Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Abstract

Background Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. Results Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. Conclusions This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis

“…SGLT2i treatment was associated with a 28% risk reduction for VT. In the recent EMBODY trial, [ 56 ] improvements in indicators of cardiac sympathetic/parasympathetic nerve activity, which are related to the risk of ventricular tachyarrhythmias, were greater in the empagliflozin group compared to the placebo group. Only the empagliflozin group achieved a significant intra-group improvement.…”

Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF

“… 32 Sodium-glucose cotransporter 2 inhibitors may also have a favourable effect on the autonomic nervous system. In the EMBODY trial, 16 empagliflozin improved both sympathetic and parasympathetic activities in patients with myocardial infarction and type 2 diabetes, a finding supported by a study with dapagliflozin in a pig model of heart failure. 33 Empagliflozin does not prolong QT interval in healthy humans and attenuated sotalol-induced QTc prolongation in rats.…”

Sodium‐glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review

“…No significant differences in heart rate variability (HRV) measures, used to assess cardiac sympathetic activity, were observed in 105 patients with MI and T2DM treated with empagliflozin 10 mg daily for 24 weeks compared with those who received placebo. 82 HRV measures did, however, decrease significantly from baseline with empagliflozin, but not with placebo. 82 HRV measures were also not significantly altered after 6 months of treatment with empagliflozin 10 mg daily compared with placebo in 66 patients with T2DM and CAD in the EMPA‐HEART study, with the exception of a significant reduction in the standard deviation of normal to normal intervals.…”

“… 82 HRV measures did, however, decrease significantly from baseline with empagliflozin, but not with placebo. 82 HRV measures were also not significantly altered after 6 months of treatment with empagliflozin 10 mg daily compared with placebo in 66 patients with T2DM and CAD in the EMPA‐HEART study, with the exception of a significant reduction in the standard deviation of normal to normal intervals. 83 The statistical significance of changes from baseline in HRV measures observed within treatment groups was not assessed in this study.…”