Association between early menopause and adverse cardiovascular events in postmenopausal women: a systematic review and meta-analysis stratified by smoking status and type 2 diabetes mellitus.

BACKGROUND: The impact of early menopause on adverse cardiovascular events may be modified by smoking and type 2 diabetes mellitus (T2DM). This study aims to investigate the effect of early menopause on adverse cardiovascular events in women, with stratification by smoking status and T2DM status. METHODS: Studies were retrieved from four databases (Embase, Web of Science, PubMed, and Cochrane Library) from their inception to January 2026. In this study, early menopause was defined as natural menopause occurring before age 45 years, encompassing both premature menopause (<40 years) and early menopause (40-45 years). This systematic review was registered with PROSPERO (Registration No.: CRD420251238709). Results were presented as hazard ratios (HR) or relative risks (RR) with corresponding 95% confidence intervals (95% CI). RESULTS: In this study, a total of seven cohort studies involving over 1.77 million postmenopausal women were included. Among non-smoking women, early menopause was associated with a higher risk of heart failure (HF: HR = 1.23, 95% CI = 1.02-1.49, p = 0.031, I 2 = 87.9%, n = 2) and coronary heart disease (CHD: RR = 1.26, 95% CI = 1.18-1.35, p < 0.001, I 2 = 0.0%, n = 2). In contrast, among smoking women, we did not find statistically significant evidence of an association between early menopause and either HF (HR = 1.15, 95% CI = 0.88-1.52, p = 0.311, I 2 = 73.7%, n = 2) or CHD (RR = 1.63, 95% CI = 0.90-2.96, p = 0.105, I 2 = 97.2%, n = 2). For women without T2DM, early menopause was associated with a higher risk of both HF (HR = 1.19, 95% CI = 1.00-1.43, p = 0.050, I 2 = 94.1%, n = 2), a borderline finding that should be interpreted with caution, and significantly associated with stroke (HR = 1.11, 95% CI = 1.09-1.13, p < 0.001, I 2 = 0.0%, n = 2). For women with T2DM, early menopause was associated with a higher risk of HF (HR = 1.29, 95% CI = 1.11-1.50, p = 0.001, I 2 = 54.3%, n = 2), but not find with stroke risk (HR = 1.11, 95% CI = 0.99-1.25, p = 0.062, I 2 = 59.6%, n = 2). In both the T2DM and non-T2DM groups, no statistically significant evidence of an association between early menopause and with all-cause mortality was found (T2DM: HR = 1.20, 95% CI = 0.83-1.74, p = 0.333, I 2 = 54.3%, n = 2; without T2DM: HR = 1.18, 95% CI = 0.94-1.47, p = 0.148, I 2 = 53.3%, n = 2, respectively). CONCLUSION: Early menopause is associated with the risk of adverse cardiovascular events in women, with divergent results by smoking status and T2DM. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251238709; identifier: CRD420251238709.