Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials - PubMed (original) (raw)

Review

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

Yuliya Lytvyn et al. Circulation. 2017.

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.

© 2017 American Heart Association, Inc.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Diuretic agents, their mechanisms of action and potential impact in patients with HF

HF = heart failure; SGLT2i = sodium glucose co-transporter 2 inhibitor; PV = pressure volume; CV = cardiovascular; HHF = hospitalization for heart failure; LV = left ventricular.

Figure 2

Figure 2

Hazard ratio and 95% confidence intervals for outcomes examined in EMPA-REG Outcome, CANVAS, LEADER and SUSTAIN 6. CV = cardiovascular; CI = confidence interval

Figure 3

Figure 3. Integrated Physiological Basis for Proposed Mechanisms Leading to Cardiorenal Benefits and Risks Associated with Sodium Glucose Cotransport-2 Inhibition

* = only reported in the CANVAS Program; RAGE = receptor for advanced glycation end products; PTH = parathyroid hormone; FGF-23 = fibroblast growth factor 23; Na+ = sodium; AKI = acute kidney injury.

Comment in

Similar articles

Cited by

References

    1. Metra M, Carubelli V, Ravera A, Stewart Coats AJ. Heart failure 2016: still more questions than answers. Internationalj cardiology. 2017;227:766–777. - PubMed
    1. AbdAlla S, Lother H, el Massiery A, Quitterer U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med. 2001;7:1003–1009. - PubMed
    1. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O’Connor CM. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64:2281–2293. - PMC - PubMed
    1. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34:29–34. - PubMed
    1. Patel PA, Liang L, Khazanie P, Hammill BG, Fonarow GC, Yancy CW, Bhatt DL, Curtis LH, Hernandez AF. Antihyperglycemic Medication Use Among Medicare Beneficiaries With Heart Failure, Diabetes Mellitus, and Chronic Kidney Disease. Circ Heart Fail. 2016;9 - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources