Menopause hormone therapy and type 2 diabetes risk and prognosis: systematic review and meta-analyses.

AIMS/HYPOTHESIS: Menopause hormone therapy (MHT) may have effects on metabolic conditions. This study was conducted to systematically review the literature, to summarise and quantify the effect of MHT on glucose or insulin levels and on new-onset type 2 diabetes among women without type 2 diabetes and to summarise and quantify the effect of MHT on glucose, insulin, lipid and blood pressure levels among women with type 2 diabetes. METHODS: Data from six electronic databases (PubMed, Embase, Cochrane, CINAHL, PsyclNFO and MEDLINE) from inception to 29 July 2025 were searched for randomised controlled trials (RCTs) and cohort studies comparing MHT users with non-users among postmenopausal women or women undergoing the menopausal transition. Eligible studies reported the effects of MHT on glucose metabolism, lipid levels or blood pressure in women with or without type 2 diabetes. The risk of bias in RCTs and cohort studies was assessed with version 2 of the Cochrane risk-of-bias for randomised trials (RoB 2) tool and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool, respectively. Certainty of evidence (CoE) was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random-effects models were used to estimate the pooled effects. RESULTS: In total, 49 articles (33 reporting on RCTs and 16 on cohort studies) from 15 countries were identified, involving 1,472,277 participants. The study durations ranged from 1 week to 13.2 years for RCTs and from 6 months to 17 years for cohort studies. Seven of these were assessed as having a low risk of bias. Among women without type 2 diabetes, MHT use was associated with small reductions in fasting insulin (11 studies: N=4262, mean difference [MD] -5.90 pmol/l [95% confidence interval (CI) -8.03, -3.77 pmol/l]; high CoE) and in homeostasis model assessment of insulin resistance score (four studies: N=2883, MD -0.21 [95% CI -0.32, -0.09]; moderate CoE), as well as a lower risk of new-onset type 2 diabetes (14 studies: N=1,450,134, risk ratio 0.83 [95% CI 0.75, 0.92]; very low CoE], compared with non-MHT users. Among women with type 2 diabetes, MHT was associated with small reductions in fasting plasma glucose (16 studies: N=1379, MD -1.07 mmol/l [95% CI -1.86, -0.28 mmol/l]; very low CoE), haemoglobin A1c (17 studies: N=15,720, MD -5.47 mmol/mol [-0.50%] [95% CI -8.32, -2.62 mmol/mol (-0.76, -0.24%)]; very low CoE), cholesterol (15 studies: N=907, MD -0.37 mmol/l [95% CI -0.50, -0.24 mmol/l]; low CoE), low-density lipoprotein cholesterol (16 studies: N=961, MD -0.33 mmol/l [95% CI -0.54, -0.13 mmol/l]; low CoE) and systolic blood pressure (nine studies: N=630, MD -3.43 mmHg (-0.46 kPa) [95% CI -4.88, -1.98 mmHg]; low CoE), compared with non-MHT users. CONCLUSIONS/INTERPRETATION: MHT showed small beneficial associations with glucose metabolism among women with and without type 2 diabetes, while the effect size was generally too small to be clinically significant. Future studies are needed to shed more light on the effect of MHT by initiation age. Study limitations include the predominantly single-reviewer screening and assessment, the high risk of bias of the included studies and restricted geographical representation. REGISTRATION: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251230387). FUNDING: This work was supported by a National Health and Medical Research Council investigator grant (APP2009577).