Closing the knowledge gap on cardiovascular disease in type 2 diabetes: the EMPA-REG OUTCOME trial and beyond

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Type 2 diabetes mellitus (T2DM) is associated with marked cardiovascular (CV) morbidity and mortality, including heartfailure (HF). Until recently, an oral glucose-lowering agent that improved hyperglycemia as well as provided CV benefits in patients with T2DM and  cardiovascular disease (CVD) was lacking. The newest class of glucose-lowering agents, sodium glucose cotransporter 2 (SGLT2) inhibitors, includes canagliflozin, dapagliflozin, and empagliflozin. Prior to the release of the LEADER trial results, the recent EMPA-REG OUTCOME study was the only dedicated CV trial to demonstrate a reduction in major adverse cardiac events, CV mortality, and all-cause mortality and a reduction in hospitalization for HF with empagliflozin, given on top of standard-of-care therapy in patients with T2DM and CVD. This paper summarizes the results from EMPA-REG OUTCOME and discusses their significance and clinical implications.

Keywords: sodium glucose cotransporter 2 inhibitor, type 2 diabetes mellitus, empagliflozin, cardiovascular disease, heart failure, glucose-lowering, major adverse cardiovascular events.

Abbreviations: ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; AE, adverse event; ARB, angiotensin receptor blocker; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; DKA, diabetic ketoacidosis; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; FPG, fasting plasma glucose; GLP-1, glucagonlike peptide-1; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac events; MI, myocardial infarction; NYHA, New York Heart Association; RAAS, renin-angiotensin-aldosterone system; SBP, systolic blood pressure; SGLT2, sodium glucose cotransporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione; UTI, urinary tract infection.

Citation: Oral EA. Closing the knowledge gap on cardiovascular disease in type 2 diabetes: the EMPA-REG OUTCOME trial and beyond. Drugs in Context 2016; 5: 212299. DOI: 10.7573/dic.212299

Disclosure and potential conflicts of interest: The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the author is available for download at: 

Dr. Oral reports non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees, and non-financial support from Aegerion Pharmaceuticals; grants and personal fees from Akcea Therapeutics and Ionis Pharmaceuticals; grants, personal fees, and non-financial support from AstraZeneca; grants, personal fees, and non-financial support from BMS and Amylin LLC.; and grants from GI Dynamics.

Acknowledgements and contributions: Writing and editorial support was provided by Linda Merkel, PhD, of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Funding declaration: The author received no compensation related to the development of the manuscript. number: NCT01131676 (EMPA-REG OUTCOME trial)

Copyright: Copyright © 2016 Oral EA. Distributed under the terms of the Creative Commons License Deed CC BY NC ND 3.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Correct attribution: Copyright © 2016 Oral E. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 3.0.

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Correspondence: Elif Arioglu Oral, MD, Associate Professor of Internal Medicine, University of Michigan, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, 1000 Wall Street, 5313 Brehm Tower, Ann Arbor, MI 48105, USA.

Provenance: Submitted, externally peer reviewed

Submitted: 9 June 2016; Peer review comments to author: 9 July 2016; Publication date: 2 September 2016

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