SGLT2 inhibitors across various patient populations in the era of precision medicine: the multidisciplinary team approach

Abstract

Sodium-glucose cotransporter-2 inhibitors have revolutionized the management of a variety of diseases. Initially developed to address glycemic control in diabetes, sodium-glucose cotransporter-2 inhibitors were identified for their ability to inhibit glucose reabsorption in the kidneys. Landmark trials for highly selective agents demonstrated cardioprotective and renoprotective effects of sodium-glucose cotransporter-2 inhibitors, leading to expanded indications for use in both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. Sodium-glucose cotransporter-2 inhibitors are now approved for a variety of clinical indications, including heart failure, chronic kidney disease, and type 2 diabetes mellitus, with increasing interest in management of steatotic diseases of the liver and weight loss. Despite this, the adoption of the drug class into clinical practice remains suboptimal, hindered by cost and clinician familiarity. This review explores the therapeutic indications for sodium-glucose cotransporter-2 inhibitors, examining their mechanisms of action, classic and prospective clinical effects, safety profile, and impact on decision-making, while highlighting emerging evidence for additional applications such as weight loss, anti-hypertensive, and anti-steatotic effects.

Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have an established role in the standard of care in type 2 diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD). This class of medications was originally developed to treat DM after the kidneys’ crucial role in glucose homeostasis was recognized and the sodium-glucose cotransporter was identified as a key target¹.

The development of SGLT2is started with the isolation of phlorizin from apple tree root bark in 1835 by French chemists. However, this compound was not suitable for therapeutic use due to its poor bioavailability and non-selective inhibition of both sodium-glucose cotransporter-1 (SGLT1) and SGLT2 receptors, resulting in severe gastrointestinal side effects¹. Dapagliflozin was among the first highly selective SGLT2is to be developed and was the first to enter phase III trials where it demonstrated significant improvements in hemoglobin A1c levels². In 2012, the Food and Drug Administration (FDA) delayed the approval of dapagliflozin for patients with DM to allow for further risk-benefit assessments, particularly concerning the risks of bladder cancer, cardiovascular issues, and liver safety. This delay allowed canagliflozin to become the first SGLT2i approved for use in DM in 2013, followed by the approval of empagliflozin and dapagliflozin in 2014^3,4.

The FDA began requiring clinical trial evidence on cardiovascular outcomes for DM medications after 2008 due to concerns about the cardiovascular risks associated with certain antidiabetic drugs, particularly thiazolidinediones. Empagliflozin was the first SGLT2i to have published cardiovascular effects in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial in 2015, showing a reduction in the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke⁵. The Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DAPA-TIMI 58) and CANagliflozin cardioVascular Assessment Study (CANVAS) trials subsequently confirmed the cardioprotective effects of dapagliflozin and canagliflozin, respectively. Ultimately, the contemporary wave of studies on SGLT2i use in HF lead to the approval of empagliflozin and dapagliflozin for use in HF with reduced ejection fraction (HFrEF) in 2020, and approval for use in HF with preserved ejection fraction (HFpEF) and CKD^6–10.

SGLT2is also represent a key advancement in precision medicine, offering tailored therapeutic benefits across diverse patient populations. Their broad clinical applicability creates the potential to address individual patient profiles, accounting for factors such as variations in renal function, cardiovascular risk, and metabolic conditions. The success of SGLT2is across a spectrum of conditions underscores their ability to target common pathophysiological mechanisms—such as sodium retention, inflammation, and oxidative stress—that contribute to multiple chronic conditions. By integrating SGLT2 inhibitors into precision medicine frameworks, clinicians can enhance patient care by selecting the appropriate therapy based on an individual’s risk factors, comorbidities, and treatment goals, ultimately improving health outcomes across diverse populations.

Nevertheless, further investigations into their clinical utilities are ongoing. This includes research into their specific effects on weight loss, diuresis, anti-arrhythmic properties, anti-steatotic benefits, and anti-hypertensive effects, among others. Despite the growing range of indications, SGLT2i remain under-prescribed, partly due to their cost and clinicians’ comfort levels with these medications¹¹. In this review, we aim to discuss the indications and supporting evidence for the use of SGLT2is, as well as the proposed mechanisms of action for these effects. We also aim to discuss the cost and the reported adverse effects and their relevance to clinical decision making.

