Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial

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Abstract

Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown.

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Epidemiology and risk profile of heart failure.

Anh Bui, Tamara B Horwich, Gregg C. Fonarow (2011)

Heart failure (HF) is a major public health issue, with a prevalence of over 5.8 million in the USA, and over 23 million worldwide, and rising. The lifetime risk of developing HF is one in five. Although promising evidence shows that the age-adjusted incidence of HF may have plateaued, HF still carries substantial morbidity and mortality, with 5-year mortality that rival those of many cancers. HF represents a considerable burden to the health-care system, responsible for costs of more than $39 billion annually in the USA alone, and high rates of hospitalizations, readmissions, and outpatient visits. HF is not a single entity, but a clinical syndrome that may have different characteristics depending on age, sex, race or ethnicity, left ventricular ejection fraction (LVEF) status, and HF etiology. Furthermore, pathophysiological differences are observed among patients diagnosed with HF and reduced LVEF compared with HF and preserved LVEF, which are beginning to be better appreciated in epidemiological studies. A number of risk factors, such as ischemic heart disease, hypertension, smoking, obesity, and diabetes, among others, have been identified that both predict the incidence of HF as well as its severity. In this Review, we discuss key features of the epidemiology and risk profile of HF.

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SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review

Subodh Verma, John J V McMurray (2018)

Sodium-glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.

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SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials

Silvio E Inzucchi, Bernard Zinman, Christoph Wanner … (2015)

Given the multi-faceted pathogenesis of atherosclerosis in type 2 diabetes mellitus (T2DM), it is likely that interventions to mitigate this risk must address cardiovascular (CV) risk factors beyond glucose itself. Sodium glucose cotransporter-2 (SGLT-2) inhibitors are newer antihyperglycaemic agents with apparent multiple effects. Inherent in their mode of action to decrease glucose reabsorption by the kidneys by increasing urinary glucose excretion, these agents improve glycaemic control independent of insulin secretion with a low risk of hypoglycaemia. In this review, we outline those CV risk factors that this class appears to influence and provide the design features and trial characteristics of six ongoing outcome trials involving more than 41,000 individuals with T2DM. Those risk factors beyond glucose that can potentially be modulated positively with SGLT-2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress. On the other hand, small increases in low-density lipoprotein (LDL)-cholesterol levels have also been observed for the class, which theoretically might offset some of these benefits. The potential translational impact of these effects is being tested with outcome trials, also reviewed in this article, powered to assess both macrovascular as well as certain microvascular outcomes in T2DM. These are expected to begin to report in late 2015.

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Journal

Title: Circulation

Abbreviated Title: Circulation

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 0009-7322

ISSN (Electronic): 1524-4539

Publication date Created: September 16 2019

Publication date (Electronic): September 16 2019

Affiliations

[1 ]Saint Luke's Mid America Heart Institute, Kansas City, MO; University ofMissouri-Kansas City, Kansas City, MO

[2 ]Saint Luke's Mid America Heart Institute, Kansas City, MO

[3 ]Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Ted Rogers Centre for Heart Research, Toronto, Canada; University of Toronto, Canada; Peter Munk Cardiac Centre, Toronto, Canada

[4 ]Yale University School of Medicine, New Haven, CT

[5 ]University of Texas Southwestern Medical Center, Dallas, TX

[6 ]University of Michigan, Ann Arbor, MI

[7 ]Brigham and Women's Hospital, Boston, MA

[8 ]University of Southern California, Los Angeles, CA

[9 ]NorthShore University, Evanston, IL

[10 ]St. Francis Hospital, New York, NY

[11 ]New York University Langone Health, New York, NY

[12 ]First Coast Cardiovascular Institute, Jacksonville, FL

[13 ]Henry Ford Hospital, Detroit, MI

[14 ]Washington University School of Medicine, St. Louis, MO

[15 ]Vanderbilt University, Nashville, TN

[16 ]Charlotte Heart Group Research Center, Port Charlotte, FL

[17 ]University of Pennsylvania, Philadelphia, PA

[18 ]Duke University, Durham, NC

[19 ]Northwestern University, Chicago, IL

[20 ]Heart Group of the Eastern Shore, Fairhope, AL

[21 ]Emory University, Atlanta, GA

[22 ]Saint Luke's Mid America Heart Institute, Kansas City, MO; University of Missouri-Kansas City, Kansas City, MO; The George Institute for Global Health, Sydney, Australia; University of New South Wales, Sydney, Australia

Article

DOI: 10.1161/CIRCULATIONAHA.119.042929

PubMed ID: 31524498

SO-VID: 8c277e76-2d51-4a89-a9b0-c6247e01150b

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Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial

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Most cited references 17

Epidemiology and risk profile of heart failure.

SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review

SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials

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