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

Wataru Shimizu, Yoshiaki Kubota, Yu Hoshika, Kosuke Mozawa, Shuhei Tara, Yukichi Tokita, Kenji Yodogawa, Yu-Ki Iwasaki, Takeshi Yamamoto, Hitoshi Takano, Yayoi Tsukada, Kuniya Asai, Masaaki Miyamoto, Yasushi Miyauchi, Eitaro Kodani, Masahiro Ishikawa, Mitsunori Maruyama, Michio Ogano, Jun Tanabe, EMBODY trial investigators, Reiko Shiomura, Isamu Fukuizumi, Junya Matsuda, Satsuki Noma, Hideto Sangen, Hidenori Komiyama, Yoichi Imori, Shunichi Nakamura, Jun Nakata, Hideki Miyachi, Gen Takagi, Takahiro Todoroki, Takeshi Ikeda, Tomoyo Miyakuni, Ayaka Shima, Masato Matsushita, Hirotake Okazaki, Akihiro Shirakabe, Nobuaki Kobayashi, Masamitsu Takano, Yoshihiko Seino, Yugo Nishi, Keishi Suzuki, Junsuke Shibuya, Tsunenori Saito, Hiroyuki Nakano, Morisawa Taichirou, Erito Furuse, Kenji Nakama, Yusuke Hosokawa, Ippei Tsuboi, Hidekazu Kawanaka, Wataru Shimizu, Yoshiaki Kubota, Yu Hoshika, Kosuke Mozawa, Shuhei Tara, Yukichi Tokita, Kenji Yodogawa, Yu-Ki Iwasaki, Takeshi Yamamoto, Hitoshi Takano, Yayoi Tsukada, Kuniya Asai, Masaaki Miyamoto, Yasushi Miyauchi, Eitaro Kodani, Masahiro Ishikawa, Mitsunori Maruyama, Michio Ogano, Jun Tanabe, EMBODY trial investigators, Reiko Shiomura, Isamu Fukuizumi, Junya Matsuda, Satsuki Noma, Hideto Sangen, Hidenori Komiyama, Yoichi Imori, Shunichi Nakamura, Jun Nakata, Hideki Miyachi, Gen Takagi, Takahiro Todoroki, Takeshi Ikeda, Tomoyo Miyakuni, Ayaka Shima, Masato Matsushita, Hirotake Okazaki, Akihiro Shirakabe, Nobuaki Kobayashi, Masamitsu Takano, Yoshihiko Seino, Yugo Nishi, Keishi Suzuki, Junsuke Shibuya, Tsunenori Saito, Hiroyuki Nakano, Morisawa Taichirou, Erito Furuse, Kenji Nakama, Yusuke Hosokawa, Ippei Tsuboi, Hidekazu Kawanaka

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 .

Keywords: Acute Myocardial Infarction; Heart rate turbulence; Heart rate variability; Randomized Controlled Trial; Sodium–glucose cotransporter 2 inhibitor; Sudden cardiac death.

Conflict of interest statement

YK, YH, KM, TY, ST, YT, KY, YI, TY, HT, YT, KA, MM, YM, EK, MI, MM, MO and JT declared no conflicts of interest. WS has received honorariums and research grants from Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
A total of 105 patients met the inclusion criteria and were randomized. Six patients in the empagliflozin group and three patients in the placebo group were excluded because of consent withdrawal before medication begun. Therefore, 96 patients were included in the full analysis set (46 in the empagliflozin group and 50 in the placebo group)
Fig. 2
Fig. 2
Changes from baseline in the heart rate turbulence. The category of heart rate turbulence reflecting abnormal autonomic nerve activity improved significantly in the empagliflozin group only. Intergroup comparison revealed no significant difference
Fig. 3
Fig. 3
Changes from baseline in the late potentials. Intragroup and intergroup comparison revealed no significant change in late potentials as an indicator of depolarization
Fig. 4
Fig. 4
Changes from baseline in systolic blood pressure, body weight, and body mass index. The shifts in systolic blood pressure, body weight, and body mass index during the trial period are presented. Compared with the placebo group, the empagliflozin group showed an early improvement with a significant difference (Intergroup; P = 0.0005, P = 0.0002 and P = 0.0002, respectively)

