Loss of Female Cardiovascular Protection in Diabetes: From Mechanisms to Intervention

Premenopausal women without diabetes have a well-established cardiovascular advantage over men of the same age, mainly due to the benefits of estrogen, which has vasoprotective, anti-inflammatory, and antioxidant effects on the vascular endothelium. However, women with type 1 or type 2 diabetes have a 40–50% higher relative risk of coronary heart disease and suffer a greater burden of heart failure and cardiovascular mortality compared with diabetic men. The mechanisms involved in the disparity are not well understood and are seldom considered in clinical guidelines or trials, where women are underrepresented. The paradoxical relationship between chronic hyperglycemia and estrogen signaling plays a critical role, since estradiol, rather than having its usual cardioprotective effect, instead leads to oxidative stress and endothelial dysfunction. This occurs through eNOS uncoupling, activation of the AGE-RAGE axis, and a shift towards pro-inflammatory signaling via estrogen receptors. Sex-related differences in body composition and the distribution of fat tissue also make a significant contribution to the variations in cardiovascular risk. Modifiable lifestyle factors, especially physical activity and skeletal muscle mass, are important targets for intervention, with evidence showing that their benefits on endothelial function, body composition, and systemic inflammation are particularly noticeable in females. In addition, the sex-specific cardiovascular responses to treatments such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors should be investigated more closely. This review summarizes the current evidence, identifies critical knowledge gaps, and proposes a framework for sex-informed cardiovascular prevention in diabetes.