Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial

Context In observational studies, postmenopausal hormone therapy has been associated with lower fasting glucose levels. No prospective, controlled trial has evaluated the effect of postmenopausal hormone therapy on the development of diabetes mellitus. Contribution Among the 2029 women in the Heart and Estrogen/progestin Replacement Study who had coronary disease but no diabetes at baseline, 6.2% of those receiving 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate and 9.5% of those receiving placebo developed diabetes. Implications Recommendations about combination postmenopausal hormone therapy should consider that for every 30 women treated for 4 years, therapy might prevent one case of diabetes. The Editors Several clinical studies have evaluated the effect of postmenopausal hormone therapy on glucose metabolism and have had disparate results. Results from randomized, controlled trials performed primarily in women without diabetes have found decreased mean fasting glucose or insulin levels among those assigned to hormone therapy (1-5) or no difference between those assigned to hormones and those assigned to placebo (6-10). Fewer clinical trials have evaluated the effect of postmenopausal hormones on fasting glucose and insulin levels among women with type 2 diabetes mellitus, but again, the results have been mixed (11-16). Observational studies have more consistently found that postmenopausal women taking hormone therapy have lower fasting glucose or hemoglobin A1c levels than those not taking hormones (17-24). In addition, some (25, 26) but not all (24, 27) observational studies have noted a decreased incidence of diabetes among users of postmenopausal hormone therapy. No randomized, controlled trial has evaluated the long-term effect of hormone therapy on diabetes incidence. To determine the effect of hormone therapy on subsequent diabetes, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), in which 2763 postmenopausal women with documented coronary heart disease (CHD) were randomly assigned to daily estrogen plus progestin therapy or to placebo. We evaluated the effect of hormone therapy on fasting glucose levels and incident diabetes over 4 years of follow-up. Methods Study Setting, Participants, and Design The design, methods, baseline characteristics (28), and main findings (29) of HERS have been published elsewhere. Briefly, HERS was a randomized, double-blind, placebo-controlled trial performed to evaluate daily doses of 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate for the prevention of coronary events in postmenopausal women with established CHD. The trial enrolled 2763 women at 20 clinical centers in the United States between January 1993 and September 1994 and followed participants for a mean of 4.1 years. To be included in the trial, women had to be younger than 80 years of age and have CHD, as evidenced by previous myocardial infarction, coronary artery bypass graft surgery, mechanical revascularization, or angiographic evidence of coronary stenosis. Women who reported a CHD event within 6 months of randomization or who had used postmenopausal hormone therapy within 3 months of the initial screening were excluded. Those with serum triglyceride levels of 3.39 mmol/L or greater ( 300 mg/dL), fasting blood glucose levels of 16.5 mmol/L or greater ( 300 mg/dL), or uncontrolled hypertension (systolic blood pres sure 200 mg Hg or diastolic blood pressure 105 mm Hg) were also excluded. Computer-generated random numbers were used to specify the allocation sequence. Women were randomly assigned to the two treatment groups by use of a tamper-proof blocked randomization stratified by clinical center. Participants, investigators, and staff at the clinical centers; Wyeth-Ayerst Research; and those adjudicating study outcomes were blinded to medication assignment. Additional details about sample size calculations, randomization, and blinding procedures have been published elsewhere (29). For our analysis, women were classified as having diabetes at the baseline visit if they reported a physician diagnosis of diabetes, were taking diabetes medication, or had a fasting plasma glucose level of 6.9 mmol/L or greater ( 126 mg/dL). Women were classified as having impaired fasting glucose if they had a fasting glucose level of 6.0 to 6.9 mmol/L (110 to 125 mg/dL) at baseline. The remaining women were considered to have normal glucose metabolism. Data Collection At baseline, participants completed a questionnaire to ascertain age, race or ethnicity, education, smoking habits (current, former, or never), alcohol consumption (drinks per week), and exercise or walking activity. Physical examination variables measured at baseline were body weight, height, waist and hip circumference, and systolic and