SGLT2 Inhibitors in Type 2 Diabetes Mellitus and Heart Failure-A Concise Review

Abstract

The incidence of both diabetes mellitus type 2 and heart failure is rapidly growing, and the diseases often coexist. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new antidiabetic drug class that mediates epithelial glucose transport at the renal proximal tubules, inhibiting glucose absorption-resulting in glycosuria-and therefore improving glycemic control. Recent trials have proven that SGLT2i also improve cardiovascular and renal outcomes, including reduced cardiovascular mortality and fewer hospitalizations for heart failure. Reduced preload and afterload, improved vascular function, and changes in tissue sodium and calcium handling may also play a role. The expected paradigm shift in treatment strategies was reflected in the most recent 2021 guidelines published by the European Society of Cardiology, recommending dapagliflozin and empagliflozin as first-line treatment for heart failure patients with reduced ejection fraction. Moreover, the recent results of the EMPEROR-Preserved trial regarding empagliflozin give us hope that there is finally an effective treatment for patients with heart failure with preserved ejection fraction. This review aims to assess the efficacy and safety of these new anti-glycemic oral agents in the management of diabetic and heart failure patients.

Keywords: diabetes mellitus type 2; heart failure; sodium-glucose co-transporter 2; sodium-glucose co-transporter 2 inhibitors.

Figure 1

The mechanism of action and location of sodium-glucose co-transporter (SGLT) proteins. SGLT2 are found in the proximal (S1) segments, whilst the SGLT1 are found in the S2 and S3 portions of the proximal tubule. Figure reprinted with permission from ref. [10]. 2016, Springer Nature. Abbreviations: GLUT1—glucose transporter 1, GLUT2—glucose transporter 2, Na⁺/K⁺-ATPase—sodium–potassiumadenosine triphosphatase, SGLT1—sodium-glucose co-transporter 1, SGLT2—sodium-glucose co-transporter 2.

Figure 2

The mechanism of action of sodium-glucose co-transporter-2 inhibitors on the cardiovascular system. Figure reprinted with permission from ref. [38]. 2020 Dr. Gary Lopaschuk. Abbreviations: NHE—sodium-hydrogen exchange, CAMKII—calmodulin-dependent protein kinase II, EPO—erythropoietin, SNS—sympathetic nervous system, Ca²⁺—calcium.

Figure 3

Major adverse effects of SGLT2i.

Figure 4

Proposal of a new algorithm for sequencing of foundational treatments in heart failure. Figure based on [6,88]. (Source: American Heart Association, Inc.; European Society of Cardiology). Abbreviations: ACEi—angiotensin-converting enzymes inhibitor, ARB—angiotensin receptor blockers, ARNI—angiotensin receptor neprilysin inhibitor, DAPA—dapagliflozin, EMPA—empagliflozin, ESC—European Society of Cardiology, MRA—mineralocorticoid receptor antagonist, SGLT2i—sodium-glucose co-transporter 2 inhibitor.