SGLT2 Inhibitors: An Evidence-Based Update on Cardiovascular Implications

Abstract

Introduction

Sodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as “gliflozins”) represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors.

Area covered

This review critically examines the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many unanswered questions in the field of gliflozins and cardiovascular disease.

Expert opinion

The favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.

1. Introduction

Sodium Glucose co-Transporter 2 (SGLT2) is a co-transporter that leads to glucose and sodium (Na⁺) reabsorption in the kidney. SGLT2 inhibitors (which are also known as “gliflozins”) are oral antidiabetic drugs that act interfering with this process, reducing glycemia. These drugs have rapidly become a main pillar to treat type 2 diabetes mellitus (T2DM) [1–3].

In 2013, the Food and Drug Administration (FDA) of the United States approved canagliflozin as the first SGLT2 inhibitor as antihyperglycemic agent for patients with T2DM, followed by empagliflozin and dapagliflozin in 2014, and ertugliflozin in 2017 [4].

Before the FDA approval of canagliflozin, numerous concerns about the cardiovascular safety of antidiabetic agents had been raised. A classic example is given by rosiglitazone; a thiazolidinedione that in 2007 was found to be associated with an increased risk of myocardial infarction and death from cardiovascular causes [5]. These findings led the FDA to issue a recommendation requiring sponsors of antidiabetic agents to “demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk” [6]. As a result, several significant trials testing cardiovascular outcomes have been conducted to assess new antidiabetic agents, including SGLT2 inhibitors.

2. Cardioprotective effects of SGLT2 inhibitors: from preclinical studies to clinical trials

Various preclinical studies have shown a potentially favorable impact on the heart of SGLT2 inhibitors (Table 1). For instance, empagliflozin was shown to prevent the worsening of cardiac function in an experimental model of heart failure (HF) induced by pressure overload [7] and to decrease lipid peroxidation [8], interstitial fibrosis [9], aortic stiffness, renal resistivity index, and kidney injury [10] in mice. Equally important, cardiomyocytes obtained from non-diabetic mice exposed to the cardiotoxic drug doxorubicin, when treated with empagliflozin display an ameliorated contractility [11], indicating that this SGLT2 inhibitor markedly reduces the cardiotoxic effects of doxorubicin, independently of glycemic control [12]. Similarly, dapagliflozin decreases infarct size, post-infarction myofibroblast infiltration, and risk of arrhythmias in rats [13,14].

Table 1.

Main preclinical studies testing the effects of SGLT2 inhibitors on cardiac function.

Year	First Author	SGLT2 inhibitor(s) tested	Main conclusions	Novel Information	Reference
2017	Byrne	Empagliflozin	Empagliflozin decreased worsening of cardiac function in a mouse model of pressure overload-induced HF.	SGLT2 inhibition prevents the progressive decline of cardiac function even in non-diabetic murine models with reduced EF both in vivo and ex vivo.	[7]
2017	Andreadou	Empagliflozin	Empagliflozin improved myocardial function, reduced infarct size, decreased iNOS expression and lipid peroxidation in mice.	Identification of the anti-oxidant and anti-inflammatory properties of empagliflozin mediated by the activation of STAT3 pathway.	[8]
2017	Lee	Dapagliflozin	Dapagliflozin reduced myofibroblast infiltration during postinfarction remodeling in infarcted rat hearts.	Demonstration of the regulation of macrophage polarization via STAT3 by dapagliflozin.	[14]
2018	Aroor	Empagliflozin	Empagliflozin improved kidney injury causing glycosuria and reducing systemic and renal artery stiffness in a mouse model of T2DM.	SGLT2 inhibition enhances eNOS activation and mitigates the hyperglycemia-induced suppression of the antifibrotic factor RECK in the kidney.	[10]
2019	Shao	Empagliflozin	Empagliflozin reduced the remodeling of atrial structural and electrical conformation reducing left atrial diameter, interstitial fibrosis.	Demonstration of the beneficial effects of empagliflozin on atrial fibrillation in diabetic rats.	[9]
2020	Lahwong	Dapagliflozin	Dapagliflozin administration in acute setting reduced cardiac infarct size, increased LV function and reduced rate of arrhythmias in rats with I/R injury.	Evidence of the direct effects of dapagliflozin on cardiac apoptosis, inflammation, ionic homeostasis, and oxidative stress pathways.	[13]
2021	Quagliariello	Empagliflozin	Empagliflozin reduced doxorubicin toxic effects on cardiomyocytes.	Identification of new anti-inflammatory and cardioprotective mechanisms of empagliflozin involving NLRP3 and MyD88-related pathways.	[11]
2021	Sayour	Canagliflozin, Dapagliflozin, Empagliflozin	SGLT2 inhibitors reduced myocardial infarct size in animal models independent of diabetes.	The reduction of infarct size is equal for the different types of SGLT2 inhibitors, suggesting a class effect.	[65]
2023	Chen	Empagliflozin	Empagliflozin (10 mg/kg/day) has protective effects in a model of cardiac ischemia/reperfusion despite the ablation of SGLT2 (global knock-out mouse).	The demonstration of the beneficial heart effects of SGLT2 inhibitors in a SGLT2 KO mouse model suggests that the reduction of the infarct size is not directly mediated by the SGLT2 protein.	[95]

