Insulin Resistance May Partly Explain Higher Cardiovascular Risk After Premature Menopause

Women who reached menopause before age 40 years had a higher long-term risk of cardiovascular disease (CVD) and coronary heart disease (CHD), and insulin resistance accounted for nearly one-fifth of that association. The findings come from an analysis of the Atherosclerosis Risk in Communities (ARIC) study presented at the 2026 Annual Meeting of The Menopause Society in San Diego.^1,2

Early menopause, occurring between ages 40 and 44 years, was not associated with increased cardiovascular risk.²

Premature menopause occurs in about 1% of women. Because of estrogen deficiency and a longer postmenopausal lifespan, it has been linked to several adverse health outcomes, including CVD and osteoporosis. The cardiometabolic mechanisms behind the elevated CVD risk, however, have been unclear.^1,2

Zailing Xing, PhD, of the University of Vermont, and colleagues analyzed data from 4,710 postmenopausal women aged 45 to 64 years in ARIC who had no CVD at baseline. Age at menopause was self-reported and categorized as premature (younger than 40 years), early (40-44 years), or 45 years or older.²

The composite CVD outcome included incident CHD, total stroke, and heart failure. Cox proportional hazards models were adjusted for demographic, lifestyle, and reproductive factors. The investigators used counterfactual mediation analyses to evaluate fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) as potential mediators.²

Key findings

During a mean follow-up of 21.4 years (SD, 9.5), 1,570 CVD events occurred. Compared with menopause at age 45 years or older, premature menopause was associated with greater risk of composite CVD (HR, 1.19; 95% CI, 1.04-1.35) and CHD (HR, 1.30; 95% CI, 1.08-1.58). It was not associated with stroke or heart failure.²

Women with premature menopause also had 9.3% higher insulin levels (P = .001) and 9.9% higher HOMA-IR (P = .002) than those with menopause at 45 or older. Fasting glucose did not differ significantly (0.8% higher; P = .38).²

In mediation analyses, insulin accounted for 19% and HOMA-IR for 19.3% of the total effect of premature menopause on CVD.²

Xing said the results suggest "insulin resistance may be one important pathway" linking premature menopause and CVD, underscoring the importance of cardiometabolic health in this population. Stephanie Faubion, MD, MBA, medical director of The Menopause Society, noted in the press release that a better understanding of these mechanisms could point to opportunities for earlier intervention and more personalized risk-reduction strategies.¹

Limitations²

Age at menopause was self-reported, which may introduce recall error. As an observational analysis, the study cannot establish causation. Insulin resistance explained only part of the association, suggesting that other pathways are also involved.

What it means for primary care

For patients with a history of menopause before age 40, these findings support including age at menopause in cardiovascular risk assessment. The normal fasting glucose levels despite higher insulin and HOMA-IR suggest that glucose alone may not reveal early metabolic risk in this group.²

References

1. The Menopause Society. Premature menopause associated with higher insulin levels and greater CVD risk. News release. October 20, 2026.
2. Xing Z, Harrington LB, Stefanick M, Kallen A, Madsen TE. Premature menopause and cardiovascular disease risk in the ARIC study: mediation by insulin resistance. Abstract P-48. Presented at: 2026 Annual Meeting of The Menopause Society; October 20-24, 2026; San Diego, CA.