Effect of Empagliflozin Versus Placebo on Cardiac Sympathetic Activity in Acute Myocardial Infarction Patients with Type 2 Diabetes Mellitus: Rationale

Abstract

IntroductionProtection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes.MethodsThe EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period.Planned OutcomesThe EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death.Trial RegistrationUnique Trial Number, UMIN000030158 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034442).FundingNippon Boehringer Ingelheim and Eli Lilly and Company.

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

“…The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with AMI and T2DM in Japan. The detailed methods have been published previously [7]. A total of 105 patients were randomized (1:1) to receive once-daily empagli ozin (10 mg) or once-daily placebo.…”

“…Recruitment for the trial began in February 2018 and ended in March 2019. The inclusion and exclusion criteria had been published [7]. Patients with AMI and T2DM were randomly assigned into an empagli ozin (10 mg/day) or a placebo group, both add-ons to conventional therapy two weeks after the onset of AMI based on allocation factors, baseline HbA1c value ( 7.0% or ≥7.0%) and max creatine kinase (CK) ( 3,000 IU/L or ≥3,000 IU/L) by a dynamic allocation method.…”

“…It was crucial to evaluate the effects of empagli ozin on the improvement in cardiac nerve activity in the early phase of AMI. Therefore, the EMBODY trial was conducted to elucidate the mechanisms by which empagli ozin reduces CV-related deaths, including SCD in patients with AMI and type 2 diabetes mellitus (T2DM) [7]. The aim of the EMBODY trial was to determine how the SGLT2 inhibitor affects cardiac sympathetic and parasympathetic activities in patients with AMI and T2DM.…”

The use of sodium‐glucose co‐transporter 2 inhibitors in the inpatient setting: Is the risk worth taking?

“…An ongoing trial in humans (EMBODY trial) aims to assess whether the suppression of cardiac sympathetic activity related to treatment with empagliflozin, could protect patients from lethal ventricular arrhythmias following acute MI. 52 Primary end point is considered the change from baseline in heart rate variability. Secondary end points are changes in heart rate turbulence, T-wave alternans and cardiac scintigraphy imaging.…”

The effect of empagliflozin on the development of chronic heart failure after myocardial infarction according to a 12-month prospective study

“…О практической пользе эмпаглифлозина для этой категории больных говорит и промежуточный анализ результатов лечения 35 000 пациентов в исследовании EMPRISE, подтвердивший, что эмпаглифлозин снижает риск госпитализаций по поводу ХСН на 44% по сравнению с терапией ингибиторами дипептидилпептидазы 4 типа (иДПП4), по данным реальной клинической практики [8]. Данный препарат эффективен, не способствует гипогликемиям, ведет к снижению массы тела [1,9,10,11], уменьшает риск госпитализаций по причине сердечной недостаточности на 35% (в том числе у больных, исходно не имевших ХСН) [3,4], характеризуется такими позитивными плейотропными эффектами, как уменьшение артериального давления без роста частоты сердечных сокращений [4,12], снижение уровня мочевой кислоты в крови [4,13], нефропротективное действие с улучшением тубуло-интерстициальных взаимодействий, уменьшением воспалительных изменений в почках и микроальбуминурии [9,14,15], снижение потребности в инсулине [9], симпатической активности сердца и риска аритмий [16]. При этом позитивный эффект эмпаглифлозина на сердечно-сосудистые риски оказался столь значительным, что его трудно объяснить даже комбинированным воздействием всех перечисленных факторов.…”