EF: Ejection Fraction; I/R: Ischemia/Reperfusion; HF: Heart Failure; HFD + STZ: high-fat diet /streptozotocin; KO: Knock-Out; LV: Left Ventricular; SGLT2: Sodium–glucose cotransporter 2; T2DM: Type 2 Diabetes Mellitus.

Moving to the clinical scenario, in 2015 Zinman and colleagues sought to determine the cardiovascular safety of empagliflozin in a cohort of patients with T2DM and high cardiovascular risk in the EMPA-REG OUTCOME (Cardiovascular Outcome Event Trial in T2DM Patients) trial: 7020 patients with T2DM at high risk for cardiovascular events were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group vs. the placebo group. The primary endpoint occurred in 490 of 4687 patients (10.5%) in the treatment group and in 282 of 2333 patients (12.1%) in the placebo group (HR in the empagliflozin group: 0.86; CI: 95.02%, 0.74 to 0.99; P=0.04). The key secondary endpoint was the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke plus hospitalization for unstable angina. No significant difference between groups in this secondary endpoint (P=0.08) occurred; similarly, there were no significant differences in the rates of myocardial infarction or stroke between groups. However, in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for HF (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction) [15,16].

To specifically explore the effects of SGLT2 inhibitors on HF, several randomized controlled trials have been completed. The DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 trial evaluated the cardiovascular outcomes of Dapagliflozin vs. placebo over a period of up to 5 years, across 33 countries and in more than 17000 adults with T2D with multiple cardiovascular risk factors or established cardiovascular disease [17]. Dapagliflozin met the primary safety endpoint of non-inferiority for major adverse cardiovascular events (MACE) and achieved a statistically-significant reduction in the composite endpoint of hospitalization for HF or cardiovascular death [17]. In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening HF) trial, the SGLT2 inhibitor Sotagliflozin, initiated in-hospital or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes, hospitalizations and urgent need of medical attention in patients with diabetes and recent worsening HF, compared to placebo [18].

Of note, in other trials, participants did not have to meet a diagnosis of diabetes to be enrolled. These include the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in HF) [19], the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic HF With Reduced Ejection Fraction) [20], and the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic HF with Preserved Ejection Fraction, HFpEF) trials [21]. Remarkably, in these studies, 40–60% of patients did not have T2DM [22]. In line with the other clinical studies conducted exclusively in diabetic patients, these trials reported a significant decrease in cardiovascular death or hospitalization for HF using SGLT2 inhibitors vs. standard of care plus placebo. Besides, this effect was significant within groups of patients both with and without T2DM. Other cardiovascular benefits of SGLT2 inhibitors substantiated by these trials include a decreased incidence of atrial/ventricular arrhythmia and anemia [23,24]. The first effect could be attributed to the modulation to oxidative stress and altered cardiac energy metabolism [25–27], whilst the second one might be due to increased erythropoiesis [28].