Mechanism of action

The kidneys play a major role in glucose homeostasis, as they reabsorb more than 99% of the glucose filtered through the glomeruli. The reabsorption of sodium and glucose in the kidney is driven by the SGLT2 and SGLT1 transporters. SGLT2 is responsible for 90% of the glucose reabsorption and is primarily expressed in the brush border membrane of the S1 and S2 segments of the proximal renal tubule (Supplementary Fig. 1). The remainder of renal reabsorption is attributed to SGLT1 expression on the S3 segment of the proximal renal tubule¹².

The SGLTs maximum transport capacity is dependent upon an individual’s glomerular filtration rate. In healthy adults this filtration rate is approximately 200 mg/dL. Meaning excess glucose above this level cannot be reabsorbed and is excreted¹³. In patients with DM, SGLT2 expression is increased in the proximal renal tubule, therefore increasing the threshold of maximum glucose transport capacity beyond the 200 mg/dL threshold. This leads to enhanced reabsorption by the kidneys and further hyperglycemia^12,13. Inhibiting SGLT2 activity thus decreases renal reabsorption via an insulin-independent action, increasing glucosuria and improving glycemic control when given to patients who have compromised renal function, as in cases of CKD^14,15. The co-transportation of sodium by SGLT2 also causes a subsequent increase in sodium reabsorption with increasing glucose reabsorption. This causes a decreased delivery of sodium to the juxtaglomerular apparatus, ultimately leading to dilation of the afferent arteriole causing hyperfiltration. Thus, the primary effect of SGLT2 inhibition also leads to increased natriuresis and a reduction in kidney hyperfiltration¹⁶.

It is also important to recognize that SGLT2is confer cardiovascular and renal protection through multiple interrelated molecular pathways beyond glycemic control and natriuresis. These will be discussed in subsequent sections in more detail, but generally include pathways involving a shift in cellular energy utilization towards ketone metabolism, suppression of pro-inflammatory cytokines, enhancement of antioxidation and inhibition of TGF-β-mediated fibrosis in the heart and kidneys. Additionally, SGLT2is improve autonomic regulation by reducing sympathetic overactivation and modulating cardiac ion channels to lower arrhythmic risk.

SGLT1 is primarily expressed in the gastrointestinal tract and its activity is the primary means of glucose and galactose uptake into enterocytes¹⁷. Early investigations of SGLT1 inhibition showed that SGLT1 knock-out mice exhibited higher levels of glucagon-like peptide-1 (GLP1) but also suffered from severe diarrhea secondary to glucose and galactose malabsorption. However, the heterozygous mice did not demonstrate these gastrointestinal side effects¹⁷. The SGLT2i class medications all demonstrate varying degrees of selectivity for SGLT2, with empagliflozin being the most selective and canagliflozin being the least selective¹⁷. Dual SGLT2 and SGLT1 inhibitors can demonstrate the beneficial effects of SGLT2 inhibition as well as the benefits of partial SGLT1 inhibition, as is the case with sotagliflozin¹⁸ (Table 1).

Table 1.

SGLTis and associated affinities and selectivities¹⁸⁹

Drug name	Target	Selectivity for SGLT2:SGLT1
Empagliflozin	SGLT2	2500-fold
Ertugliflozin	SGLT2	2235-fold
Dapagliflozin	SGLT2	1200-fold
Canagliflozin	SGLT2	200-fold
Sotagliflozin	SGLT2 and SGLT1	20-fold

SGLT sodium-glucose cotransporter.

Glycemic control and weight loss

SGLT2is have become the standard of care in the treatment of DM due to their multifaceted benefits beyond glycemic control. The primary mechanism by which SGLT2i lower hemoglobin A1c is through glucosuria, which effectively decreases both fasting and postprandial blood glucose levels^16,19,20. Additionally, SGLT2is lower A1c levels by reducing glucotoxicity to improve β-cell function and insulin sensitivity^19,20. Several studies have quantified the degree of A1c reduction and evidence suggests reduction at 1 year is between 0.5% and 0.6%^21–23. The initial reductions of A1c and blood glucose levels are maintained over an extended period despite continuous use²⁴. This durability suggests that longer duration treatment without an increase in dosage is still beneficial. A shift in substrate utilization from carbohydrates to lipids observed with chronic SGLT2i use also contributes to improved glycemic control²⁰. It has also been noted that SGLT2is can reduce fasting plasma glucose levels as early as within one week of treatment initiation²⁴. Unlike insulin or sulfonylureas, which can lower blood glucose regardless of initial levels, SGLT2i optimize glycemic control through glucosuria, which is dependent upon baseline blood glucose levels. Such a mechanism confers a low risk of hypoglycemia with SGLT2is.

