Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey.

Donato Cappetta,Antonella De Angelis,Daniele Torella,Gabriella Bellocchio,Marialucia Telesca,Eleonora Cianflone,Liberato Berrino,Konrad Urbanek,Francesco Rossi

doi:10.3389/fcvm.2021.810791

Abstract

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na+ levels with consequent positive effects on Ca2+ handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs.

Highlights

Donato Cappetta 1†, Antonella De Angelis 1†, Gabriella Bellocchio 1, Marialucia Telesca 1, Eleonora Cianflone 2, Daniele Torella 3, Francesco Rossi 1, Konrad Urbanek 3‡ and Liberato Berrino 1*‡
Evaluation of the Effects of Canagliflozin on Renal and CV Outcomes in Participants With Diabetic Nephropathy The CREDENCE study was a randomized, double-blind, placebo-controlled, multicenter clinical trial assessing the effects of canagliflozin (100 mg daily) or placebo on renal outcomes in 4,401 patients with diabetic nephropathy
Different from the CANVAS program, the rate of amputation and fracture was comparable in the canagliflozin and placebo groups and consistent with trials of other sodium-glucose cotransporter 2 (SGLT2) inhibitors

Summary

PART I. AT THE BEDSIDE

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, insulin resistance, dyslipidemia, inflammation, and thrombophilia. Five large CV outcome trials were carried out to assess the effects of SGLT2 inhibitors These studies revealed robust cardioprotection in patients with T2DM at high risk for HF. Despite concerns about the renal safety of SGLT2 inhibitors, renal function was maintained with empagliflozin, and results regarding the new onset or worsening of nephropathy demonstrated a significant reduction (−39%) in the empagliflozin-treated group as compared to placebo These findings proved the superiority of empagliflozin over standard care, with solid effectiveness in lowering mortality [10]. The Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events The DECLARE-TIMI 58 trial was a randomized, double-blind, placebo-controlled study of dapagliflozin (10 mg daily) or a TABLE 1 | Summary of clinical trials assessing the efficacy of SGLT2 inhibitors on cardiovascular and renal outcomes

Study design

PART I: CONCLUSIONS

PART II. BACK TO THE BENCH

PART II