References

    1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/nejmoa1504720.
    1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in Type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/nejmoa1611925.
    1. Wiviott SD, Raz I, Bonaca MP. Dapagliflozin and cardiovascular outcomes in Type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/nejmoa1812389.
    1. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90–100. doi: 10.1177/1479164114559852.
    1. Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116:1887–1906. doi: 10.1161/circresaha.116.304521.
    1. Verschure DO, van Eck-Smit BL, Somsen GA, Knol RJ, Verberne HJ. Cardiac sympathetic activity in chronic heart failure: cardiac 123I-mIBG scintigraphy to improve patient selection for ICD implantation. Neth Heart J. 2016;24:701–708. doi: 10.1007/s12471-016-0902-y.
    1. Kubota Y, Yamamoto T, Tara S, Tokita Y, Yodogawa K, Iwasaki Y, et al. Effect of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: rationale. Diabetes Ther. 2018;9:2107–2116. doi: 10.1007/s13300-018-0480-7.
    1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, De Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362–e425. doi: 10.1161/cir.0b013e3182742cf6.
    1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2354–2394. doi: 10.1161/cir.0000000000000133.
    1. Barthel P, Schneider R, Bauer A, Ulm K, Schmitt C, Schömig A, et al. Risk stratification after acute myocardial infarction by heart rate turbulence. Circulation. 2003;108:1221–1226. doi: 10.1161/01.cir.0000088783.34082.89.
    1. Abe A, Kobayashi K, Yuzawa H, Sato H, Fukunaga S, Fujino T, et al. Comparison of late potentials for 24 hours between Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy using a novel signal-averaging system based on Holter ECG. Circ Arrhythm Electrophysiol. 2012;5:789–795. doi: 10.1161/circep.111.969865.
    1. Yoshioka K, Amino M, Zareba W, Shima M, Matsuzaki A, Fujii T, et al. Identification of high-risk Brugada syndrome patients by combined analysis of late potential and T-wave amplitude variability on ambulatory electrocardiograms. Circ J. 2013;77:610–618. doi: 10.1253/circj.cj-12-0932.
    1. Hashimoto K, Kasamaki Y, Soma M, Takase B. Diurnal variation of frequency domain T-wave alternans on 24-hour ambulatory electrocardiogram in subjects without heart disease: significant effect of autonomic nervous activity of the heart. Ann Noninvasive Electrocardiol. 2019;24:e12620. doi: 10.1111/anec.12620.
    1. Ulgen MS, Akdemir O, Toprak N. The effects of trimetazidine on heart rate variability and signal-averaged electrocardiography in early period of acute myocardial infarction. Int J Cardiol. 2001;77:255–262. doi: 10.1016/s0167-5273(00)00441-1.
    1. Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, Lee FA. Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the beta-blocker Heart Attack Trial. Am J Cardiol. 2003;91:137–142. doi: 10.1016/s0002-9149(02)03098-9.
    1. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059–2068. doi: 10.1097/hjh.0000000000001434.
    1. Kiuchi S, Hisatake S, Kabuki T, Fujii T, Oka T, Dobashi S, et al. Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in a patient with heart failure: a case report. Drug Discov Ther. 2018;12:51–54. doi: 10.5582/ddt.2017.01069.
    1. Schwartz PJ. The autonomic nervous system and sudden death. Eur Heart J. 1998;19:F72–F80. doi: 10.1053/euhj.1998.1292.
    1. Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, et al. Genotype-phenotype correlation of SCN5A mutation for clinical and electrocardiographic characteristics of probands with Brugada Syndrome: a Japanese multicenter registry. Circulation. 2017;135:2255–2270. doi: 10.1161/circulationaha.117.027983.
    1. Shimizu W, Makimoto H, Yamagata K, Kamakura T, Wada M, Miyamoto K, et al. Association of genetic and clinical aspects of congenital long QT syndrome with life-threatening arrhythmias in Japanese patients. JAMA Cardiol. 2019;4:246–254. doi: 10.1001/jamacardio.2018.4925.
    1. Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, et al. AzimiLide post Infarct surVival Evaluation (ALIVE) Investigators. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation. 2004;109:990–996. doi: 10.1161/01.cir.0000117090.01718.2a.
    1. Bigger JT, Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85:164–171. doi: 10.1161/01.cir.85.1.164.
    1. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85:I77–91.
    1. Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–1396. doi: 10.1016/s0140-6736(98)08428-1.
    1. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333–1339. doi: 10.1007/s00125-016-3956-x.
