Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease

Abstract

Objectives: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).

Background: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.

Methods: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.

Results: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m2; 95% CI: -2.6 to -0.5 ml/m2; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m2; 95% CI: -3.8 to 0.3 ml/m2; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.

Conclusions: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).

Keywords: LV remodeling; SGLT2 inhibition; T1 mapping; diabetes; empagliflozin; extracellular volume fraction.

Conflict of interest statement

Funding Support And Author Disclosures This trial was supported by an unrestricted investigator-initiated study grant from Boehringer Ingelheim. The study sponsor was not involved in the study design; data collection, analysis and interpretation; writing of this report or in the decision to submit for publication. Dr. Mason was the recipient of a Boehringer Ingelheim Diabetes and Cardiovascular Disease Scholarship. Dr. Coelho-Filho was partially supported by a National Council for Scientific and Technological Development (CNPq) Productivity in Research award grant (303366/2015-0) and a Young Investigators Grant from The São Paulo Research Foundation (2015/15402-2). Dr. Verma holds a Canada Research Chair in Cardiovascular Surgery. Dr. Gilbert holds a Canada Research Chair in Diabetes Complications. Dr. Jüni holds a Canada Research Chair in Clinical Epidemiology of Chronic Diseases. Dr. Mazer is the recipient of a Merit Award from the University of Toronto Department of Anesthesia. Dr Connelly is supported by a Merit Award from the Department of Medicine, University of Toronto. Dr. Coelho-Filho has received research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Shire, and Pfizer. Dr. Verma has received research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd., HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr. Teoh has received honorarium from Boehringer Ingelheim and writing fees for unrelated manuscripts from Merck. Dr. Gilbert has received institutional research grants from AstraZeneca and Boehringer Ingelheim; served on advisory panels for AstraZeneca, Boehringer Ingelheim, and Janssen; received CME speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen; and owns stock in Certa, OccuRx, and Fibrocor Therapeutics. Dr. Leiter has received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, GlaxoSmithKline, Novo Nordisk, and Sanofi; served on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi; and received CME speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. Dr. Jüni has served as unpaid member of the steering group of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St. Jude Medical, Terumo, and The Medicines Company; received institutional research grants from AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and received institutional honoraria for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius but has not received personal payments by any pharmaceutical company or device manufacturer. Dr. Zinman has received research grants and/or advisory board honorarium from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr. Mazer has received honoraria from Amgen, Boehringer Ingelheim, Octapharma, and AstraZeneca. Dr. Yan has received research support from AstraZeneca. Dr. Connelly is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure; has received institutional research grants from AstraZeneca, Servier, and Boehringer Ingelheim; has received support for travel to scientific meetings from Boehringer Ingelheim; has received honoraria for speaking engagements and ad hoc participation in advisory boards from Servier, Merck, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Ferring, Novo Nordisk, Novartis, and Janssen; and is supported by a Merit Award from the Department of MEdicine, University of Toronto. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2021. Published by Elsevier Inc.