The DAPA-HF trial evaluated the impact of dapagliflozin compared to placebo as add-on recommended therapy on the incidence of worsening HF or cardiovascular death in patients with HFrEF (HF with Reduced Ejection Fraction). The primary outcome was a composite of cardiovascular death or episodes of worsening HF. In 4744 patients with EF ≤40%, moderately elevated levels of N-terminal pro B-type natriuretic peptide, and an estimated glomerular filtration rate ≥30 mL/min/1.73 m², dapagliflozin was shown to reduce the risk of worsening HF or death from cardiovascular causes compared to placebo, regardless of the presence of diabetes [29–33]. Another gliflozin, ertugliflozin, was tested by randomizing 8246 patients with T2DM and atherosclerotic cardiovascular disease, establishing as primary outcome a composite of MACE. In the ertugliflozin group, MACE occurred in 653 out of 5493 patients (11.9%) vs. 327 out of 2745 patients (11.9%) in the placebo group (HR 0.97; CI 95.6%, 0.85 to 1.11; P<0.001) demonstrating the non-inferiority of ertugliflozin. Death from cardiovascular causes or hospitalization for HF occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (HR 0.88; CI 95.8%, 0.75 to 1.03; P = 0.11). The HR for death from cardiovascular causes and HR for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level were 0.92 (CI 95.8%, 0.77 to 1.11) and 0.81 (CI 95.8%, 0.63 to 1.04), respectively [34–36].

The results of the EMPEROR-Reduced trial were published in 2021, showing that empagliflozin decreases the risk of inpatient and outpatient worsening HF events in patients with HFrEF. The authors analyzed data from 3730 subjects randomized to receive empagliflozin or placebo in addition to recommended treatments for HF. Empagliflozin reduced the total number of hospitalizations for HF that required intensive care (HR, 0.67; CI 95%, 0.50–0.90; P=0.008) or that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; CI 95%, 0.47–0.87; P=0.005). Patients assigned to empagliflozin had a greater likelihood (20–40%) of improvement in New York Heart Association (NYHA) functional class and were less likely to experience worsening of their NYHA class [37,38]. When evaluating patients with volume overload, data from this trial confirmed that the diuretic effect of SGLT2 inhibitors does not have a dominant role in their physiological changes and clinical benefits [39]. In most of the above-mentioned trial, the main adverse effects of gliflozins were infections of the genito-urinary tract and volume depletion, without an increased risk of hypoglycemia [40–44].

A wide range of clinical conditions where gliflozins could exert their beneficial effect on the cardiovascular system are being currently evaluated. Especially thrilling is the interest of the scientific community in gliflozins to treat HFpEF, a clinical syndrome for which there is not a universally accepted therapy, lacking evidence for a specific disease-modifying medication [45–49]. This aspect represents a critical unmet need and according to available evidence in the quest to find a valid therapeutic regimen for HFpEF, it would seem that gliflozins could respond to this need.

To evaluate the effects of SGLT2 inhibition in HFpEF, in the EMPEROR-Preserved trial, 5988 patients with HFpEF (NYHA class II-IV) were randomized to receive empagliflozin or placebo in addition to usual therapy. Notably, in this trial, not having diabetes was not considered an exclusion criterion. The primary outcome, a composite of cardiovascular death or hospitalization for HF, occurred in 13.8% of patients receiving empagliflozin vs. 17.1% of subjects in the placebo group (HR, 0.79; CI 95%, 0.69 to 0.90; P<0.001). Furthermore, the total number of hospitalizations for HF was lower in the empagliflozin group than in the placebo group (HR, 0.73; CI 95%, 0.61 to 0.88; P<0.001). Strikingly, these results were consistent regardless of the presence of diabetes [21,50–52]. Other pieces of evidence support the use of SGLT2 inhibitors in HFpEF [53,54]: SGLT2 inhibitors have been indeed shown to improve the quality of life in patients with HFpEF [55–57], and significant favorable effects of empagliflozin on cognitive and physical impairment have been reported in subjects with diabetes and HFpEF [58]. Neuroprotective effects of empagliflozin have been recently demonstrated also in zebrafish, through mechanisms that include ketogenesis and autophagy [59]. A new microRNA signature functionally involved in the regulation of endothelial function was shown to be significantly regulated in frail patients with HFpEF and diabetes, and the treatment with empagliflozin was demonstrated to attenuate endothelial dysfunction and rescue the modifications of the microRNA signature [60], thereby identifying in these microRNAs novel reliable biomarkers of disease and response to therapy.

The EMPA-TROPISM (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity?) trial demonstrated that empagliflozin can improve adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in non-diabetic patients with HFrEF, providing new insights on the potential mechanisms of action of SGLT2 inhibitors [61]. Intriguingly, a recent meta-analysis of 60 randomized trials has investigated the effects of SGLT2 inhibitors on cholesterol and triglycerides, concluding that SGLT2-inhibition significantly decreases circulating levels of triglycerides but increases total, LDL, and HDL cholesterol [62]. Collectively, these data suggest the possible application of these medications not only in HF but also in other clinical conditions. Thus, the cardioprotective effects of SGLT2 inhibitors are also being investigated in other settings; in fact, in a variety of preclinical studies gliflozins have been shown to reduce acute myocardial ischemia/reperfusion injury [63,64]. The main drug tested was dapagliflozin, which was shown to have the capacity of reducing the infarct size and the risk of arrhythmias and to improve EF in obese rats undergoing cardiac ischemic-reperfusion injury [13] and even to have a negative effect on myofibroblast infiltration and cardiac fibrosis after AMI [14]. Similarly, empagliflozin has been shown to improve myocardial function and reduce infarct size in mice [8]. In a recent meta-analysis, these results were confirmed to be independent of the presence of diabetes [65].

Acute decompensated HF is another enthralling setting in which SGLT2 inhibitors effects are being evaluated. In this sense, SGLT2 inhibitors have been shown to increase the urine output without worsening the renal function when started in-hospital in addition to standard diuretic therapy in patients admitted for acute decompensated HF [66–69]. In the EMPULSE (Empagliflozin in Patients Hospitalized for Acute HF) trial, 530 patients hospitalized for acute HF were randomized to receive empagliflozin or placebo; the primary outcome was a hierarchical composite of death from any cause, number of HF events, and time to first HF event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom (used to independently measure the patients’ perception of their health status). The empagliflozin group met the primary endpoint showing a greater clinical benefit than placebo group (stratified win ratio, 1.36; CI 95%, 1.09–1.68; P = 0.0054) [68,70,71].

To specifically assess the effects of gliflozins in acute cardiovascular conditions, the AMI PROTECT (Cardioprotective Effect of SGLT2-Inhibitors in Diabetic Patients With Acute Myocardial Infarction; NCT05261867) study has been designed, evaluating the use of SGLT2 inhibitors in patients with T2DM and acute myocardial infarction; the study has shown a lower risk of adverse cardiovascular outcomes during hospitalization, as well as long-term follow-up and a lower risk of new-onset arrhythmic events (particularly ventricular arrhythmias) during the hospitalization for myocardial infarction [57,72,73]. Additionally, a significantly reduced inflammatory response and smaller infarct size has been observed in diabetic patients treated with SGLT2 inhibitors compared to those receiving other oral anti-diabetic agents, independently of glucose-metabolic control [74]. Consistent with these findings, the investigators of the EMMY (Impact of EMpagliflozin on Cardiac Function and Biomarkers of HF in Patients With Acute MYocardial Infarction, NCT03087773) trial recently demonstrated that an early administration of empagliflozin (within 72h) after myocardial infarction is associated with a significantly greater NT-proBNP reduction over 26 weeks, mirrored by a significant improvement in echocardiographic functional and structural parameters [75].

The potential pleiotropic effects of SGLT2 inhibitors have been also evaluated in terms of antiarrhythmic actions, based on the concept that the prevention or attenuation of oxidative and inflammatory stress might have an influence on the reduction of pro-arrhythmic factors and on the development of a pro-arrhythmic substrate [76,77]. The EMBODY (Effect of Empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with T2DM: Multi-center placebo-controlled Double-Blind Randomized) trial was the first clinical study to assess the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and myocardial infarction via ECG Holter monitoring, evidencing that the early administration of SGLT2 inhibitors in T2DM patients with myocardial infarction could be effective in improving cardiac nerve activity without major adverse events [78]. Similarly, a post-hoc analysis of the DAPA-HF trial pointed out that dapagliflozin, compared to placebo, significantly reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF (HR 0.79; CI 95%, 0.63–0.99; P = 0.037) [79].

