Abstract
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.