Metformin for Prediabetes in Perimenopausal Women: What the Evidence Shows

Prediabetes has more than doubled in prevalence over two decades, with impaired glucose tolerance affecting 9.1% of the global population in 2021 and projected to reach 10% by 2045. Women show higher rates of both impaired glucose tolerance and impaired fasting glucose than men, and diabetes prevalence in women surpasses that of men starting in the 70–74 age group—a pattern likely driven by the loss of protective sex hormones during and after menopause. Despite this burden, research specifically addressing prediabetes management in perimenopausal women remains sparse.

This narrative review from researchers at the National University of Singapore and National Taiwan University Hospital covers four domains: epidemiology, pharmacology, clinical practice, and future perspectives. Metformin's mechanisms are reviewed in depth, including AMPK activation in hepatocytes and intestinal cells, suppression of gluconeogenesis via PKA inhibition, enhancement of GLUT-4 expression, GLP-1 elevation, gut microbiome modulation (increased Akkermansia muciniphila and Lactobacillus), and production of the appetite-suppressing metabolite N-lactoyl-phenylalanine. The drug is not metabolized and is excreted unchanged in urine with a half-life of approximately 5 hours.

A central finding is that metformin's efficacy appears to differ by menopausal status. Premenopausal women may derive greater benefit, partly because estradiol itself activates AMPK in skeletal muscle—the same pathway metformin engages—suggesting synergistic effects that diminish post-menopause. Sex-specific differences in gut microbiome composition, body fat distribution, and inflammatory marker profiles further modulate metformin response. The Diabetes Prevention Program (DPP) and the CODYCE study are cited as landmark evidence supporting metformin for prediabetes, especially in high-risk individuals where lifestyle changes alone are insufficient.

Beyond glycemic control, the review highlights metformin's emerging roles relevant to perimenopausal women: reducing testosterone in PCOS, mitigating breast tissue inflammation, offering an endometrial alternative to progesterone therapy, and modulating the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes. These pleiotropic effects suggest the drug may address multiple menopausal comorbidities simultaneously. Newer agents like tirzepatide are acknowledged as emerging alternatives, but metformin's established safety profile, low cost, and breadth of benefits maintain its clinical relevance.

The authors conclude that dedicated RCTs in perimenopausal and postmenopausal women are urgently needed to determine optimal dosing, timing relative to menopausal stage, and combination strategies with lifestyle interventions. Understanding how declining estrogen alters metformin's pharmacodynamics could unlock more personalized treatment protocols for a population at rapidly rising T2D risk.