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

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Abstract

Type 2 diabetes mellitus (T2DM) is associated with marked cardiovascular (CV) morbidity and mortality, including heart failure (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.

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Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

A.G. Olsson, J McMurray, G Thorgeirsson … (1994)

Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p < 0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures. This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.

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Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.

Sunder Mudaliar, Sindura Alloju, Robert Henry (2016)

Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energetics-based mechanisms for the CV/renal benefits.

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CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY.

Alan J. Garber, Martin Abrahamson, Joshua I. Barzilay … (2016)

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Journal

Journal ID (nlm-ta): Drugs Context

Journal ID (iso-abbrev): Drugs Context

Journal ID (publisher-id): DIC

Title: Drugs in Context

Publisher: Just Medical Media Limited

ISSN (Print): 1745-1981

ISSN (Electronic): 1740-4398

Publication date Collection: 2016

Publication date (Electronic): 02 September 2016

Volume: 5

Electronic Location Identifier: 212299

Affiliations

Division of Metabolism, Endocrinology and Diabetes (MEND), Brehm Center for Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

Author notes

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: http://www.drugsincontext.com/wp-content/uploads/2016/08/dic.212299-COI.pdf 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.

ClinicalTrials.gov number: NCT01131676 (EMPA-REG OUTCOME trial)

Article URL: http://www.drugsincontext.com/closing-the-knowledge-gap-on-cardiovascular-disease-in-type-2-diabetes-the-empa-reg-outcome-trial-and-beyond

Provenance: Submitted, externally peer reviewed

Peer review comments to author: 9 July 2016;

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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. eliforal@ 123456umich.edu

Article

Publisher ID: dic-5-212299

DOI: 10.7573/dic.212299

PMC ID: 5017828

SO-VID: e7789535-c2a6-40d0-a52c-c446d1770f8b

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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.

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

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Most cited references 37

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.

CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY.

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