SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Abstract

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.

Keywords: SGLT2 inhibitors; autophagy; diabetes; endothelial function; heart failure; inflammation; mitochondria; oxidative stress.

Figure 1

Mechanistic insights into the role of gliflozins at systemic, vascular, cardiac, and renal levels. Preclinical evidence suggests a potential beneficial effect of gliflozins in preclinical models mimicking renal, cardiac, and vascular pathologies. Involving a variety of mechanisms independently of their glucose-lowering effects, SGLT2 inhibition reduces inflammatory signalling, mitigates oxidative stress, improves autophagic flux, and enhances mitochondrial function, therethrough contributing to their cardiorenal/-vascular benefits. SGLT2, sodium-glucose transporter 2; NHE, sodium/hydrogen exchanger. Created with content provided by BioRender.com.

Figure 2

Systemic effects of gliflozins. Gliflozins exert natriuretic effects, impact tissue sodium handling, increase ketogenesis, and reduce both plasma uric acid and glucose levels, leading to a variety of beneficial effects which collectively results in improved renal and CV outcomes. Note that neutral or negative effects are highlighted in bright blue, with lower urinary tract infections ranking among the most frequently observed side-effects. Created with content provided by BioRender.com.

Figure 3

The cardiac effect of gliflozins across the HF spectrum. Empagliflozin and dapagliflozin reduce adverse CV outcomes in patients with HF independently of the ejection fraction. The upper panel shows the clinical benefits of SGLT2 inhibition, with treatment effects shown as hazard ratios (HR) along with their 95% confidence intervals (CI). The lower panel provides insights into potential mechanisms underpinning cardiac benefits. ATP, Adenosine triphosphate; CD, cardiovascular death; CI, confidence interval; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; HR, hazard ratio; LV, left-ventricular; NHE, sodium/hydrogen exchanger; WHF, worsening of heart failure. Created with content provided by BioRender.com. ^aRefers to the EMPEROR-Reduced Trial and EMPEROR-Preserved Trial.  ^bRefers to the DAPA-HF Trial and DELIVER Trial.