Does empagliflozin modulate the autonomic system among patients with type 2 diabetes and coronary artery disease? Insights from the Holter sub-study of the EMPA-Heart CardioLink-6 Randomised Trial

Abstract Introduction The mechanism behind how empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, reduces all-cause and cardiovascular mortality among patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) is unknown. Autonomic tone, as reflected by changes in heart rate variability (HRV), is an established prognosticator in patients with CAD and/or heart failure. Purpose To assess if empagliflozin treatment changes HRV in subjects with T2DM and CAD. Methods In the double-blind EMPA-Heart trial, 97 subjects with T2DM and CAD were randomised to empagliflozin 10 mg/day or placebo for 6 months and underwent 24-hour Holter monitoring at baseline and 6 months. Using automated algorithms, time and frequency HRV domain measures were obtained (standard deviation of NN intervals (SDNN); SD of the average NN intervals for each 5-minute segment (SDANN); root mean square of successive RR interval differences (rMSSD); % interval differences of successive NN intervals >50 ms (pNN50); ratio of low to high frequency (LF/HF)). Changes of these HRV parameters were calculated over 6 months. Between-group differences in HRV parameters were compared using ANCOVA. Results Complete Holter data (baseline and 6-month) were available for 68% (n=66) of the cohort. The average heart rate (HR) at baseline/6 months was 69.5±9.8 bpm/72.8±8.1 bpm and 76±10.4 bpm/76.5±10.6 in the placebo group and empagliflozin group, respectively. Both groups had similar changes in average HR over 6 months. Key Holter data are summarised in the table. SDNN and SDANN were higher in the placebo vs. empagliflozin group at 6 months; no significant difference was noted for all other measures. Empagliflozin 10 mg/day (n=33) Placebo (n=33) Adjusted difference between Empagliflozin and Placebo (ANCOVA) Baseline, Mean (SD) 6-month, Mean (SD) Baseline, Mean (SD) 6-month, Mean (SD) Mean, (95% CI) P-value SDNN (ms) 100.49 (43.74) 98.05 (38.86) 109.35 (30.02) 125.08 (43.83) −18.55 (−34.28, −2.82) 0.022 SDANN (ms) 86.84 (39.34) 83.76 (35.53) 94.70 (28.52) 118.28 (77.41) −20.24 (−37.27, −3.21) 0.021 rMSSD (ms) 27.00 (11.84) 27.22 (13.48) 28.00 (11.58) 27.17 (9.38) −1.23 (−6.02, 3.55) 0.608 pNN50 (%) 7.81 (7.59) 8.32 (9.51) 8.26 (7.8) 6.93 (5.35) 0.51 (−2.61, 3.62) 0.746 LF/HF ratio 1.63 (0.52) 1.65 (0.51) 1.53 (0.43) 1.83 (0.82) −0.08 (−0.38, 0.22) 0.602 Conclusions Among subjects with T2DM and CAD, changes in HRV over 6 months were similar in the empagliflozin and placebo arms suggesting that the mortality benefit conferred by empagliflozin is not associated with positive modulation of autonomic tone. Acknowledgement/Funding This trial was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim.