Impact of empagliflozin on right ventricular parameters and function among patients with type 2 diabetes

Bradley Sarak, Subodh Verma, C David Mazer, Hwee Teoh, Adrian Quan, Richard E Gilbert, Shaun G Goodman, Karan Bami, Otávio R Coelho-Filho, Vineeta Ahooja, Djeven P Deva, Vinay Garg, Sumeet Gandhi, Kim A Connelly, Andrew T Yan, Bradley Sarak, Subodh Verma, C David Mazer, Hwee Teoh, Adrian Quan, Richard E Gilbert, Shaun G Goodman, Karan Bami, Otávio R Coelho-Filho, Vineeta Ahooja, Djeven P Deva, Vinay Garg, Sumeet Gandhi, Kim A Connelly, Andrew T Yan

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular events in type 2 diabetes (T2DM) and is associated with a reduction in left ventricular (LV) mass index. However, the impact on right ventricular (RV) remodeling is unknown. Accordingly, the objective of this study was to assess the impact of SGLT2 inhibition on RV parameters and function in T2DM and coronary artery disease (CAD).

Methods: In EMPA-HEART CardioLink-6, 97 patients with T2DM and CAD were randomly assigned to empagliflozin 10 mg (n = 49) once daily or placebo (n = 48). Cardiac magnetic resonance imaging was performed at baseline and after 6 months. RV mass index (RVMi), RV end-diastolic and end-systolic volume index (RVEDVi, RVESVi) and RV ejection fraction (RVEF) were assessed in blinded fashion.

Results: At baseline, mean RVMi (± SD) (11.8 ± 2.4 g/m2), RVEF (53.5 ± 4.8%), RVEDVi (64.3 ± 13.2 mL/m2) and RVESVi (29.9 ± 6.9 mL/m2) were within normal limits and were similar between the empagliflozin and placebo groups. Over 6 months, there were no significant differences in RVMi (- 0.11 g/m2, [95% CI - 0.81 to 0.60], p = 0.76), RVEF (0.54%, [95% CI - 1.4 to 2.4], p = 0.58), RVEDVi (- 1.2 mL/m2, [95% CI - 4.1 to 1.7], p = 0.41) and RVESVi (- 0.81 mL/m2, [95% CI - 2.5 to 0.90], p = 0.35) in the empaglifozin group as compared with the placebo group. In both groups, there was no significant correlation between RVMi and LVMi changes from baseline to 6 months.

Conclusions: In this post-hoc analysis, SGLT2 inhibition with empagliflozin had no impact on RVMi and RV volumes in patients with T2DM and CAD. The potentially differential effect of empagliflozin on the LV and RV warrants further investigation.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT02998970?cond=NCT02998970&draw=2&rank=1 . Unique identifier: NCT02998970.

Keywords: Right ventricle; Sodium-glucose transporter 2 inhibition; Type 2 diabetes.

Conflict of interest statement

Bradley Sarak, None. Subodh Verma, Tier 1 Canada Research Chair in Cardiovascular Surgery. Research grant support and/or speaking honoraria from Amarin (modest), Amgen (modest), AstraZeneca (significant), Bayer (modest), Boehringer Ingelheim (signficiant), Bristol-Myers Squibb (modest), Eli Lilly (significant), EOCI Pharmacomm Ltd (modest), HLS Therapeutics (significant), Janssen (modest), Merck (modest), Novartis (modest), Novo Nordisk (modest), Pfizer (modest), PhaseBio (significant), Sanofi (modest), Sun Pharmaceuticals (significant), and the Toronto Knowledge Translation Working Group (significant). President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. C. David Mazer, Research grant support and/or speaking/consulting honoraria from Amgen, Boehringer Ingelheim, and OctaPharma (all modest). Hwee Teoh, Consulting honoraria from Boehringer Ingelheim and manuscript writing fees for unrelated topics from Merck and Servier (all modest). Adrian Quan, None. Richard E. Gilbert, Canada Research Chair in Diabetes Complications. Research grant support and/or speaking/consulting honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen (all significant). Shaun G. Goodman, Research grant support (including steering committee or data and safety monitoring committees) and/or speaker/consulting honoraria (including advisory boards) from: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, and PERFUSE Research Institute (all relationships significant except Pendopharm, Servier, and Valeo). Karan Bami, Conference support from Boehringer Ingelheim (modest). Otávio R Coelho-Filho, None. Vineeta Ahooja, Research grant support and/or speaking/consulting honoraria AstraZeneca, Bayer, Boehringer Ingelheim, NovoNordisk. SubInvestigator for EMPEROR PRESERVED, EMPEROR REDUCED, EMPA HEART, DELIVER, DETERMINE, DapaHF, SOLOIST, PRIORITIZE, SELECT, EMPACT MI (all modest). Djeven P. Deva, None. Vinay Garg, None. Sumeet Gandhi, None. Kim A. Connelly, Research grant support and/or speaking/consulting honoraria from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Edwards, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier (all significant). Andrew T. Yan, Research grant support from AstraZeneca (modest).

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Example of contouring of the right ventricular endocardium (yellow) and epicardium (blue) in one patient at end-diastole (a) and end-systole (b). Endocardial borders at end–diastole and at end–systole in contiguous short–axis images were manually traced. The epicardial borders at end–diastole were also traced. The difference in area at end-diastole was multiplied by the slice thickness and the sum of these differences throughout the entire right ventricle was multiplied by the myocardial specific density to calculate right ventricular mass. Right ventricular trabeculations were considered part of the blood pool
Fig. 2
Fig. 2
a Six-month mean changes in RVMi following treatment with empagliflozin versus placebo. b Six-month mean changes in RVEDVi following treatment with empagliflozin versus placebo. c Six-month mean changes in RVESVi following treatment with empagliflozin versus placebo. d Six-month mean changes in RVEF following treatment with empagliflozin versus placebo. (*) Data analyzed using ANCOVA adjusting for baseline values. RVMi, right ventricular mass index; RVEDVi, right ventricular end diastolic volume index; RVESVi, right ventricular end systolic volume index; RVEF, right ventricular ejection fraction. Baseline and 6-month data were available for 44 individuals in the in the empagliflozin group and 46 in the placebo group. Mean changes in RVMi, RVEDVi, RVESVi and RVEF are presented as mean (95% CI), and the adjusted differences between groups are shown with 95% CI. Data were analyzed using ANCOVA adjusting for baseline values

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