Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial
Authors: Shimizu Wataru , Kubota Yoshiaki , Hoshika Yu , Mozawa Kosuke , Tara Shuhei , Tokita Yukichi , Yodogawa Kenji , Iwasaki Yu-ki , Yamamoto Takeshi , Takano Hitoshi , Tsukada Yayoi , Asai Kuniya , Miyamoto Masaaki , Miyauchi Yasushi , Kodani Eitaro , Ishikawa Masahiro , Maruyama Mitsunori , Ogano Michio , Tanabe Jun ,   EMBODY trial investigators, Shiomura Reiko , Fukuizumi Isamu , Matsuda Junya , Noma Satsuki , Sangen Hideto , Komiyama Hidenori , Imori Yoichi , Nakamura Shunichi , Nakata Jun , Miyachi Hideki , Takagi Gen , Todoroki Takahiro , Ikeda Takeshi , Miyakuni Tomoyo , Shima Ayaka , Matsushita Masato , Okazaki Hirotake , Shirakabe Akihiro , Kobayashi Nobuaki , Takano Masamitsu , Seino Yoshihiko , Nishi Yugo , Suzuki Keishi , Shibuya Junsuke , Saito Tsunenori , Nakano Hiroyuki , Taichirou Morisawa , Furuse Erito , Nakama Kenji , Hosokawa Yusuke , Tsuboi Ippei , Kawanaka Hidekazu 
Published: September 2020

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.