Why Women Have Less Heart Disease Than Men and How Diabetes Modifies Women's Usual Cardiac Protection: A 40-Year Rancho Bernardo Cohort Study

Forty years ago, few cohort studies of cardiovascular disease (CVD) included women and fewer still included diabetes or glycemia as risk factors. I describe here the Rancho Bernardo Study (RBS), a single-site, >40-year cohort study of sex differences in heart disease and how diabetes modifies women's natural cardioprotection. More than 6,000 participants were followed for morbidity and mortality, with nearly 3,000 survivors (and death certificates for >85% of decedents). In RBS, more than one-half of diabetes cases were undiagnosed without an oral glucose tolerance test (OGTT); more women than men had isolated post-challenge hyperglycemia as their only glucose evidence of diabetes; men had more diabetes, with higher fasting but lower post-challenge glucose levels than did women; women with diabetes had more classic CVD risk factors than did men; and excess risk factor clustering partially explained how diabetes eradicates female cardioprotection. Post-challenge glucose was a stronger CVD risk factor than was fasting glucose. Endogenous insulin was not an independent CVD risk factor in women or men. Men with higher testosterone levels developed fewer cases of diabetes and had fewer metabolic syndrome components. In men, higher total testosterone levels predicted reduced risks for all-cause and CVD but not cancer mortality. In women, both extremes of bioavailable testosterone predicted fatal coronary heart disease but not all-cause mortality. Summary point estimates from large systematic reviews of individual data have replicated most RBS findings. Ongoing research can further clarify how diabetes modifies women's cardioprotection from mid-life to old age.