Sodium glucose transporter 2 inhibitors for heart failure

Abstract

Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality, affecting over 64 million individuals worldwide. Despite advances in guideline-directed medical therapy, patients with HF continue to experience poor outcomes, highlighting the need for novel therapeutic approaches. Sodium glucose transporter 2 (SGLT2) inhibitors, initially developed for diabetes management, have emerged as groundbreaking therapies for HF. These agents demonstrate remarkable cardiovascular benefits that extend beyond their glucose-lowering effects, including significant reductions in HF hospitalization and cardiovascular mortality rates. Landmark trials including Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction, and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure have established the efficacy of SGLT2 inhibitors across the spectrum of HF phenotypes, regardless of diabetes status. The mechanisms underlying these benefits are multifaceted, involving improvements in cardiac energetics, mitochondrial function, reduction of oxidative stress, attenuation of inflammation, and favorable effects on cardiac remodeling and fibrosis. This comprehensive review examines the current evidence supporting the use of SGLT2 inhibitors in HF management, explores the mechanistic pathways responsible for their cardiovascular benefits, analyzes key clinical trial data, and discusses future prospects for this transformative drug class in cardiovascular medicine.

Key Words: Sodium glucose transporter 2 inhibitor; Heart failure; Cardiovascular benefit; Mechanistic pathway; Current evidence; Prospects

Core Tip: Heart failure (HF) affects over 64 million people worldwide, with persistently poor outcomes despite advances in treatment. Sodium glucose transporter 2 inhibitors, originally developed for diabetes, have emerged as breakthrough HF therapies with cardiovascular benefits beyond glucose control, including reduced risk of hospitalization and mortality. Landmark trials (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction, Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) have demonstrated efficacy across all HF types, regardless of diabetes status. Their benefits stem from improved cardiac energetics, enhanced mitochondrial function, reduced oxidative stress and inflammation, and favorable cardiac remodeling. This review examines current evidence, mechanistic pathways, and future prospects for sodium glucose transporter 2 inhibitor use in cardiovascular medicine.

INTRODUCTION

Heart failure (HF) is a multifaceted clinical syndrome in which the heart cannot pump blood sufficiently to meet the metabolic needs of peripheral tissues[1]. In developed countries, HF affects approximately 1%-2% of the adult population, with a prevalence of over 10% in individuals aged ≥ 70 years[2]. The worldwide burden of HF continues to increase, driven by the aging population, improved survival after acute myocardial infarction, and the increasing rates of diabetes, hypertension, and obesity[3].

Classification of HF is traditionally based on left ventricular ejection fraction (LVEF), with HF with reduced ejection fraction (HFrEF) defined by an LVEF ≤ 40%, HF with mildly reduced ejection fraction defined by an LVEF (41%-49%), and HF with preserved ejection fraction (HFpEF) defined by an LVEF ≥ 50%[4]. Each phenotype exhibits unique pathophysiology, clinical features, and treatment responses. HFpEF accounts for approximately 50% of cases and treatment options are particularly limited[5].

HF pathophysiology involves complex neurohormonal activation, including the renin-angiotensin-aldosterone and sympathetic nervous systems, resulting in vasoconstriction, sodium retention, and progressive cardiac remodeling[6]. Current guidelines for medical treatment of HFrEF recommend angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and more recently, angiotensin receptor-neprilysin inhibitors[7]. Despite these evidence-based treatments, patients with HF still experience high hospitalization and mortality rates, with a five-year survival rate of approximately 50%[8].

The diverse and complex nature of HF, especially HFpEF, poses major therapeutic challenges[9]. Characterized by diastolic dysfunction, increased left ventricular stiffness, and impaired relaxation, HFpEF is also frequently associated with diabetes, obesity, chronic kidney disease (CKD), and atrial fibrillation[9]. The limited treatment options for HFpEF highlights the urgent need for novel therapeutic approaches targeting the pathophysiological mechanisms common to both HFrEF and HFpEF[10].

