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 msec 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

Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

“…Blood pressure was not significantly reduced by dapagliflozin in the current study; however, blood pressure was numerically reduced, as observed in previous studies 5,10,12 . The concomitant lowering of heart rate suggests decreased sympathetic nervous system activity, as found in animal studies 32 and recently observed in patients postmyocardial infarction 33 …”

“…5,10,12 The concomitant lowering of heart rate suggests decreased sympathetic nervous system activity, as found in animal studies 32 and recently observed in patients postmyocardial infarction. 33 Previous studies have suggested a reduced preload by SGLT2is based on findings of reduced plasma volume. 10,12 In this study, functional indications of reduced preload were observed, including reduced maximal LA volume and global LV radial strain.…”

The role of parasympathetic mechanisms in the infarct-limiting effect of SGLT2 inhibitor ertugliflozin

“…If a neural mechanism is required for cardioprotection by SGLT2 it might involve the sympathetic or parasympathetic arms. Recent experimental 11,12,13 and clinical data 14 strongly suggest that SGLT2 expression may be up-regulated by the sympathetic nervous system 11,13 , and, vice versa , SGLT2 inhibition is associated with sympatho-inhibition 12,14 . However, sympatho-inhibition by SGLT2 inhibitors has only been directly demonstrated in kidneys 12 , and not in the heart 12,14 .…”

“…Recent experimental 11,12,13 and clinical data 14 strongly suggest that SGLT2 expression may be up-regulated by the sympathetic nervous system 11,13 , and, vice versa , SGLT2 inhibition is associated with sympatho-inhibition 12,14 . However, sympatho-inhibition by SGLT2 inhibitors has only been directly demonstrated in kidneys 12 , and not in the heart 12,14 . In addition, it cannot be excluded that inhibition of sympathetic tone by this class of drugs might be secondary to improvements in haemodynamics and metabolic stress, and not causally related to cardioprotection 15 .…”

Effect of Empagliflozin Versus Placebo on Plasma Volume Status in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus

“…The EMBODY trial is a prospective, multicenter, randomized, double-blind, and placebo-controlled trial for identifying the effect of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac sympathetic hyperactivity in patients with acute myocardial infarction (AMI) and type 2 diabetes mellitus (T2DM) in Japan [4,5].…”