Beneficial effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes in patients with type 2 diabetes (T2D) have been reported. We hypothesized that these benefits may be due to modulatory effects on the sympathetic/parasympathetic imbalance through blunting of the expected compensatory increase in heart rate associated with lowering blood pressure. We aimed to evaluate the effect of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN) in patients with T2D. We performed a pilot, randomized, 2-period crossover clinical trial comparing 12 weeks of glucose lowering intervention with DAPA versus glimepiride on measures of CAN [cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV)] assessed at baseline and end of each drug period. Signed rank tests and mixed models were used to evaluate the differences in CARTs and HRV indices from baseline to 12 weeks between each drug period. Preliminary data are presented for forty-one participants with T2D on metformin monotherapy (mean age 57±8 years, mean diabetes duration 7±6 years, mean HbA1c 7.8±1.3%) at baseline. Although there were no significant differences in indices of CAN in each drug period, there was a trend for higher expiration and inspiration ratio on DAPA compared to glimepiride (mean change 0.02±0.10; p=0.07). We found significant or near significant interactions between sex and treatment for the root mean square of the differences of successive RR intervals (rmsSD) (p=0.021) and Valsalva ratio (p=0.06) in women on DAPA versus glimepiride compared with men. In women, the mean 12-week change for both measures on DAPA was larger than the mean change on glimepiride, whereas in men, the mean 12-week change was larger on glimepiride than DAPA. These preliminary short-term data suggest that DAPA may have beneficial effects on measures of CAN particularly in women with T2D. These findings need to be confirmed in larger prospective studies with longer follow-up.


L. Ang: None. K.M. Kidwell: None. J. Reiss: None. B.R. Dillon: None. K.R. Mizokami-Stout: None. V.A. Leone: None. R. Pop-Busui: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at