The effects of SGLT2 inhibitors are also being investigated on the incidence of atrial fibrillation (AF), an aspect particularly relevant if we consider that AF is more frequent in patients with HF and in patients with diabetes [80,81]. In preclinical assays conducted in a diabetic rat model, empagliflozin was shown to modify atrial remodeling, both structural and electrical, decreasing left atrial diameter and interstitial fibrosis, therefore reducing the incidence of AF [9]. In the clinical setting, dapagliflozin was shown to reduce epicardial fat volume in patients with T2DM [82], potentially suggesting a beneficial influence of the drug on the reduction of AF episodes, especially if we consider that an analysis from the Framingham Heart Study established that epicardial fat volume is directly associated with prevalent AF [26,83]. In the DECLARE-TIMI 58 trial, dapagliflozin was actually shown to decrease the incidence of reported episodes of AF/Atrial Flutter in high-risk patients with T2DM [84]. Furthermore, a pooled analysis of 31 trials totaling 75000 patients confirmed that SGLT2 inhibitors reduced the incidence and recurrence of AF [85]. However, it is not clearly known whether the effects of SGLT2 inhibitors on AF are an indirect consequence of the benefits on the HF phenotype and/or if there is an underlying direct action [86].

3. Ongoing clinical trials

Due to the extreme potentiality of gliflozins, various studies are about to be published or are currently ongoing with an estimated completion date within the next 2 years. These trials could potentially answer several points on the clinical applications of SGLT2 inhibitors that remain outstanding.

The main purpose of the EMPA-AF (Empagliflozin and Atrial Fibrillation Treatment; NCT04583813) trial is to evaluate the impact of empagliflozin, as compared with placebo, in patients with T2DM or overweight, HF and AF; DAPA-AF (Use of Dapagliflozin to Reduce Burden of Atrial Fibrillation in Patients Undergoing Catheter Ablation of Symptomatic Atrial Fibrillation; NCT04792190) will study the impact of treatment with dapagliflozin vs. placebo following catheter ablation of AF on the burden of AF during 6–12 months of follow-up; DAPA-MI (Dapagliflozin Effects on Cardiometabolic Outcomes in Patients With an Acute Heart Attack; NCT04564742) has been designed to investigate the effects of dapagliflozin on cardiovascular events in patients with acute myocardial infarction; ERASE (Ertugliflozin to Reduce Arrhythmic Burden in ICD/CRT patientS; NCT04600921) has the aim to analyze the impact of ertugliflozin on the incidence of ventricular arrhythmias; the scope of the EMPACT-MI (A Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack; NCT04509674) study is to find out whether empagliflozin can reduce the rate of hospitalization for HF and the rate of cardiovascular death in patients with acute myocardial infarction. The results obtained from these trials, summarized in Table 2, could give additional information on the use and future applications of SGLT2 inhibitors in a wide range of clinical conditions.

Table 2.

Ongoing trials testing SGLT2 inhibitors.

Acronym, NCT	Official Name	Current primary outcome	State	Estimated completion date
DAPA-AF, NCT04792190	Use of Dapagliflozin to Reduce Burden of Atrial Fibrillation in Patients Undergoing Catheter Ablation of Symptomatic Atrial Fibrillation (DAPA-AF)	Mean percentage of time spent in AF	Active, not recruiting	June, 2023
EMPACT-MI, NCT04509674	A Streamlined, Multicenter, Randomized, Parallel Group, Double-blind Placebo-controlled Superiority Trial to Evaluate the Effect of EMPAgliflozin on Hospitalization for HF and Mortality in Patients With aCuTe Myocardial Infarction	Composite of time to first HF hospitalization or all-cause mortality	Recruiting	August, 2023
DAPA-MI, NCT04564742	A Registry-based, Randomized, Double-blind, Placebo-Controlled Cardiovascular Outcomes Trial to Evaluate the Effect of Dapagliflozin on the Incidence of HF or Cardiovascular Death in Patients Without Diabetes With Acute Myocardial Infarction at Increased Risk for Subsequent Development of HF	Time to the first occurrence of any of the components of this composite: hospitalization for HF or cardiovascular death	Recruiting	September, 2023
EMPA-AF, NCT04583813	Efficacy of Empagliflozin in Patients With HF and Atrial Fibrillation	Maintenance of sinus rhythm after the blanking period	Not yet recruiting	January, 2024
ERASe, NCT04600921	Ertugliflozin to Reduce Arrhythmic Burden in ICD/CRT patientS - a Phase III Study	Episodes of supraventricular tachycardia and ventricular fibrillation.	Recruiting	April, 2024

AF: Atrial Fibrillation; CRT: Cardiac Resynchronization Therapy; HF: Heart Failure; ICD: Implantable Cardioverter-defibrillators.

