Dapagliflozin Improves Cardiac Autonomic Function Measures in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy

Background: Cardiac autonomic neuropathy is a frequent complication of type 2 diabetes mellitus. Cardiac autonomic neuropathy, in which sympathetic tone predominates over parasympathetic activity, increases both cardiovascular morbidity and mortality and unfortunately has no definitive treatment. Sodium-glucose cotransporter-2 inhibitors have been suggested to reduce sympathetic nervous system activity, based on the results from previous studies. In this study, we aimed to investigate the effect of 24-week treatment with dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, on cardiac autonomic function measures in patients with type 2 diabetes mellitus and cardiac autonomic neuropathy. Methods: Dapagliflozin 10 mg/day (n=42) or non-sodium-glucose cotransporter-2 inhibitor oral antidiabetic(s) (n=38) was added to the treatment of patients whose glycemic control could not be achieved with existing treatments. The patients with definite or confirmed cardiac autonomic neuropathy diagnosed by cardiovascular autonomic reflex tests underwent 24-hour Holter-electrocardiogram recordings to obtain heart rate variability and heart rate turbulence parameters before starting additional medication and after a 24-week treatment period. Results: In-group analyses showed that dapagliflozin 10 mg/day for 24 weeks improved heart rate variability and heart rate turbulence parameters and decreased the frequency of ventricular premature beats relative to their baseline values. No such findings were observed in the control group despite similar glycemic control. Comparisons between dapagliflozin group and the control group showed that these effects of dapagliflozin were significantly better than non-sodium-glucose cotransporter-2 inhibitor oral antidiabetics. Conclusion: Dapagliflozin improves measures of cardiac autonomic function compared to the control group in type 2 diabetic patients with cardiac autonomic neuropathy. This intergroup benefit, demonstrated for the first time, may be promising for the regression of cardiac autonomic neuropathy with sodium-glucose cotransporter-2 inhibitors.