Investigation of the Effect of Empagliflozin on Cardiac Sympathetic and Parasympathetic Nerve Activity Analyzed From Heart Rate Variability Frequency in Japanese Patients With Type 2 Diabetes　― Results From the EMPYREAN Study ―

Abstract

Background: The EMPA-REG OUTCOME trial confirmed empagliflozin reduced mortality and heart failure hospitalization risk. These findings raised the possibility that empagliflozin may modulate cardiac autonomic function in patients with type 2 diabetes (T2D).

Methods and Results: The EMPYREAN study was a prospective randomized open-label assessor-blinded multicenter investigation of patients with T2D without prior antidiabetic therapy with sodium-glucose cotransporter 2 or dipeptidyl peptidase 4 inhibitors. Electrocardiographic monitoring was performed at study onset and after 12 and 24 weeks of treatment. Heart rate variability was analyzed using the MemCalc method. The primary endpoint was the change in the low frequency (LF; 0.04–0.15 Hz)/high frequency (HF; 0.15–0.4 Hz) ratio from baseline to 24 weeks. In all, 113 patients were randomized. The median age in the empagliflozin and sitagliptin groups was 60 and 63 years, respectively. There were no significant differences in serial changes in the LF/HF ratio (0.52, 95% confidence interval [CI] −0.15 to 1.19, P=0.126) or HF (16.13, 95% CI −11.58 to 43.84, P=0.251) between the 2 groups. In time domain analysis, serial changes in root mean square successive difference (1.90, 95% CI −0.56 to 4.38, P=0.12) and percent of difference between adjacent normal RR intervals >50 ms (1.04, 95% CI −0.32 to 2.41, P=0.13) were not significantly different.

Conclusions: The effects of empagliflozin and sitagliptin on autonomic nerve activity did not differ significantly in patients with T2D.