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.13 It is unclear if this risk varies with individual statins or if this is a dose-driven class effect.9,14 Although 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.
The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 and followed consenting participants. Of these women, 68 132 were enrolled in 1, 2, or all 3 of the clinical trial (CT) arms: the Dietary Modification Trial, the Hormone Trial, and the Calcium and Vitamin D Trial. Another 93 676 women were enrolled into a prospective observational study (OS).20- 23 The WHI eligibility criteria included the ability to complete study visits with expected survival and local residency for at least 3 years. Original exclusion criteria addressed conditions that would limit full participation in the study. This analysis used WHI data through 2005. After exclusion for prevalent DM, missing data, and use of cerivastatin (this medication was withdrawn from the market in 2001 for safety reasons), a total of 153 840 women were included (Figure).
Figure. Flowchart for statin users and diabetes mellitus (DM) analyses using data sets from the Women's Health Initiative.
MEASUREMENT AND CLASSIFICATION OF STATIN MEDICATIONS
The current medication regimens of all CT participants were inventoried at baseline and at years 1, 3, 6, and 9. In the OS, medication data were inventoried at baseline and year 3. At each inventory, the brand or generic name on the medication label was matched to the corresponding item in the Master Drug Data Base (Medi-Span, Indianapolis, Indiana). We sorted for statin use as users or nonusers at baseline and year 3. Given that Sattar et al9 found a null effect of lipophilicity among statins, and in the absence of dose information, we determined statin categories by relative potency of action to decrease low-density lipoprotein cholesterol. Accordingly, statins were designated as low (fluvastatin, lovastatin, pravastatin) or high (simvastatin, atorvastatin) potency.24- 25
IDENTIFICATION OF DM
At baseline and at each semiannual (CT) or annual (OS) contact, incident treated DM was identified by questionnaire and was defined as a self-report of a new physician diagnosis of treated DM. This method of identification of prevalent and incident DM has been used in prior publications by the WHI investigators.18,26- 28 The accuracy of self-reported DM in the WHI trials has been assessed using medication and laboratory data, and self-reported DM was found to be reliable.29
Baseline questionnaires ascertained demographic and health history information, including race/ethnicity, age, educational attainment, family history of DM, family history of depression, self-report of CVD, hormone therapy use, and smoking status. Baseline self-report for CVD has been previously validated in the WHI30- 31 and found to have reasonable agreement with hospital discharge International Classification of Diseases, Ninth Revision (ICD-9) codes.
The metabolic equivalents of physical activities and average daily nutrient intake were computed, using detailed methods described elsewhere.32- 33 Trained and certified clinic staff measured height using a fixed stadiometer and weight by a calibrated balance-beam scale. Relative weight as BMI was calculated from these values. Blood was analyzed for glucose and insulin for the random 6% WHI-CT blood subsample at baseline, year 1, year 3, year 6, and year 9. Fasting glucose was analyzed using the hexokinase method with interassay coefficients of variation less than 2%.26 Insulin was measured by enzyme-linked immunosorbent assay. The WHI used the homeostasis model assessment of insulin resistance (HOMA-IR), which was developed for application in large epidemiologic investigations as an alternative to the glucose clamp. HOMA-IR = fasting plasma insulin (μIU/mL) × fasting plasma glucose (mmol/L)/22.5.34
Cox proportional hazards (PH) models were used to estimate hazard ratios (HRs) of DM by statin medication use. The dependent variable was time to occurrence of DM determined by self-report (ie, time to event). The time to event was calculated as the interval between enrollment date and the earliest of the following: (1) date of annual medical history update when new DM was ascertained (observed outcome) and (2) date of the last annual medical update during which DM status was ascertained (censored outcome). The primary independent variable in these analyses was statin use at baseline, coded as a binary variable. We present 3 Cox PH models to examine the association between baseline statin use and DM: model 1 estimates the unadjusted HRs (and associated 95% CIs) of the effects of statin use on incident DM; model 2 presents age- and race/ethnicity–adjusted HRs; and model 3 presents HRs adjusted for all potential confounding variables at baseline (age, race/ethnicity, education, cigarette smoking, BMI, physical activity, alcohol intake, energy intake, family history of DM, hormone therapy use, study arm, and self-report of CVD). Similar analyses were conducted for specific type of statin medication use at baseline, categorized as low vs high potency.
Since individuals using statins may have different underlying conditions that could put them at elevated risk for DM, we conducted several subgroup analyses to control confounding by indication. First, we conducted subgroup analyses by age, race/ethnicity, and BMI categories to examine whether the associations of statin use and onset of DM differed by categories of these variables. Age was categorized into 3 groups (50-59 years, 60-69 years, and ≥70 years). Race/ethnicity was assessed according to 4 major groups (white, African American, Hispanic, Asian). Body mass index was categorized into 3 groups (<25 .0="" 25.0-29.9="" 2="" analyses="" analysis="" at="" baseline.="" conducted="" cvd="" either="" finally="" in="" of="" or="" propensity="" score="" second="" self-reported="" similar="" subgroups="" sup="" we="" with="" without="" women="">3525>
After exclusion for cases of DM before year 3 (146 women), use of cerivastatin (651 women), and missing medication data at year 3 (2 women), our longitudinal analyses were conducted in a subset of 125 575 women from the OS and the CT arm at baseline and year 3 visits. Statin use was sorted into 4 categories: (1) never took statin; (2) use at both baseline and at the year 3 visit, (3) use only at baseline; and (4) use only at the year 3 visit. The HRs for DM by statin use were estimated similarly based on Cox PH models.