Sodium glucose transporter 2 (SGLT2) inhibitors are a groundbreaking class of antidiabetic drugs initially designed to treat type 2 diabetes mellitus (T2DM) by selective inhibition of renal glucose reabsorption; however, unexpectedly, they have demonstrated significant cardiovascular benefits that extend beyond glycemic control[11].

The development of SGLT2 inhibitors originated from 19^th-century discovery of phlorizin, a natural compound from apple tree bark that induces glycosuria[12]. However, phlorizin’s non-selective inhibition of both SGLT1 and SGLT2 and poor pharmacokinetic properties have limited its clinical use[12]. Modern SGLT2 inhibitors have been developed through structure-activity relationship studies to selectively target SGLT2 and inhibit it, while maintaining favorable pharmacological profiles[13].

Canagliflozin was the first SGLT2 inhibitor approved in 2013, followed by dapagliflozin and empagliflozin[14]. These drugs block approximately 90% of filtered glucose reabsorption in the proximal tubule of the kidney, causing glucosuria and modest insulin-independent improvements in glycemic control[15]. This mechanism also promotes caloric loss, weight reduction, and mild osmotic diuresis[16].

The paradigm shift was driven by the results of cardiovascular outcome trials assessing the cardiovascular safety of SGLT2 inhibitors in patients with T2DM and established cardiovascular disease. The 2015 EMPA-REG OUTCOME trial showed that empagliflozin significantly reduced the risk of cardiovascular death (CD), myocardial infarction, and stroke in high-risk patients with diabetes[17], while reducing HF hospitalizations by 35%, an effect that was evident early and independent of baseline HF status[18].

Subsequent cardiovascular outcome trials on canagliflozin (CANVAS Program) and dapagliflozin (DECLARE-TIMI 58) confirmed consistent cardiovascular benefits across different SGLT2 inhibitors, particularly reduced HF hospitalizations[14,19]. These results suggested that SGLT2 inhibitors may exert direct cardiovascular benefits independent of glycemic control, prompting further studies on patients with established HF regardless of diabetes status[20].

Since SGLT2 inhibitors have emerged as a feasible pharmacological strategy, no paper has systematically summarized the latest evidence and knowledge, and a review and update on this topic is urgently needed. Therefore, this narrative review aims to provide a focused overview of SGLT2 inhibitors, including their structure, expression, regulatory roles, effect on the heart and HF, evidence from clinical trials, adverse effects, and prospects.

METHODOLOGY

We searched the PubMed database to identify key human studies reporting the most recent advances in SGLT2 inhibitor research. We identified relevant literature, and the findings are summarized below by category.

STRUCTURE, EXPRESSION, AND REGULATORY ROLES OF SGLT2 INHIBITORS

SGLT2 inhibitors are small-molecule compounds exhibiting common structural similarities while maintaining distinct pharmacokinetic and pharmacodynamic profiles[21]. In terms of molecular structure, clinically available SGLT2 inhibitors demonstrate a glucose-like moiety linked to various aromatic systems conferring selectivity for each particular SGLT2 transporter[21]. Empagliflozin and dapagliflozin feature a glucose molecule linked to a chlorophenyl group, whereas canagliflozin contains a thiophene ring system[22].

SGLT2 is a high-capacity, low-affinity glucose transporter expressed primarily in the S1 segment of the renal proximal tubule[23]. SGLT2 reabsorbs approximately 90% of filtered glucose, with SGLT1 reabsorbing the remaining 10% in the distal proximal tubule segments[23]. Glucose uptake is driven against its concentration gradient using the sodium gradient generated by basolateral sodium-potassium adenosine triphosphatase[24].

Recent studies show that SGLT2 is expressed beyond the kidney, extending to the heart, skeletal muscle, liver, and intestine, though at much lower levels[25]. In the heart, SGLT2 is present in cardiomyocytes, with expression elevated in HF and diabetic cardiomyopathy[26]. This extrarenal expression may contribute to the direct cardiovascular effects of SGLT2 inhibitors, independent of their renal effects.

