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.

Clinical Parameters Affecting the Therapeutic Efficacy of SGLT-2—Comparative Effectiveness and Safety of Dapagliflozin and Empagliflozin in Patients with Type 2 Diabetes

“…SGLT2i have been studied in various clinical trials for their benefit in preventing heart failure [ 39 , 40 , 41 ]. Recent research has shown a cardio-renal mechanism of inhibition of Na + /H + exchanger (NHE) isoforms: NHE1 isoform in the myocardium, with a further effect of reducing cytoplasmic ions calcium and sodium levels and NHE3 in the proximal renal tube, which mediates tubular sodium reuptake [ 42 , 43 ].…”

“…In the cases studied, the ROC curve only confirms BMI as a good predictor in selecting SGLT2 treatment, with threshold levels of 34.1 with 65% sensitivity and 56% specificity (AUC = 0.632; IC95%) (Figure 9). SGLT2i have been studied in various clinical trials for their benefit in preventing heart failure [39][40][41]. Recent research has shown a cardio-renal mechanism of inhibition of Na + /H + exchanger (NHE) isoforms: NHE1 isoform in the myocardium, with a further effect of reducing cytoplasmic ions calcium and sodium levels and NHE3 in the proximal renal tube, which mediates tubular sodium reuptake [42,43].…”

“…Another mechanism by which sodium ion is reduced is the inhibition of adipokine leptin by SGLT2i (effect demonstrated for canagliflozin), combined with the pro-activation of anti-inflammatory adipokines (e.g., adiponectin), thus preventing heart failure [44]. Furthermore, studies on rats have demonstrated a positive effect of some SGLT2i in preventing and even reducing SGLT2i have been studied in various clinical trials for their benefit in preventing heart failure [39][40][41]. Recent research has shown a cardio-renal mechanism of inhibition of Na + /H + exchanger (NHE) isoforms: NHE1 isoform in the myocardium, with a further effect of reducing cytoplasmic ions calcium and sodium levels and NHE3 in the proximal renal tube, which mediates tubular sodium reuptake [42,43].…”

Non-coding RNAs in diabetes mellitus and diabetic cardiovascular disease

“…These drugs mainly include the following categories: metformin and insulin secretion stimulators, alpha-glucosidase inhibitors, thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-dependent glucose co-transport protein inhibitors (SGLT2-Is), all of which have potentially toxic side effects ( 54 , 55 ). Despite the extensive research on T2DM and the development of novel drugs, T2DM remains a disease that cannot be treated and continues to severely affect humans ( 56 , 57 ).…”

Biomolecular Mechanisms of Cardiorenal Protection with Sodium-Glucose Co-Transporter 2 Inhibitors

“…A number of large clinical trials have been conducted to evaluate the safety and efficacy of SGLT2-Is in patients with diabetes and established vascular disease, multiple cardiovascular risk factors, or renal failure and in patients with established HF and reduced ejection fraction, with and without T2DM [ 31 ]. The most important results of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcomes Event Trial in Type 2 Diabetes Mellitus Patients—Removing Excess Glucose) trial showed that T2DM patients who were at high risk for CV disease had early reductions in major CV and renal sequelae [ 32 ].…”