Beyond glycemic control, the SGLT2i have demonstrated efficacy in weight loss (Table 2). The CANVAS Program, encompassing the CANVAS and A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R) trials, showed that canagliflozin in patients with DM and high cardiovascular risk was effective in lowering A1c by approximately 0.58% to 0.73% and led to an average weight loss of about 2–4 kg compared to placebo⁷. In parallel, the cardiovascular outcomes trials of dapagliflozin and ertugliflozin suggested a mean weight reduction of approximately 2–3 kg compared to placebo^25,26. Meta-analyses also suggest that the overall weight loss associated with SGLT2is is between 1.79 and 2.36 kg²⁷. Among the various SGLT2is, there is evidence that canagliflozin 300 mg may lead to the most significant weight loss compared to other SGLT2is, with an average of 2.26 kg more than metformin and 2.78 kg more than placebo²⁸. Collectively, these studies highlight the weight loss benefits of SGLT2is in patients with DM, showing consistent results across different agents and dosages.

Table 2.

Average weight loss (kg) of various SGLT2is²⁸

Drug name (mg)	Average weight loss vs placebo (CI 95%)
Canagliflozin 300	2.78 kg (3.09–2.57)
Ertugliflozin 15	2.07 kg (2.74–1.42)
Canagliflozin 100	1.94 kg (2.21–1.59)
Empagliflozin 25	1.82 kg (2.15–1.47)
Ertugliflozin 5	1.80 kg (2.54–1.06)
Empagliflozin 10	1.74 kg (2.07–1.39)
Dapagliflozin 5	1.53 kg (1.89–1.19)

CI confidence interval.

SGLT2is primarily promote weight loss via their primary action of inducing glucosuria, resulting in caloric loss through urine excretion^29,30. Additionally, SGLT2is may also influence weight loss through activation of the liver-brain-adipose neurocircuitry, which promotes lipolysis and depletion of hepatic glycogen stores, thus triggering a signal to the brain, resulting in activation of protein kinase A in adipocytes, ultimately leading to increased fat breakdown³¹. The sustained efficacy of SGLT2i suggests that they can be a reliable long-term therapy for maintaining glycemic and weight control²⁴. The American Diabetes Association (ADA) and American Association for Clinical Endocrinology (AACE) guidance acknowledge the weight loss benefits in their recommendations for managing DM³².

It is also important to recognize that SGLT2is can interact with the gut microbiome to aid in potential treatment of obesity. One key mechanism involves the modulation of the gut microbiota composition. Studies have demonstrated that SGLT2is, such as luseogliflozin and dapagliflozin, increase the prevalence of short-chain fatty acid-producing bacteria in the gut³³. Such fatty acids are known to play a role in energy homeostasis and have anti-obesity effects by promoting satiety and enhancing energy expenditure. Additionally, SGLT2is have been found to alter the metabolic activity of the gut microbiota. For example, luseogliflozin treatment in mice resulted in increased levels of short-chain fatty acids in rectal feces, which are associated with improved metabolic health and reduced adiposity³⁴. These changes in the gut microbiota and their metabolites can influence host metabolism, including enhanced fatty acid oxidation and reduced fat mass. Furthermore, SGLT2is may reduce the production of harmful metabolites by the gut microbiota. For instance, SGLT2is have been shown to lower the relative abundance of bacteria capable of fermenting aromatic amino acids to uremic toxins which are associated with adverse metabolic effects³⁵. Overall, the interaction between SGLT2is and the gut microbiome involves the promotion of beneficial short-chain fatty acid-producing bacteria, alteration of microbial metabolic activity, and reduction of harmful metabolites, contributing to their anti-obesity effects.

Autophagy

While SGLT2is have become a cornerstone therapy in managing DM, it is also worth noting that their benefits extend beyond glucose reduction. Several studies have explored the relationship between SGLT2is and autophagy, uncovering a nuanced interaction that underpins their therapeutic efficacy across a spectrum of indications. There is increasing evidence suggesting that autophagy plays a role in the cardioprotective mechanisms of SGLT2is via a process mediated through adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways³⁶. Similarly, reduction of tubular workload and hypoxia, conditions that promote autophagy, are suggested to be the primary drivers of the nephroprotective effects of SGLT2is³⁷. The SGLT2is modulate signaling pathways involving mammalian target of rapamycin, SIRT1, and HIF and have demonstrated the ability to either activate or suppress autophagy depending on the cellular context, highlighting their role as dynamic regulators³⁸. Of note, the cardioprotective and renoprotective benefits of SGLT2is are significantly reduced when autophagy, AMPK, or sirtuins are inhibited, underscoring their essential role in these protective effects³⁶.