Multiple transcriptional and post-transcriptional factors are associated with the regulatory mechanisms governing SGLT2 expression[27]. High glucose levels upregulate SGLT2 expression via signaling pathways such as the protein kinase C activation and transforming growth factor-β signaling pathways[27]. Additionally, inflammatory cytokines, oxidative stress, and neurohormonal activation typical of HF can modulate SGLT2 expression and activity[28]. Figure 1 summarizes the systemic effects of SGLT2 inhibitors and their pleiotropic effects across multiple organ systems.

Figure 1 Systemic effects of sodium glucose transporter 2 inhibitors. Physiological mechanisms and clinical outcomes from major cardiovascular outcome trials. Orange asterisks indicate effects with established statistical significance (P < 0.05) in major cardiovascular or renal outcome trials (e.g., EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, DAPA-Chronic Kidney Disease). Unmarked items represent known physiological mechanisms. CD: Cardiovascular death; CKD: Chronic kidney disease; GFR: Glomerular filtration rate; HF: Heart failure; LV: Left ventricular.

SGLT2 inhibitors are highly select for SGLT2 over SGLT1, with selectivity ratios of approximately 2500-fold for empagliflozin and 1200-fold for canagliflozin[29]. This selectivity is important because SGLT1 mediates intestinal glucose absorption and plays key roles in the heart and kidneys[29]. Pharmacokinetically, SGLT2 inhibitors exhibit good oral bioavailability, extensive protein binding, and are primarily metabolized in the liver with minimal renal elimination of the parent drug[30]. The characteristics of each SGLT2 inhibitor – particularly their pharmacological properties and structural features – are shown in Supplementary Table 1.

EFFECTS OF SGLT2 INHIBITORS ON THE HEART AND HF

The cardiovascular benefits of SGLT2 inhibitors extend beyond renal glucose inhibition[31] encompassing hemodynamic, metabolic, and direct cellular effects that synergistically promote cardiovascular health and slow HF progression[32].

Hemodynamic effects

SGLT2 inhibitors induce favorable hemodynamic effects that contribute to benefits in HF[33]. Glucosuria-driven osmotic diuresis produces a mild natriuretic effect, reducing plasma volume and decreasing preload without significantly activating neurohormonal systems[33]. In contrast to conventional diuretics, SGLT2 inhibitors preserve or improve renal function while alleviating congestion, which can be attributed to enhanced renal hemodynamics and reduced intraglomerular pressure[34].

Additionally, the benefits of SGLT2 inhibitors on arterial stiffness and blood pressure contribute to decreased afterload and improved ventricular-arterial coupling[35]. Clinical studies have shown reductions in both systolic and diastolic blood pressure by 3-5 mmHg with SGLT2 inhibitors, and greater effects are observed in patients with baseline hypertension[36]. Moreover, blood pressure reduction is accompanied by improved endothelial function and reduced vascular inflammation[37].

Metabolic effect and cardiac energetics

Cardiac metabolism is profoundly altered by SGLT2 inhibitors via promotion of a shift from glucose to more efficient fuel sources, notably ketone bodies and fatty acids[38]. This metabolic reprogramming is especially beneficial in HF, where myocardial energy efficiency is impaired[38]. Elevated ketone availability, particularly β-hydroxybutyrate, provides a high-efficiency energy source, generating more adenosine triphosphate per oxygen molecule than glucose[39].

The “thrifty fuel hypothesis” suggests that ketone bodies act as a “super fuel” for the failing heart, enhancing cardiac efficiency and function[40]. Clinical studies show that SGLT2 inhibitors increase circulating ketone levels, even in patients without diabetes, underscoring the contribution of ketone metabolism to cardiovascular health[16]. Moreover, SGLT2 inhibitors improve myocardial glucose uptake by enhancing insulin sensitivity and promoting glucose transporter type 4 translocation[41].