Participant characteristics are listed in Table 1. At baseline, the mean (SD) age of women included in our sample was 63.2 (7.3) years. Approximately 16.30% of the women were from racial/ethnic groups other than white, of which the largest representation was African American (8.32%). Only 2.56% (3922 women) were Asian. At baseline, 7.04% of participants took statin medication. Of these, 30.29% took simvastatin; 27.29%, lovastatin; 22.52%, pravastatin; 12.15%, fluvastatin; and 7.74%, atorvastatin. Comparison between statin users and nonusers showed significant differences in baseline characteristics.
A total of 10 242 incident cases of DM were reported over 1 004 466 person-years of follow-up. Table 2 presents results regarding the association between statin use at baseline and risk of incident DM. In unadjusted models, statin use at baseline was significantly associated with an increased DM risk (HR, 1.71; 95% CI, 1.61-1.83) when compared with nonuse. This association was decreased but remained significant after adjusting for potential confounders (HR, 1.48; 95% CI, 1.38-1.59). This association was observed for all types of statin. Similar risk associations were found in use of either high- or low-potency statins, with multivariate-adjusted HRs of 1.45 (95% CI, 1.36-1.61) and 1.48 (95% CI, 1.36-1.61) compared with nonusers, respectively. Table 3 shows subgroup analyses by race/ethnicity, BMI category, and age group. In both unadjusted and adjusted models, statin use was consistently associated with increased risk of DM across subgroups by age. We observed significantly increased risk of DM by statin use within subgroups of white, Hispanic, and Asian women in both unadjusted and adjusted models. In adjusted models, we observed HRs of 1.49 (95% CI, 1.38-1.62), 1.18 (95% CI, 0.96-1.45), 1.57 (95% CI, 1.14-2.17), and 1.78 (95% CI, 1.32-2.40) among whites, African Americans, Hispanics, and Asians, respectively. Statin use was also associated with a significantly increased risk of DM within 3 subgroups according to BMI (<25 .0="" 1.09-1.33="" 1.20="" 1.48-1.87="" 1.57-2.29="" 1.66="" 1.89="" 25.0-29.9="" 25.0="" 29.9="" 30.0="" a="" adjusted="" adjusting="" after="" all="" among="" and="" associated="" bmi="" ci="" compared="" confounders.="" dm="" for="" groups="" higher="" hrs="" in="" increased="" less="" lower="" models="" moreover="" observed="" of="" or="" p="" potential="" respectively.="" risk="" significantly="" statin="" than="" the="" to="" use="" was="" were="" when="" with="" within="" women="">25>
Table Graphic Jump Location Table 2. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline in 153840 Participants
To address potential confounding and selection bias, we conducted subgroup analyses among postmenopausal women with and without a history of CVD (Table 4). Among a subset of 24 842 women who self-reported CVD at baseline, we found that statin use was associated with an increased risk of DM (HR, 1.52; 95% CI, 1.36-1.71). These associations remained significant after adjusting for potential confounders (HR, 1.46; 95% CI, 1.29-1.65). Similar findings were observed among women without CVD at baseline.
Table Graphic Jump Location Table 4. Risk of Diabetes Mellitus (DM) by Statin Use Among Women With and Without Medical History of Cardiovascular Disease (CVD) at Baseline
PROPENSITY SCORE ANALYSES
In unadjusted models, statin use was significantly related to DM risk (HR, 1.71; 95% CI, 1.61-1.83). When the propensity score was included, the estimated HR attenuated to 1.38 (95% CI, 1.29-1.47). On inclusion of other confounders in the model, the HR was essentially unaltered (HR, 1.40; 95% CI, 1.31-1.51). Propensity score adjusted models yielded HRs of 1.38 (95% CI, 1.23-1.54) and 1.40 (95% CI, 1.29-1.53) for respective increased risk with either high- or low-potency statin use at baseline compared with nonuse.
LONGITUDINAL MEASURES OF STATIN USE AND RISK OF DM
When compared with those who never received statin therapy, unadjusted HRs of 1.82 (95% CI, 1.65-2.00), 1.75 (95% CI, 1.43-2.14), and 1.81 (95% CI, 1.67-1.97) were observed for the groups of women who reported statin use at both baseline and at the year 3 visit, reported statin use only at baseline, and reported statin use only at the year 3 visit, respectively (Table 5). The risk associations remained significant after adjusting for age, race/ethnicity, other potential confounders, and propensity score. The multivariate adjusted HRs were 1.47 (95% CI, 1.32-1.64), 1.44 (95% CI, 1.15-1.80), and 1.60 (95% CI, 1.47-1.75), respectively.
A sensitivity analysis was conducted on a subset of 3706 women without DM at baseline and enrolled in the WHI CT for whom fasting glucose measurements were available at baseline and at least 1 additional follow-up visit. Diabetes mellitus was identified based on fasting glucose levels of 126 mg/dL (6.99 mmol/L) or higher. In unadjusted models, statin use at baseline was not significantly related to DM risk (HR, 1.06; 95% CI, 0.61-1.86). However, using baseline through year 6 data in the CT arm, we found that the statin users had higher fasting glucose levels and HOMA-IR compared with non–statin users, with increasing values from baseline to year 6 follow-up.
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