Kidney disease

SGLT2is have demonstrated significantly improved long-term renal outcomes and potential disease-modifying effects in both diabetic and non-diabetic patients with CKD. For instance, the Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial focused on canagliflozin use in patients with DM and CKD. The trial results were striking, showing a 30% reduction in the risk of the composite outcome of end-stage renal disease (ESRD), doubling of serum creatinine, or renal or cardiovascular death³⁹. For dapagliflozin, the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) trial showed that dapagliflozin significantly reduced the risk of a composite renal outcome (≥50% decline in estimated glomerular filtration rate [eGFR], ESRD, or renal/cardiovascular death) by 39% in patients with CKD, including those without DM⁴⁰. The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY) trial further established nephroprotection as a class effect of SGLT2is. The trial demonstrated a reduction in the progression of CKD with empagliflozin⁴¹. Moreover, the nephroprotective effects of SGLT2is have been validated in a meta-analysis with data from 66,601 patients across eight major trials showing significant reduction in the risk of composite renal outcomes by nearly 40%⁴².

While both diabetic and non-diabetic populations benefit from reduced CKD progression and ESRD risk, the mechanisms for renal effects differ vary. In diabetic patients, the glucose-lowering effects primarily contribute to renal protection, whereas in non-diabetic patients, the benefits are likely mediated through hemodynamic changes, reduced intraglomerular pressure, and anti-inflammatory effects. By reducing glomerular hyperfiltration, SGLT2is enhance tubuloglomerular feedback, leading to afferent arteriole vasoconstriction. This vasoconstriction helps alleviate stress on the glomerular filtration barrier^43,44. Additionally, SGLT2is demonstrate anti-inflammatory and antifibrotic effects by decreasing pro-inflammatory markers and inhibiting extracellular matrix accumulation⁴⁵. SGLT2is also lower oxidative stress by reducing pro-oxidant enzyme activity and boosting antioxidant defenses to shield renal cells from harm⁴⁶. Moreover, SGLT2is improve renal hemodynamics by temporarily decreasing eGFR to prevent maladaptive hyperfiltration. SGLT2is also induce a metabolic shift towards lipid and ketone body utilization, which may enhance renal cell function and modulate the complement system to mitigate renal inflammation and damage^47–49. The effects have shown prominence in even the later stages of CKD3b and CKD4 in patients with DM, with a reduction in risk of primary kidney outcomes by nearly 35%, as well as an overall slower decline by 35%⁵⁰. Ongoing data from trials like EMPA-KIDNEY continues to evaluate the long-term effects of SGLT2is on CKD progression and cardiovascular mortality in patients with CKD, regardless of DM status⁵¹. These studies collectively highlight the significant nephroprotective effects of SGLT2is and have been incorporated into clinical guidelines, as evidenced in the ADA and AACE⁵². Current ADA and Kidney Disease: Improving Global Outcomes guidelines now recommend SGLT2is as the first-line treatment for patients with DM and CKD who have an eGFR of at least 20 mL/min/1.73 m², and in some cases, even if the eGFR level drops below this threshold⁵².

Beyond benefits in CKD, SGLT2i have demonstrated safety in kidney transplant recipients. Consistent with the non-transplanted populations, kidney transplant recipients have a demonstrated 68% reduction in the risk of all-cause mortality, and a 52% reduction in the risk of cardiovascular endpoints⁵³. The effect is demonstrated without increasing a composite risk of dialysis, re-transplantation, acute kidney failure, or acute rejection⁵⁴. A separate study involving diabetic kidney transplant recipients indicated that SGLT2is improved graft function and reduced the risk of graft failure, all-cause mortality, and serum creatinine doubling. These findings suggest that SGLT2is can be safely used in kidney transplant recipients, potentially offering renoprotective benefits similar to those observed in non-transplant populations⁵⁵. Nevertheless, true randomized controlled trials are warranted to provide insight into SGLT2i use for this patient population.