Mitochondrial function and oxidative stress

Mitochondrial dysfunction is a hallmark of HF, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species, and dysregulated calcium handling[42]. Growing evidence indicates that SGLT2 inhibitors can improve mitochondrial function through multiple mechanisms, including stimulation of mitochondrial biogenesis, enhancement of respiratory chain complex activity, and attenuation of oxidative stress[43].

Preclinical studies have shown that empagliflozin improves mitochondrial respiratory capacity and reduces production of mitochondrial reactive oxygen species in cardiomyocytes[44]. The antioxidant effects of SGLT2 inhibitors are mediated in part by upregulation of endogenous antioxidant systems, such as superoxide dismutase and catalase, alongside suppression of pro-oxidant enzymes including nicotinamide adenine dinucleotide phosphate oxidase[45]. Collectively, these actions help preserve mitochondrial membrane potential and enhance adenosine triphosphate production[46].

The ketone body β-hydroxybutyrate is produced during SGLT2 inhibitor therapy and also functions as a signaling molecule, activating longevity pathways such as sirtuin-1 and 5’-adenosine monophosphate-activated protein kinase. Activation of these pathways promotes mitochondrial biogenesis and resistance to cellular stress[47]. In addition, SGLT2 inhibitors have been shown to reduce mitochondrial fission while promoting fusion, thereby improving mitochondrial network dynamics[48].

Anti-inflammatory effects

Chronic inflammation is a key contributor to HF pathogenesis, driving myocardial dysfunction, adverse remodeling, and disease progression[49]. SGLT2 inhibitors exhibit potent anti-inflammatory effects through multiple mechanisms, including suppression of pro-inflammatory cytokine production and enhanced resolution of inflammation[50].

Clinical studies have shown that treatment with SGLT2 inhibitors lowers circulating levels of inflammatory markers such as C-reactive protein, interleukin-6, and tumor necrosis factor-α[51]. These anti-inflammatory actions are mediated in part by inhibition of the nucleotide-binding and oligomerization domain-like receptors protein 3 inflammasome, a key regulator of sterile inflammation in cardiovascular disease[52]. Furthermore, SGLT2 inhibitors promote immune homeostasis by enhancing macrophage polarization toward the anti-inflammatory M2 phenotype[53], thereby limiting chronic inflammation.

The molecular basis of these anti-inflammatory effects involves modulation of nuclear factor kappa B signaling, activation of anti-inflammatory transcription factors such as nuclear factor-erythroid 2-related factor 2, and direct effects on immune cell function[54]. Collectively, these anti-inflammatory actions attenuate myocardial injury and improve healing following cardiac stress[55].

Cardiac remodeling and fibrosis

Adverse cardiac remodeling – characterized by myocyte hypertrophy, interstitial fibrosis, and chamber dilatation – is a fundamental mechanism driving HF progression[56]. SGLT2 inhibitors demonstrate beneficial effects on cardiac remodeling via multiple mechanisms, including reduction of myocardial fibrosis, improvement in cardiomyocyte function, and favorable changes in extracellular matrix composition[57].

Preclinical studies show that SGLT2 inhibitor treatment reduces cardiac fibrosis by suppressing transforming growth factor-β signaling and limiting collagen deposition[58]. These antifibrotic effects are mediated by the downregulation of profibrotic genes and proteins, such as α-smooth muscle actin and collagen types I and III[59]. In addition, SGLT2 inhibitors enhance matrix metalloproteinase activity, facilitating excess extracellular matrix degradation[60].

Cardiac magnetic resonance imaging studies have confirmed that SGLT2 inhibitor therapy is associated with regression of myocardial fibrosis and improvements in left ventricular function in patients with HF[61]. Notably, these remodeling benefits have been observed across different HF phenotypes and appear to be independent of diabetes status[62].

EVIDENCE FROM CLINICAL TRIALS

Robust clinical evidence supports the use of SGLT2 inhibitors in HF management, including multiple landmark randomized controlled trials that have fundamentally changed treatment paradigms. Collectively, these trials have demonstrated significant cardiovascular benefits across diverse HF phenotypes and patient populations[63]. The key characteristics of the major clinical trials evaluating SGLT2 inhibitors in HF are shown in Supplementary Table 2.

Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial with HFrEF

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial was a pivotal randomized, double-blind, placebo-controlled study that enrolled 4744 patients with HFrEF, irrespective of diabetes status[64]. Dapagliflozin (10 mg daily) significantly reduced the primary composite endpoint of CD or worsening HF by 26% [hazard ratio (HR) = 0.74, 95%CI: 0.65-0.85, P < 0.001] compared with a placebo over a median follow-up of 18.2 months[7].

Importantly, the benefits of dapagliflozin were consistent across subgroups stratified by diabetes status, with comparable risk reductions observed in patients with and without diabetes[65]. Among patients without diabetes, dapagliflozin reduced the primary endpoint by 27% (HR = 0.73, 95%CI: 0.60-0.88), demonstrating that HF benefits extend beyond glucose-lowering effects[66]. The number required to treat for the primary endpoint was 21 patients over 18 months[67].

Secondary analyses of the DAPA-HF trial revealed additional clinical benefits including improved quality of life (assessed using the Kansas City Cardiomyopathy Questionnaire), reduced HF hospitalizations, and preserved renal function[68]. The safety profile was favorable, with low rates of diabetic ketoacidosis, amputations, and fractures, and no increased risk of hypoglycemia among patients without diabetes[69].

Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction trial with HFrEF

The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) trial enrolled 3730 patients with HFrEF, demonstrating that empagliflozin (10 mg daily) reduced the rates of CD and HF hospitalization by 25% (HR = 0.75, 95%CI: 0.65-0.86, P < 0.001) compared with a placebo[33].

This trial confirmed a class effect of SGLT2 inhibitors in HF, with consistent benefits observed irrespective of diabetes status. Empagliflozin reduced HF hospitalizations by 30% and showed a favorable trend toward reduced CD. Notably, the EMPEROR-Reduced population included patients with more severe HF, including lower mean LVEF and higher baseline N-terminal pro-brain natriuretic peptide levels, compared with that of the DAPA-HF[70]. A rapid onset of benefit was observed, with early separation of event curves within the first month of therapy[71]. In addition, empagliflozin reduced the risk of CKD progression by 50%[72]. The safety profile was consistent with that of previous SGLT2 inhibitor trials, with no increase in the risk of major adverse events[55].

Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction trial with HFpEF

The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial marked a breakthrough in HFpEF therapy, being the first large, randomized trial to demonstrate significant clinical benefits in this challenging population[73]. The trial enrolled 5988 patients with HFpEF and demonstrated that empagliflozin reduced the rates of CD or HF hospitalization by 21% (HR = 0.79, 95%CI: 0.69-0.90, P < 0.001).

The observed benefit was primarily driven by a 29% reduction in HF hospitalizations, with no significant effect on CD[74]. Importantly, the benefits were consistent across the full spectrum of ejection fraction, with comparable effects observed in patients with an LVEF of 41%-49% and those with an LVEF of ≥ 50%[75]. Moreover, benefits were observed in patients with and without diabetes[76].

Subgroup analyses indicated the greatest benefits in patients with an LVEF < 60%, suggesting that SGLT2 inhibitors may be particularly effective for mildly reduced or borderline preserved ejection fraction[77]. Treatment with empagliflozin also led to significant and clinically meaningful improvements in quality-of-life[78].

Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trial with HFpEF

The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial complemented EMPEROR-Preserved by evaluating dapagliflozin in 6263 patients with HFpEF[79]. This trial demonstrated that dapagliflozin reduced rates of CD or worsening HF by 18% (HR = 0.82, 95%CI: 0.73-0.92, P < 0.001)[65].

DELIVER confirmed the class effect of SGLT2 inhibitors in HFpEF, with benefits primarily driven by reductions in HF events. The trial enrolled a broader population than EMPEROR-Preserved, including patients with LVEF up to 65% and application of less stringent natriuretic peptide criteria[72]. The safety profile was consistent with prior SGLT2 inhibitor trials[80].

