Sex differences in diabetes and risk of incident coronary artery disease in healthy young and middle-aged adults

Abstract

Objective: Controversy exists about the coronary artery disease (CAD) risk conveyed by diabetes in young and middle-aged women. We investigated sex differences in CAD by diabetes status among healthy individuals with different underlying risks of heart disease.

Research design and methods: We examined subjects aged <60 years without CAD at enrollment in the high-risk GeneSTAR Study (n = 1,448; follow-up ∼12 years), Multi-Ethnic Study of Atherosclerosis (MESA; n = 3,072; follow-up ∼7 years), and National Health and Nutrition Examination Survey III (NHANES III) Mortality Follow-up Study (n = 6,997; follow-up ∼15 years). Diabetes was defined by report, hypoglycemic use, and/or fasting glucose ≥126 mg/dL. The outcome was any CAD event during follow-up (fatal CAD in NHANES).

Results: In the absence of diabetes, CAD rates were lower among women in GeneSTAR, MESA, and NHANES (4.27, 1.66, and 0.40/1,000 person-years, respectively) versus men (11.22, 5.64, and 0.88/1,000 person-years); log-rank P < 0.001 (GeneSTAR/MESA) and P = 0.07 (NHANES). In the presence of diabetes, CAD event rates were similar among women (17.65, 7.34, and 2.37/1,000 person-years) versus men (12.86, 9.71, and 1.83/1,000 person-years); all log-rank P values > 0.05. Adjusting for demographics, diabetes was associated with a significant four- to fivefold higher CAD rate among women in each cohort, without differences in men. In meta-analyses of three cohorts, additionally adjusted for BMI, smoking, hypertension, HDL, and non-HDL cholesterol, antihypertensive and cholesterol-lowering medication use, the hazard ratio of CAD in men versus women among nondiabetes was 2.43 (1.76-3.35) and diabetes was 0.89 (0.43-1.83); P = 0.013 interaction by diabetes status.

Conclusions: Though young and middle-aged women are less likely to develop CAD in the absence of diabetes, the presence of diabetes equalizes the risk by sex. Our findings support aggressive CAD prevention strategies in women with diabetes and at similar levels to those that exist in men.

Figure 1

Kaplan-Meier curves for CAD event-free survival in men and women with and without diabetes, <60 years old at baseline. Time-to-event analyses for incident CAD events in men without diabetes (blue solid line), men with diabetes (blue dashed line), women without diabetes (red solid line), and women with diabetes (red dashed line) are displayed by cohort. In all three cohorts, CAD event-free survival is significantly lower in young and middle-aged women with versus without diabetes (log-rank P < 0.001 for GeneSTAR; P = 0.002 in MESA; P = 0.007 in NHANES), but similar between men with versus without diabetes (all log-rank P > 0.05). Interestingly, among those without diabetes, women had significantly better survival than men in all cohorts (log-rank P < 0.001 for GeneSTAR; P < 0.001 for MESA; P = 0.07 for NHANES). However, the presence of diabetes equalized CAD-event free survival between men versus women (log-rank P > 0.05 in all cohorts). Only fatal CAD events were ascertained in NHANES. (A high-quality color representation of this figure is available in the online issue.)

Figure 2

Meta-analysis of three cohort studies demonstrating HRs of incident CAD, adjusted for traditional cardiovascular risk factors, in persons with versus without diabetes by sex. In meta-analyses, after accounting for age, race, education, BMI, smoking, hypertension, HDL and non-HDL cholesterol, and antihypertensive and cholesterol-lowering medication, the fully adjusted HR for incident CAD in those with versus without diabetes was significant in women (HR 3.61 [1.97–6.61]) and nonsignificant in men (HR 1.17 [0.71–1.94]). The interaction by sex was significant (P = 0.005). Only fatal CAD events were ascertained in NHANES.