Heart failure

Clinical trials examining cardiovascular outcomes of SGLT2is in the setting of DM consistently demonstrate a reduction in HF hospitalizations⁵⁶. This prompted studies on SGLT2i use in patients with HF, regardless of DM status. The Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) and the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trials were large outcome-based trials investigating dapagliflozin and empagliflozin, respectively, in reducing worsening HF in symptomatic patients with HFrEF. Both medications demonstrated efficacy in reducing the composite outcome of cardiovascular death and HF hospitalization by approximately 25%, with an impressive reduction in hospitalization for HF by 30%^8,57. The counterpart study for canagliflozin, the effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in DM and HF with reduced ejection fraction (CANA-HF) study, was set to investigate the cardiovascular effects of canagliflozin over sitagliptin in HFrEF patients, but was terminated early after DM guidelines began to recommend SGLT2is over dipeptidyl peptidase-4 (DPP-4) inhibitors⁵⁸. In patients with reduced left ventricular ejection fraction (LVEF), a recent meta-analysis and systematic review investigated the effects of each combination of guideline-directed therapy in the treatment of HFrEF. Authors found the combination of angiotensin receptor neprilysin inhibitor, beta blocker, mineralocorticoid receptor antagonist, and SGLT2i to be the most effective combination, reducing the risk of cardiovascular mortality or HF hospitalization by over 60%⁵⁹. These studies led to the FDA approval of empagliflozin and dapagliflozin for use in HFrEF, and the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) 2022 guidelines designated a class 1a recommendation for SGLT2i use in patients with chronic HFrEF, as well as in patients with DM and cardiovascular disease (CVD)⁶⁰. The dual SGLT1 and SGLT2 inhibitor, sotagliflozin, is also FDA-approved for treatment of HF, as it has also demonstrated a 28% reduction of cardiovascular death or hospitalization of HF in patients with HFrEF and DM, when compared to placebo⁶¹. Furthermore, the selective SGLT2i ertugliflozin was investigated in the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS CV) trial, where it demonstrated efficacy in reducing HF hospitalizations, although no benefit was observed in reducing cardiovascular-related deaths²⁶. Subsequently, SGLT2is, notably dapagliflozin, empagliflozin, and sotagliflozin, have become a cornerstone in the management of patients with HFrEF, particularly those with DM.

The therapeutic options for management of patients with HFpEF are fewer than those with HFrEF. Before the integration of SGLT2is, only mineralocorticoid receptor antagonists and angiotensin-neprilysin inhibitors had demonstrated any degree of efficacy, and results were not enough to warrant strong recommendations in HF guidelines⁶⁰. The Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved) trial sought to investigate if the benefits of empagliflozin established in HFrEF extended to those with HFpEF. The study demonstrated strong statistical significance in reducing the risk of readmission for decompensated HF by 29% compared to placebo; however, it did not demonstrate efficacy in reducing mortality⁶². The Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial sought similar evidence for dapagliflozin and found that dapagliflozin reduced worsening HF compared to placebo, however, it also did not reduce the risk of cardiovascular death⁶³. After the Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial demonstrated improved outcomes across the spectrum of LVEF in patients with DM, sotagliflozin is actively being investigated for utility in patients with HFpEF regardless of DM status in the active Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial^61,64. For SGLT2is as a whole, a 2022 meta-analysis investigating the use of empagliflozin, dapagliflozin, and sotagliflozin for use in patients with HFpEF found a 15% decrease in serious adverse events in patients receiving SGLT2is compared to placebo⁶⁵. Given the lack of medical options with established benefit in HFpEF, the emergence of SGLT2is has invigorated studies exploring the mechanisms of their benefits in this patient population. These investigations have suggested the benefit is due to efficacy in reducing epicardial adipose tissue, aortic stiffness, and interstitial fibrosis, as well as improving cardiac mass and contractility⁶⁶. However, further studies are warranted.

With regards to precision medicine and HF treatment with SGLT2i, it is worth mentioning the role of specific biomarkers that may predict patient response and efficacy with SGLT2is. For example, biomarkers such as N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-cTnT) have been shown to decrease with SGLT2i therapy, indicating improved cardiac function and reduced myocardial stress^67,68. Additionally, inflammatory markers like interleukin-6 and tumor necrosis factor-1 are reduced, suggesting anti-inflammatory benefits⁶⁸. Elevated baseline levels of NT-proBNP and hs-cTnT may identify patients who derive greater benefit from SGLT2is.