Meta-analyses and pooled results

Consistent benefits of SGLT2 inhibitors across HF populations have been confirmed in several meta-analyses. A comprehensive meta-analysis including five major HF trials (DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DELIVER, and SOLOIST-WHF) and encompassing 21947 patients demonstrated a reduced risk of CD or HF hospitalization of 23% (HR = 0.77, 95%CI: 0.72-0.82)[55].

The benefits were consistent across the full spectrum of ejection fractions, with similar relative risk reductions in HFrEF and HFpEF populations[81]. Another meta-analysis confirmed the safety of SGLT2 inhibitors, with no increased risk of major adverse events such as diabetic ketoacidosis, amputations, or fractures[82]. The number required to treat for the primary endpoint was approximately 19 patients over 2 years.

ADVERSE EFFECTS OF SGLT2 INHIBITORS

SGLT2 inhibitors – including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin – are commonly used to treat T2DM, HF, and CKD because of their cardiovascular and renal protective effects[83,84]. Clinicians, however, should be mindful of potential adverse effects.

The most frequent class-related side effects include genital mycotic infections, occurring three to five times more often than with a placebo, presenting as vulvovaginal candidiasis in women and balanitis in men[83,84]. Euglycemic diabetic ketoacidosis is a rare but life-threatening complication, marked by metabolic acidosis with ketosis despite blood glucose levels of less than 250 mg/dL[85], with risk factors including surgery, fasting, low carbohydrate intake, and acute illness[85]. Osmotic diuresis may cause volume depletion, leading to hypotension and dizziness, though severe cases are uncommon with provided patients are properly monitored and stay hydrated[84]. Dapagliflozin is particularly associated with increased risk of urinary tract infection, while canagliflozin has been linked to an elevated risk of lower-limb amputations, particularly in patients with pre-existing peripheral vascular disease[83,84,86]. In 2020, the Food and Drug Administration removed its boxed warning for canagliflozin based on updated safety data[84]. Contrary to initial concerns, current evidence does not indicate an increased risk of acute kidney injury or bone fracture with SGLT2 inhibitor administration[84]. The initial drop in estimated glomerular filtration rate after treatment initiation is typically transient and reversible, reflecting hemodynamic effects rather than kidney damage[84]. Hypoglycemia risk is very low with monotherapy but may rise when combined with insulin or sulfonylureas[84].

Prevention strategies include educating patients on genital hygiene, maintaining adequate hydration, and recognizing early warning signs[84]. SGLT2 inhibitors should be temporarily discontinued 3-4 days before scheduled surgeries to minimize the risk of euglycemic DKA[85,86]. Most adverse effects can be managed without permanent discontinuation of therapy, enabling patients to continue receiving the substantial cardiovascular and renal protective effects of these medications[83,84].

PROSPECTS

The success of SGLT2 inhibitors in HF has created multiple avenues for future research. Ongoing clinical trials are exploring their effects in specific HF populations and clinical scenarios, while mechanistic studies continue to identify novel therapeutic targets[87].

Acute HF

The role of SGLT2 inhibitors in acute HF is under intense investigation. The DAPA-ACT HF-TIMI 68 trial is assessing the safety and efficacy of initiating dapagliflozin during HF hospitalization[88]. Early findings suggest that these agents can be initiated safely in the acute setting, potentially accelerating decongestion and shortening hospital stay[89].

Mechanistic benefits include rapid onset of natriuretic effects, improved renal function, and reduced neurohormonal activation[90]. Future studies should focus on determining the optimal timing of treatment initiation and identifying patients most likely to benefit from early SGLT2 inhibitor therapy[91].

Combination therapies

Research evaluating the benefits of combining SGLT2 inhibitors with other novel HF therapies is ongoing. Combining SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists is of particular interest because of the complementary mechanisms of action and potential synergistic cardiovascular benefits[92]. Preclinical studies suggest additive effects on metabolism, inflammation, and cardiac remodeling[93].

