Disproportionate Cardiovascular Risk in Women with Type 2 Diabetes: A Narrative Review of Diet, Metabolic Phenotypes, and Gene-Diet-Epigenetic Interactions Across the Life Course.

Background

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM). Although women generally exhibit a more favorable cardiovascular risk profile than men in the general population, this protection is substantially reduced in the presence of diabetes, resulting in a disproportionately greater relative increase in CVD risk among women.

Objective

This review aims to integrate the roles of metabolic phenotypes, dietary exposures, and genetic susceptibility in shaping cardiovascular risk in women with T2DM, with a focus on diet-gene and diet-epigenetic interactions across critical stages of the female life course.

Methods

A narrative review of epidemiological, clinical, and mechanistic evidence from recent literature was conducted to synthesize current knowledge on sex-specific cardiometabolic pathways and nutritional determinants of vascular risk in T2DM.

Results

Current evidence indicates that several interconnected mechanisms contribute to enhanced cardiovascular vulnerability in diabetic women, including (i) adipose tissue dysfunction and ectopic fat accumulation; (ii) insulin resistance with metabolic inflexibility and lipotoxicity; and (iii) endothelial and microvascular dysfunction driven by impaired nitric oxide signaling. Dietary patterns modulate these pathways through effects on inflammation, oxidative stress, postprandial lipid metabolism, and vascular function. Emerging evidence highlights that genetic variants (e.g., APOE; CETP; TCF7L2) significantly modify metabolic responses to dietary exposures in patients with T2DM; supporting a role for nutrigenetic interactions in shaping cardiovascular risk. In parallel, diet-related epigenetic mechanisms-including metabolic memory and early-life programming-may contribute to long-term and potentially intergenerational cardiometabolic risk.

Conclusions

Integrating dietary patterns with genetic susceptibility and epigenetic regulation provides a mechanistic framework for understanding the disproportionate cardiovascular risk in diabetic women and supports the development of sex-specific, life-course-oriented precision nutrition strategies for cardiovascular risk reduction.