diastolic blood pressure. At baseline, at year 1, and at the end-of-trial visit, participants had fasting blood tests for levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) measured by the Lipoprotein Analytical Laboratory at Johns Hopkins Hospital, Baltimore, Maryland. Fasting serum glucose level was measured at baseline, at year 1, and at the end-of-trial visit. Venous blood was obtained in the morning after a 12-hour fast, and SmithKline Beecham Clinical Laboratory, Van Nuys, California, analyzed the samples using the hexokinase enzymatic method. We determined coefficients of variation by using ChemTrac (Medical Analysis Systems, Inc., Camarillo, California) control. The coefficient of variation for serum glucose level was 1.6% at a mean value (SD) of 4.2 0.05 mmol/L (77 1.0 mg/dL) and 1.1% at a mean value (SD) of 14.6 0.16 mmol/L (266 3.0 mg/dL). Adherence to study medication was reassessed every 4 months, at each visit. Ascertainment of Outcomes Diabetes incidence was not a secondary end point of the main HERS trial, but blood glucose level was prespecified as a variable that may mediate the effects of hormone therapy on CHD outcomes. We defined incident cases of diabetes by the presence of a fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL) at year 1 or at the end-of-trial visit, self-report of new diabetes or a complication directly related to diabetes, or initiation of hypoglycemic medication at any point during follow-up. Self-reported complications included diabetic neuropathy, diabetic retinopathy, diabetic foot ulcer, and diabetic renal disease. Hypoglycemia was considered a complication of diabetes if a participant taking an antidiabetic medication reported it to the study staff as an adverse event. Statistical Analysis To compare fasting glucose levels by treatment assignment at baseline, at year 1, and at the end-of-trial visit, t-tests were used. In addition, mixed linear models for repeated measures were used to assess treatment effects on fasting glucose level measured at year 1 and at the end-of-trial visit. Since mean values changed little after the year 1 visit, treatment effects were modeled by using the interaction between treatment assignment and an indicator for follow-up compared with baseline. These analyses were repeated after stratification by baseline diabetes status (diabetes, impaired fasting glucose, or normal glucose metabolism). We calculated the number needed to treat for benefit by taking the inverse of the absolute risk reduction of incident diabetes between the treatment groups. The effect of treatment assignment on incident diabetes was assessed by using Cox proportional-hazards models. Primary analyses used unadjusted intention-to-treat models; in supplementary analyses, we adjusted first for age and then for a range of potential confounders selected a priori, including age; ethnicity; education; current smoking; alcohol use; exercise; body mass index; waist circumference; and baseline use of diuretics, -blockers, angiotensin-converting enzyme inhibitors, and statins. In addition to intention-to-treat analyses, we also performed as treated analyses to determine whether the observed effect of hormone therapy on glucose levels and incident diabetes was also seen among women who adhered to the study medication. In these analyses, follow-up was censored at the beginning of the first 2-week period in which participants did not adhere to medication. To minimize potential confounding, these analyses were adjusted for baseline variables that differed between adherent and nonadherent women. We hypothesized that certain characteristics (body mass index, waist circumference, weight change, smoking, triglyceride level, high-density lipoprotein cholesterol level, hypertension, and certain cardiac medications) may mediate the effect of hormone therapy on fasting glucose level and diabetes incidence. To test this theory, we added postrandomization values of one or more hypothesized mediators as covariates to Cox regression models for incident diabetes. All analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design or conduct of this analysis or in the decision to submit the paper for publication. Results Characteristics of women enrolled in HERS did not differ substantially between the hormone therapy group and the placebo group (Table 1). At the baseline examination, 734 women (26.6%) were classified as diabetic based on self-report of diagnosis or medication use (n = 640 [87.2%]) or by a fasting serum glucose level of 6.9 mmol/L or greater ( 126 mg/dL) (n = 101 [13.8%]). Impaired fasting glucose (fasting serum glucose level, 6.0 to 6.9 mmol/L [110 to 125 mg/dL]) was noted in 218 women (7.9%), and 1811 women (65.5%) were classified as nondiabetic (Table 2). Women with diabetes had higher body mass index, waist circumference, systolic