Sex Differences in the Association Between Cardiovascular Autonomic Neuropathy and Mortality in Patients With Type 2 Diabetes: The ACCORD Study

Background Cardiovascular autonomic neuropathy (CAN) is a severe complication of type 2 diabetes. Significant sex-related differences have been observed in type 2 diabetes consequences such as mortality. However, the effect of sex on the association between CAN and mortality in patients with type 2 diabetes is currently unknown. Methods and Results We assessed 7866 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 4730 men and 3136 women. CAN was diagnosed using a combination of heart rate variability and QT interval index, which has 3 different definitions. There were 1364 cases of all-cause mortality and 452 cases of cardiovascular disease mortality during a median follow-up of 9.7 years. We used multivariable Cox regression models to assess the association between different CAN definitions and mortality. In women, various CAN measures were statistically significant associated with an increased risk of all-cause mortality (CAN1: hazard ratio [HR], 1.64 [95% CI, 1.28-2.09]; CAN2: HR, 1.58 [95% CI, 1.17-2.15]; CAN3: HR, 1.78 [95% CI, 1.20-2.65]) and mortality (CAN1: HR, 2.25 [95% CI, 1.44-3.52]; CAN 2: HR, 2.22 [95% CI, 1.28-3.87]; CAN3: HR, 3.31 [95% CI, 1.67-6.57]). CAN was not significantly associated with mortality in men. A significant multiplicative interaction of CAN and sex was observed on both mortality outcomes (P<0.01). Conclusions Significant sex-related differences were observed in CAN and its associated mortality. In terms of mortality risk prevention, CAN should be given greater consideration in women with type 2 diabetes.