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Circulation. 2017 Oct 24;136(17):1643-1658. doi: 10.1161/CIRCULATIONAHA.117.030012.

Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials.

Author information

1
From Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Ontario, Canada (Y.L., J.A.L., D.Z.I.C.); Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora (P.B.); Women's College Research Institute and Department of Medicine, Division of Cardiology, Women's College Hospital, University of Toronto, Ontario, Canada (J.A.U.); Peter Munk Cardiac Centre, University Health Network, University of Toronto, Ontario, Canada (J.A.U.); and Department of Medicine, Division of Endocrinology and Metabolism, University Health Network and Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada (J.A.L.).
2
From Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Ontario, Canada (Y.L., J.A.L., D.Z.I.C.); Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora (P.B.); Women's College Research Institute and Department of Medicine, Division of Cardiology, Women's College Hospital, University of Toronto, Ontario, Canada (J.A.U.); Peter Munk Cardiac Centre, University Health Network, University of Toronto, Ontario, Canada (J.A.U.); and Department of Medicine, Division of Endocrinology and Metabolism, University Health Network and Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada (J.A.L.). david.cherney@uhn.ca.

Abstract

Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor. The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and HF hospitalization risk. Although SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload as well, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2D. Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D. Because these favorable effects presumably occur independent of blood glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.

KEYWORDS:

clinical trial; heart failure; sodium glucose transporter 2

PMID:
29061576
PMCID:
PMC5846470
DOI:
10.1161/CIRCULATIONAHA.117.030012
[Indexed for MEDLINE]
Free PMC Article

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