Dual SGLT1/SGLT2 inhibitors, such as sotagliflozin, have shown promising results in HF trials by targeting SGLT1 inhibition in the heart and other tissues[94]. The ideal balance between SGLT1 and SGLT2 inhibition for optimal cardiovascular benefit remains an area of active investigation[95].

Precision medicine approaches

Future research will also need to focus on identification of biomarkers and patient characteristics that can predict the response to SGLT2 inhibitor therapy. Genomic studies are exploring genetic variants that influence SGLT2 inhibitor efficacy and safety[96], while metabolomics and proteomics may uncover novel biomarkers for personalized treatment.

Incorporating clinical, laboratory, imaging, and genetic data into predictive models may enable precision medicine approaches to optimize SGLT2 inhibitor treatment. Machine learning algorithms are also being developed to predict optimal dosing strategies and identify patients most likely to benefit from SGLT2 inhibitor therapy[97].

Novel indications

The pleiotropic effects of SGLT2 inhibitors have prompted evaluation of their benefits in other cardiovascular conditions. Ongoing trials are investigating the use of SGLT2 inhibitors in patients with myocardial infarction, atrial fibrillation, and peripheral artery disease[98], given that the anti-inflammatory and metabolic effects of SGLT2 inhibitors may provide benefits across the spectrum of cardiovascular diseases.

Researchers are also exploring the potential role of SGLT2 inhibitors in preventing HF in high-risk populations, leveraging the cardioprotective effects observed in patients with diabetes and other risk factors in cardiovascular outcome trials.

Mechanistic understanding

Ongoing research into the mechanisms underlying SGLT2 inhibitor cardiovascular benefits will guide future drug development and optimize therapy. Key areas of investigation include cardiac SGLT2 expression, the contribution of various metabolic pathways, and the interaction between renal and cardiac effects[99].

Advanced imaging techniques, such as positron emission tomography and cardiac magnetic resonance spectroscopy, are being used to assess the metabolic effects of SGLT2 inhibitors in real-time, offering insights into the temporal relationship between metabolic changes and cardiovascular benefits.

DISCUSSION

In this study, we identified key human studies reporting the most recent advances in SGLT2 inhibitor research. However, despite the established cardiovascular and renal benefits, several questions surrounding SGLT2 inhibitors remain unanswered[100]. The precise mechanisms driving cardioprotection extend beyond glycosuria and natriuresis[100], with uncertainties surrounding the relative contributions of metabolic shifts toward ketone utilization, anti-inflammatory pathways, improved myocardial sodium homeostasis via sodium-hydrogen exchanger 1 inhibition, and autophagy activation[100]. Notably, empagliflozin retains cardioprotective effects in SGLT2 knockout mice, suggesting potential off-target effects[101]. Additional unresolved issues include the optimal timing for perioperative management to prevent euglycemic diabetic ketoacidosis, the lack of long-term safety data in specific populations such as kidney transplant recipients, and the durability of benefits across different CKD stages[100]. The precise mechanisms mediating arrhythmia reduction, and whether benefits are truly class effects or agent-specific, also remain areas of active research[100,101]. Clarifying these mechanistic gaps and population-specific safety concerns are critical priorities for optimizing SGLT2 inhibitor therapy in clinical practice.

CONCLUSION

The use of SGLT2 inhibitors represents a paradigm shift in HF management, delivering significant clinical benefits across all HF phenotypes, independent of diabetes status. Landmark clinical trials – including DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER – have firmly established SGLT2 inhibitors as integral to guideline-directed HF therapy.

Moving forward, the integration of SGLT2 inhibitors into clinical practice guidelines and routine HF care will be essential for reducing the global burden of HF. The transformation of these glucose-lowering agents into cornerstone HF therapies exemplifies the importance of continued cardiovascular outcome research and highlights the potential for unexpected therapeutic breakthroughs in medicine.