4. Conclusions

SGLT2 inhibitors represent molecules with a very broad clinical potential, confirmed by numerous studies. Nevertheless, further data are needed to better clarify their precise mechanism of action and off-target effects (see the section below) as well as to assess their efficacy and safety in other clinical conditions. Many ongoing trials, discussed in detail in the section above, could potentially answer several points that remain outstanding.

5. Expert opinion

Gliflozins have rapidly become part of the keystone tools of HFrEF therapy thanks to the (initially unexpected) results obtained in numerous clinical trials. Among these findings, a substantial improvement of different cardiovascular outcomes emerged, suggesting their potential use even in other cardiovascular conditions. Promising results have already been reached for HFpEF, although more data are needed to assess their effective role in this type of HF.

The use of SGLT2 inhibitors in acute HF could represent another valuable application, considering their effects on urine output without worsening kidney function [87,88]. The cardioprotective actions of these medications have been confirmed even in terms of myocardial remodeling, showing a benefit both in acute myocardial ischemia/reperfusion injury and on the incidence of ventricular and atrial arrhythmias, albeit at the moment the exact mechanisms of action remain not fully clear. Many of the mechanisms proposed in the context of HF—including blood pressure reduction, altering parenchymal lipid-glucose metabolism, inhibition of Na⁺/H⁺ Exchanger 1 (NHE1), and decreasing pro-fibrotic/inflammatory molecules—have also been suggested to play a reno-protective role [64,89–91].

Owing to their antidiabetic properties and protective effects on the cardiovascular system, SGLT2 inhibitors have been recommended by the American Diabetic Association (ADA) in its 2023 “Standards of Medical Care in Diabetes” [1]. In particular, the ADA recommends SGLT2 inhibitors in patients with T2DM in presence of established (or high risk of) atherosclerotic cardiovascular disease, defined as coronary heart disease, cerebrovascular disease, or peripheral arterial disease of atherosclerotic origin [92]. Moreover, in the current update of the American Council of Cardiologists consensus practice guidelines, gliflozins are indicated as add-on therapy to Angiotensin Receptor Neprilysin Inhibitors (ARNI)/Angiotensin Converting Enzyme Inhibitors (ACEI)/Angiotensin Receptor Blockers (ARB) and evidence-based Beta Blocker (BB) with diuretic agents, especially in patients belonging to New York Heart Association (NYHA) class II-IV and meeting GFR criteria [93]. In the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic HF, SGLT2 inhibitors dapagliflozin and empagliflozin are recommended in all patients affected by HFrEF already in treatment with ARNI/ACEI/ARB, beta blockers, and Mineralocorticoid Receptor Antagonists, to reduce cardiovascular death and worsening HF. Hence, unless contraindicated or not tolerated, SGLT2 inhibitors are suitable regardless of whether the patient has or not diabetes [46,94].

Another compelling aspect of the pharmacological properties of SGLT2 inhibitors relies on their off-target effects. Indeed, in 2023, a collaborative study between research groups from the Netherlands and Greece has generated a novel global SGLT2 knock-out mouse demonstrating that the beneficial cardiovascular effects of empagliflozin are independent of SGLT2 [95], at least in a model of cardiac ischemia/reperfusion injury. These findings clearly indicate off-target effects of empagliflozin. Several non-canonical mechanisms have been proposed to explain the beneficial cardiac effects of empagliflozin, including an inhibitory action on NHE1, thereby causing a reduction in intracellular [Na⁺] ([Na⁺]_i) [96,97]. However, a recent paper from Coert Zuurbier’s research group seems to disprove these theories [95]. Alternative mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors, including modifications in the metabolic substrate preference and more efficient mitochondrial energy production, improved endothelial function, and enhanced ventricular loading secondary to an amelioration of renal fitness [98–100]. Further studies are therefore warranted to clarify the exact mechanisms underlying the beneficial cardiovascular effects of SGLT2 inhibitors.

Article highlights.

• Sodium Glucose co-Transporter 2 (SGLT2) inhibitors emerged as a main therapeutic option for patients with type 2 diabetes mellitus.

• Recent randomized clinical trials unveiled unprecedented cardioprotective actions of SGLT2 inhibitors.

• The favorable effects of SGLT2 inhibitors on cardiovascular outcome are not dependent on the presence of diabetes.

• We present an overview of the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors, including ongoing clinical trials.