Sex Differences in Diabetes, Heart Disease, and Beyond

The Rancho Bernardo Study (RBS) [1] has had animportant and lasting contribution to the literatureaddressing sex differences in cardiovascular disease and, inparticular,howdiabetesmodiﬁestheserisks.Itbeganas1ofthe 12 LRC (Lipid Research Clinic) prevalence study sitesand was a unique cohort study in which 82% of a targetpopulationwasenrolled,resultinginlowselectionbias.RBSwasamongtheﬁrstcohortstudiestofocusonsexdifferencesintheassociationofdiabetesandcardiovasculardiseaseandhas had lasting effects on how we diagnose and perhapsmanagewomen withdiabetes.Itwasamongthefew studiesatthetimethatfocusedonolderpersons;thus,itbrokenewground in geriatric epidemiology as well.RBS was the ﬁrst cohort study to perform oral glucosetolerance tests to assess insulin resistance and diabetes. Thestudy documented important differences between men andwomen in fasting glucose and impaired glucose tolerance,including a diabetes detection bias in women becausea higher proportion of women than men had diabetesdiagnosed only after an oral glucose tolerance test. In addi-tion to ﬁnding a source of underdetection of diabetes inwomen, the RBS also documented a linear relationship inmenwithfastingglucoseandheartdiseasemortalityrisk,butin women a threshold effect was found; an associationbetween fasting glucose and coronary heart disease (CHD)mortality existed only after the fasting glucose level reached100 mg/dl.The RBS study also showed CHD mortality differencesin men and women, thereby showing that the presence ofdiabetes eliminated cardioprotection in women. In theirJAMA publication [2] on this topic that examined 14-yearrisk of fatal ischemic heart disease, the relative hazard asso-ciated with diabetes after adjustment for age and other riskfactors was 1.9 in men and 3.3 in women. The RBS alsomeasured endogenous sex hormones using the most sensi-tive and speciﬁc assays available at the time for total andbioavailable testosterone and estradiol. Although they didnot ﬁnd a direct relationship between sex hormones andCHD, they found evidence that perhaps the effect ofchanginghormones,particularlyinapost-menopausalstateinwomenwasmediatedthroughimpairedglucosetoleranceand diabetes. The relationships found were complex. Therisk of diabetes was increased in men if their bioavailabletestosteronewasinthelowestquartileandinwomeniftheirbioavailable testosterone was in the highest quartile.In addition, low levels of total testosterone weresigniﬁcantly associated with incident CHD events in theRBS women. Therefore, both low and high testosteronewere associated with higher risk of CHD events in women,high bioavailable testosterone was associated with obesity,diabetes, and metabolic syndrome components, whereaslow total testosterone may have a different mechanism.RBS is a very important cohort study in delineatingdifferences in men and women in how diabetes modulatesrisk for CHD. It helped close gaps in knowledge of howdiabetes eradicates cardioprotection in women. Observa-tional studies, including the RBS, have been invaluable fortesting hypotheses among “real women seen in practice,”who are often more representative than those selected forclinical trials, often representing a wider socioeconomicand ethnic distribution than that used in clinical trials.Moreover, such studies will include those who may beexcluded from clinical trials, such as women with severemenopausal symptoms, who are typically excluded fromclinical trials [3].Whereas we have focused on the contributions the RBShas made in the area of sex differences in diabetes andcardiovascular disease, the study has made countless othercontributionsthataretoogreattomentionhere.Asasampler,most recently, the predictive role of biomarkers such astroponinandN-terminalproeB-typenatriureticpeptidehavebeenstudiedinrelationtodementia[4]andmortality[5],andfactors such as abdominal obesity and kidney function havebeen examined in relation to progression of atherosclerosismeasuredbynovelfactorssuchascoronarycalciﬁcation[6,7].In 2009, in her 2009 Distinguished Scientist Lectureawarded by the American Heart Association, Dr. Barrett-Connor described how her simple addition of fastingglucose and information about diabetes to the LRC study inRancho Bernardo shaped what was to become among themost pre-eminent studies examining sex differences incoronary heart disease and diabetes that would ultimatelycontribute greatly to awareness of the problems of diabetesand heart disease in women [8]. With the many investi-gators who have participated and continue to participate inexploring new hypotheses in the RBS, the future of thestudy, now in its ﬁfth decade, continues to hold greatpromise.REFERENCES