Microvascular endothelial function predicts incident diabetes mellitus: the ELSA-Brasil cohort study

Background Diabetes mellitus is known to be associated with endothelial dysfunction (ED) in cross-sectional studies. However, the directionality of this association remains debated, largely due to the limited availability of longitudinal studies addressing this issue. The few longitudinal studies in this area show conflicting results: while diabetes has been linked to the development of future ED, few studies have demonstrated that ED may predict incident diabetes. Furthermore, the potential effect modification by obesity status—another factor closely related to ED—has yet to be thoroughly investigated. Purpose Our objective was to evaluate the association of microvascular EF with incident diabetes in adults from Brazil, a middle-income country with a growing prevalence of diabetes, and also whether this association was modified by obesity status. Methods In 1,315 participants from the ELSA-Brasil cohort study, free of diabetes, and with valid EF exams at baseline, we evaluated the association between EF and incident diabetes after 8.8 years (SD=2.1) of follow-up. Microvascular EF was assessed by peripheral arterial tonometry (PAT). The variables mean basal pulse amplitude (BPA) that represents basal vascular tone, and PAT ratio, that represents the vasodilatory capacity in response to reactive hyperemia, were analyzed in sex-specific quartiles. Higher BPA and lower PAT ratio reflect more impaired EF. Diabetes was defined according to the American Diabetes Association criteria. Cox proportional hazard models were used for statistical analyses, and multivariable models were adjusted for sex, age, educational level, physical activity level, smoking, alcohol use and body mass index (BMI). Then, the models were run stratified by obesity/overweight vs. normal weight to evaluate if there was effect modification by BMI group. Results Mean age was 51±8 years, with 45% women, and mean BMI was 26.4±4.4 kg/m2. After follow-up, we identified 159 new cases of diabetes. The incidence rates ranged from 6.3 (95%CI 4.0-9.9) in the first quartile to 18.8 (95%CI 14.3-24.5) in the fourth quartile for BPA and from 7.03 (CI 95% 4.6-10.8) in the fourth quartile to 14.8 (CI 95% 11.0- 20.0) in the first quartile for PAT ratio(Figure 1). The risk of diabetes increased significantly in those with more impaired EF, for both BPA (HR 2.05, CI95% 1.19 – 3.52) and PAT ratio (HR 1.53, CI95% 0.90 – 2.60). There was no effect modification according to obesity status(Figure 2). Conclusions In Brazilian adults, having more impaired EF at baseline predicted diabetes after 8.8 years of follow-up, independent of obesity status. These findings may have implications for the understanding of cardiometabolic diseases in the context of pathophysiology, prognosis and treatment.