Influence of Cardiometabolic Status on Cardiovascular Effects of Oral Menopausal Hormone Therapy

OBJECTIVE: To assess risk of adverse cardiovascular outcomes from menopausal hormone therapy (MHT) by cardiometabolic status. METHODS: Secondary analysis of two double-blind placebo-controlled randomized controlled trials of conjugated equine estrogens ([CEE] 0.625 mg/d) or CEE with medroxyprogesterone acetate ([MPA] 2.5 mg/d) compared with placebo in postmenopausal women aged 50-79 years. The primary outcome was coronary heart disease ([CHD], nonfatal myocardial infarction or CHD death). Cardiometabolic status was evaluated by lipid profile, blood pressure, blood glucose, and presence of metabolic syndrome (MetS). RESULTS: The CEE-alone trial enrolled 10,739 participants who had undergone hysterectomy, and the CEE+MPA trial enrolled 16,608 participants with an intact uterus. Randomization to oral MHT did not increase CHD risk in participants with a history of treated hyperlipidemia or in untreated participants with favorable lipid profiles, but risk increased in those with unfavorable lipid profiles. In the CEE+MPA trial, the CHD risk in untreated participants with normal low-density lipoprotein (LDL) cholesterol levels (less than 130 mg/dL) was similar to that of placebo-treated participants (hazard ratio [HR] 0.59; 95% CI, 0.31-1.10); however, for elevated LDL 190 mg/dL or higher, the risks were more than doubled (HR 2.77; 95% CI, 1.42-5.40; P-trend=.002). Risk of CHD increased with higher LDL/high-density lipoprotein (HDL) ratios (ratio less than 2.5: HR 0.73; 95% CI, 0.39-1.37 vs ratio 4 or higher: HR 1.76; 95% CI, 1.08-2.88 (P-trend=.008). Similar but nonsignificant risk patterns risk by increasing level of LDL/HDL ratio were seen for CEE-alone compared with placebo. Participants with HDL cholesterol levels 60 mg/dL or greater (vs less than 50 mg/dL) appeared to be at somewhat lower risk (HRs 0.68 and 1.24, P-trend=.02). The patterns for effect modification on CHD risk by untreated LDL cholesterol levels within 10-year age groups (50-59, 60-69, and 70-79 years) were consistent with the overall results in both trials. Blood pressure, blood glucose, triglycerides, or MetS did not modify CHD risk due to CEE or CEE+MPA. CONCLUSION: Higher baseline levels of LDL cholesterol when using CEE+MPA or lower levels of HDL cholesterol when using CEE resulted in an increased risk for CHD across all age groups. Prior treatment of hyperlipidemia demonstrated no increased risk of CHD in patients treated with CEE+MPA or CEE compared with those receiving placebo. Assessment of blood lipids could assist with selection of patients for treatment with CEE of CEE+MPA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT0000611.