Patient Phenotypes and SGLT-2 Inhibition in Type 2 Diabetes: Insights From the EMPA-REG OUTCOME Trial

Abstract

Objectives: Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.

Background: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.

Methods: Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).

Results: In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30).

Conclusions: Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).

Keywords: cardiovascular diseases; empagliflozin; latent class analysis; sodium-glucose transporter 2 inhibitors.

Conflict of interest statement

Funding Support and Author Disclosures The EMPA-REG OUTCOME trial was funded by Boehringer Ingelheim and Eli-Lilly. Dr. Sharma has been supported by Canada Institute for Health Research - (Grant Number: 175095), the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars program, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer Ingelheim, Novartis, and Takeda. Drs. Ofstad, Zwiener and Hantel are employees of Boehringer Ingelheim. Dr. Ahmad has been a consultant for Amgen and Cytokinetics. Dr. Zinman has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca and Novo Nordisk, and has received honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk, and Merck Sharp & Dohme. Dr. Wanner has received personal fees from Boehringer Ingelheim; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Gilead, Merck Sharpe Dohme, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr. George was an employee of Boehringer Ingelheim at the time of the study conduct. Dr. Desai has worked under contract with the Centers for Medicare and Medicaid Services; and has been a consultant for Amgen, Boehringer Ingelheim, Cytokinetics, Relypsa, Novartis, and SC Pharmaceuticals. Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, and Windtree Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.