    1. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, et al. How does Empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:356–363. doi: 10.2337/dc17-1096.
    1. Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180–1193. doi: 10.1111/dom.12572.
    1. Sano M. A new class of drugs for heart failure: sGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–476. doi: 10.1016/j.jjcc.2017.12.004.
    1. Grassi G. Role of the sympathetic nervous system in human hypertension. J Hypertens. 1998;16:1979–1987. doi: 10.1097/00004872-199816121-00019.
    1. Kario K, Okada K, Kato M, Nishizawa M, Yoshida T, Asano T, et al. 24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study. Circulation. 2018;139:2089–2097. doi: 10.1161/circulationaha.118.037076.
    1. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with Type 2 diabetes. Diabetes. 2016;65:1190–1195. doi: 10.2337/db15-1356.
    1. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: a ‘Thrifty Substrate’ hypothesis. Diabetes Care. 2016;39:1108–1114. doi: 10.2337/dc16-0330.
    1. Arima Y, Izumiya Y, Ishida T, Takashio S, Ishii M, Sueta D, et al. Myocardial ischemia suppresses ketone body utilization. J Am Coll Cardio. 2019;73:246–247. doi: 10.1016/j.jacc.2018.10.040.
    1. Oshima H, Miki T, Kuno A, Mizuno M, Sato T, Tanno M, et al. Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and antioxidants in diabetic rats. J Pharmacol Exp Ther. 2019;368:524–534. doi: 10.1124/jpet.118.253666.
    1. van der Meer P, Lipsic E. Erythropoietin: repair of the failing heart. J Am Coll Cardiol. 2006;48:185–186. doi: 10.1016/j.jacc.2006.04.007.
    1. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8:844–847. doi: 10.14740/jocmr2760w.
    1. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2:1025–1029. doi: 10.1001/jamacardio.2017.2275.
    1. Cao WH, Morrison SF. Disinhibition of rostral raphe pallidus neurons increases cardiac sympathetic nerve activity and heart rate. Brain Res. 2003;980:1–10. doi: 10.1016/s0006-8993(03)02981-0.
    1. Chiba Y, Yamada T, Tsukita S, Takahashi K, Munakata Y, Shirai Y, et al. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PLoS ONE. 2016;11:e0150756. doi: 10.1371/journal.pone.0150756.
    1. Andreadou I, Efentakis P, Balafas E, Togliatto G, Davos CH, Varela A, Dimitriou CA, et al. Empagliflozin limits myocardial infarction in vivo and cell death in vitro: role of STAT3, mitochondria, and redox aspects. Front Physiol. 2017;8:1077. doi: 10.3389/fphys.2017.01077.
    1. Matsutani D, Sakamoto M, Iuchi H, Minato S, Suzuki H, Kayama Y, et al. Glycemic variability in continuous glucose monitoring is inversely associated with baroreflex sensitivity in type 2 diabetes: a preliminary report. Cardiovasc Diabetol. 2018;17:36. doi: 10.1186/s12933-018-0683-2.
    1. Williams SM, Eleftheriadou A, Alam U, Cuthbertson DJ, Wilding JPH. Cardiac autonomic neuropathy in obesity, metabolic syndrome and prediabetes: a narrative review. Diabetes Ther. 2019;10:1995–2021. doi: 10.1007/s13300-019-00693-0.
    1. Tran HV, Gore JM, Darling CE, Ash AS, Kiefe CI, Goldberg RJ. Hyperglycemia and risk of ventricular tachycardia among patients hospitalized with acute myocardial infarction. Cardiovasc Diabetol. 2018;17:136. doi: 10.1186/s12933-018-0779-8.
    1. Weidner K, Behnes M, Schupp T, Rusnak J, Reiser L, Bollow A, et al. Type 2 diabetes is independently associated with all-cause mortality secondary to ventricular tachyarrhythmias. Cardiovasc Diabetol. 2018;17:125. doi: 10.1186/s12933-018-0768-y.
    1. van Bommel EJ, Smits MM, Ruiter D, Muskiet MH, Kramer MH, Nieuwdorp M, et al. Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes. J Hypertens. 2020;38(9):1811–1819.
    1. Zhang N, Feng B, Ma X, Sun K, Xu G, Zhou Y. Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovasc Diabetol. 2019;18:107. doi: 10.1186/s12933-019-0914-1.
    1. Durak A, Olgar Y, Degirmenci S, Akkus E, Tuncay E, Turan B. A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol. 2018;17:144. doi: 10.1186/s12933-018-0790-0.
    1. Beitelshees AL, Leslie BR, Taylor SI. Sodium-glucose cotransporter 2 inhibitors: a case study in translational research. Diabetes. 2019;68:1109–1120. doi: 10.2337/dbi18-0006.
    1. Coleman RL, Gray AM, Broedl Md UC, Fitchett D, George JT, Woerle HJ, et al. Can the cardiovascular risk reductions observed with empagliflozin in the EMPA-REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels? Diabetes Obes Metab. 2020;22:1151–1156.
    1. Handelsman Y. Rationale for the early use of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes. Adv Ther. 2019;36:2567–2586. doi: 10.1007/s12325-019-01054-w.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi