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

Tamique Mason; Otavio R Coelho-Filho; Subodh Verma; Biswajit Chowdhury; Fei Zuo; Adrian Quan; Kevin E Thorpe; Christopher Bonneau; Hwee Teoh; Richard E Gilbert; Lawrence A Leiter; Peter Jüni; Bernard Zinman; Michael Jerosch-Herold; C David Mazer; Andrew T Yan; Kim A Connelly

doi:10.1016/j.jcmg.2020.10.017

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

JACC Cardiovasc Imaging. 2021 Jun;14(6):1164-1173. doi: 10.1016/j.jcmg.2020.10.017. Epub 2021 Jan 13.

Authors

Tamique Mason¹, Otavio R Coelho-Filho², Subodh Verma³, Biswajit Chowdhury⁴, Fei Zuo⁵, Adrian Quan⁴, Kevin E Thorpe⁶, Christopher Bonneau⁴, Hwee Teoh⁷, Richard E Gilbert⁸, Lawrence A Leiter⁹, Peter Jüni¹⁰, Bernard Zinman¹¹, Michael Jerosch-Herold¹², C David Mazer¹³, Andrew T Yan¹⁴, Kim A Connelly¹⁵

Affiliations

¹ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
² Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil; Division of Cardiology, Department of Medicine, State University of Campinas, Campinas, Brazil.
³ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
⁴ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
⁵ Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
⁶ Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁷ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
⁸ Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁹ Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
¹² Heart and Vascular Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹³ Department of Anesthesia, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁵ Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: kim.connelly@unityhealth.to.

PMID: 33454272
DOI: 10.1016/j.jcmg.2020.10.017

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.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Benzhydryl Compounds
Coronary Artery Disease* / diagnostic imaging
Coronary Artery Disease* / drug therapy
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / drug therapy
Glucosides
Humans
Predictive Value of Tests

Substances

Benzhydryl Compounds
Glucosides
empagliflozin

Associated data

ClinicalTrials.gov/NCT02998970