Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure and Diabetes.

Objectives: The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype).
Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear.
Methods: The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus >40%.
Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF >40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction >0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints.
Conclusions: In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF >40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF.
Competing Interests: Funding Support and Author Disclosures This work was supported in part by an American Heart Association (AHA) grant award #16SFRN30180010 (to Dr DeVore). The GWTG-HF program is provided by the AHA and sponsored, in part, by Novartis, Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Sharma has received support from the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 Clinical Research Scholar, Canada Institute for Health Research grant #175095, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer Ingelheim, Novartis, AstraZeneca, and Takeda. Dr DeVore has received research funding through the Duke Clinical Research Institute from the AHA, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, Inc, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and the Patient-Centered Outcomes Research Institute; and consulting for AstraZeneca. Dr Felker has received research grants from National Heart, Lung, and Blood Institute (NHLBI), AHA, Amgen, Bayer Merck, Cytokinetics, and Myokardia; has been a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer Ingelheim, American Reagent, Abbott, Eidos Therapeutics, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Hernandez has received consulting fees from AstraZeneca, Bayer, Boston Scientific, Merck, Novartis, and Sanofi; and research support from AstraZeneca, GlaxoSmithKline, Luitpold, Merck, and Novartis. Dr Butler has been a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. Dr Peterson has received research funding from the NHLBI; and personal fees from American Heart Association outside the submitted work. Dr Fonarow has received research funding from the National Institutes of Health; and has been a consultant for Amgen, Bayer, Medtronic, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, the AHA, NHLBI, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, and Cytokinetics; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)