The Rancho Bernardo Study: 40 years studying why women have less heart disease than men and how diabetes modifies women's usual cardiac protection.

Forty years ago, few cohort studies of cardiovascular disease (CVD) included women and fewer still included diabetes or glycemia as a risk factor. 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 6000 participants were followed for morbidity and mortality, with nearly 3000 survivors (and death certificates for >85% of decedents). In RBS more than half of diabetes was undiagnosed without an oral glucose tolerance test (OGTT); more women than men had isolated post-challenge hyperglycemia (IPH) as their only glucose evidence of diabetes; men had more diabetes than women, with higher fasting but lower post-challenge glucose levels than women; women with diabetes had more classical CVD risk factors than men; excess risk-factor clustering partially explained how diabetes eradicates female cardioprotection. Post-challenge glucose was a stronger CVD risk factor than fasting glucose. Endogenous insulin was not an independent CVD risk factor in women or men. Men with higher testosterone levels developed less diabetes and had fewer metabolic syndrome components. In men higher total testosterone levels predicted a reduced risk of 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.