierny, MD, MPH; Fridtjof Thomas, PhD; Jeffrey S. Berger, MD, MS; Judith K. Ockene, PhD, MEd, MA; J. David Curb, MD; Yunsheng Ma, MD, PhD
Background: This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Women’s Health Initiative (WHI).
Methods: The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification.
Results: This investigation included 153 840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10 242 incident cases of self-reported DM over 1 004 466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125 575 women confirmed these findings.
Conclusions: Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.
Given the success of statins in both primary and secondary prevention of cardiovascular morbidity and mortality,1- 6 their use is progressively increasing, especially among older Americans.7 With such widespread use, even small risks are apparent alongside benefits. One emerging risk is an increased incidence of diabetes mellitus (DM). There is evidence that incident DM associated with statin use may be more common in the elderly, in women, and in Asians.8- 12 A recent analysis suggests that preexisting metabolic risk factors control incident DM rate with statin medication.13It is unclear if this risk varies with individual statins or if this is a dose-driven class effect.9,14Although experimental and clinical studies find that individual statins act differently on glucose homeostasis as a function of relative lipophilicity and/or potency of action,15 other findings differ. A recent meta-analysis of 17 randomized controlled trials by Mills et al16 found a class effect increase of new-onset DM with statins (odds ratio [OR], 1.09; 95% CI, 1.02-1.16) similar to that reported by Sattar et al.9 Possibly, the grouping of statins masks the effect variation of individual statins. Still, at some given dose threshold, differences may be overcome, as implied by a meta-analysis of 5 trials comparing intensive to moderate dosing regimens using mainly atorvastatin and simvastatin.13,17 Notably, meta-analysis results display intertrial and intratrial variability in diagnostic and statistical methods and do not consistently consider confounding factors. Moreover, contributing sample sizes do not permit balanced comparison by statin type, sex, race/ethnicity, and age. Similarly, single studies may uncover only part of a greater topography.
As a large part of the aging population, postmenopausal women have not been fully represented in past clinical trials.16 Sex differences in DM pathogenesis are well recognized.18,19 Using the Women’s Health Initiative (WHI) data, we evaluated the overall effect of statin medication use on incident DM risk and examined these associations by specific statin agent. We stratified analyses by race/ethnicity, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) category, and age group to determine if any associations were modified by these factors. In addition, we conducted subgroup analysis in women with and without self-reported cardiovascular disease (CVD) at baseline to address potential confounding and selection bias.