Timing of initiation in HF

There is strong evidence supporting the early initiation and inpatient uptitration of Guideline-Directed Medical Therapy (GDMT) in HF patients, demonstrating significant improvements in survival rates and reductions in HF readmissions⁶⁹. Moreover, SGLT2is have been found to provide benefits in cardiovascular mortality or worsening HF as early as 26 days post-initiation⁷⁰. The mechanisms of action of SGLT2is imply a degree of natriuretic and diuretic effects, leading to a reasonable hypothesis that initiation in patients with acute decompensated HF could improve decongestion. The EMPagliflozin in patients hospitalized with acUte heart faiLure who have been StabilizEd (EMPULSE) trial investigated the efficacy of initiating empagliflozin in patients experiencing an acute decompensation and found a significant benefit over placebo in reducing symptoms and cardiovascular outcomes across a range of LVEF⁷¹. Similarly, a post hoc analysis of the SOLOIST-WHF study found that initiating sotagliflozin prior to discharge reduced 90-day all-cause mortality risk by 60% and the risk of cardiovascular death or HF event by 55%⁷².

Natriuresis, diuresis

Following the established benefits of SGLT2is in HF, one proposed mechanism for their advantage is enhanced diuresis. Such an effect of SGLT2is, combined with loop diuretics, has been investigated for improved diuresis and natriuresis. SGLT2is reduce the reabsorption of sodium and glucose in the proximal tubule which would, theoretically, enhance the effect of loop diuretics to excrete sodium and free water by decreasing the gradient between the distal tubular fluid and the interstitium.

The SGLT2 Inhibition in Combination With Diuretics in Heart Failure (RECEDE-CHF) trial was a randomized, double-blind, placebo-controlled, crossover trial assessing the diuretic effect of empagliflozin in combination with loop diuretics. Although limited by small sample size, the trial did find a significant increase in 24-h urine volume at day 3 (mean difference, 535 mL [95% confidence interval (CI), 133–936]; p = 0.005) and week 6 (mean difference, 545 mL [95% CI, 136-954]; p = 0.005). However, the effects on natriuresis were transient, with no change in 24-h urinary sodium at 6 weeks⁷³. The transient natriuresis effects have been reproduced in several other clinical trials, with ranges from no increase in sodium excretion to a return to baseline sodium excretion in 3 months^74–76. The rebound effect, however, does not extend to the glucosuria⁷⁷. Consistent with the results found in the RECEDE-HF trial, increases in total urine volume after use of SGLT2i have remained ubiquitous^78–80. Nevertheless, there is evidence that this increase diminishes with time and is related to the decrease in natriuresis, as well as an increase in urea solutes and water reabsorption mediated by vasopressin⁸¹.

Loop diuretic resistance via several mechanisms have been described, including the “braking phenomenon,” post diuretic effect, rebound sodium retention, and renal adaptation. Consequently, supplementation of loop diuretics with thiazide diuretics have been studied and applied in clinical practice as a method to inhibit distal sodium reabsorption, interfering with the renal adaptation to chronic loop diuretic therapy and improving diuresis and natriuresis^82,83. In patients with loop diuretic resistance, SGLT2is have augmented the use of loop diuretics but do not demonstrate any increase in body weight reduction or total urine volume as compared to metolazone with loop diuretics⁸⁴. Current evidence suggests that SGLT2is can be used early in HF treatment to assist with decongestion but should not be relied upon as a chronic or sole decongestive therapy.

Anti-arrhythmic effects

Another potential benefit of SGLT2is is their antiarrhythmic effect. The Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) trial demonstrated that amongst individuals with DM, dapagliflozin reduced the incidence of atrial fibrillation (AF) and atrial flutter (AFL) by 19%, and all AF/AFL events by 23%, compared to placebo, regardless of baseline CVD, HF, or AF status^85–87. One meta-analysis noted that SGLT2is can reduce the risk for AF and embolic stroke risk in patients with DM, irrespective of baseline HF or CKD. However, there was only a modest reduction in AFL and no significant risk reduction in cardiac arrest⁸⁷. This effect has been shown to persist until at least 1-year follow-up in patients with DM and CVD⁸⁸. Dapagliflozin has also been shown to reduce re-occurrence rate of atrial arrythmias following catheter ablation by nearly 50%, and to reduce the risk for cardioversion, initiation of new antiarrhythmic agents, or the need for repeat ablation^86,89–91. In head-to-head comparisons with the DPP-4 inhibitor anagliptin, tofogliflozin reduced the rates of atrial arrhythmias post-catheter ablation by nearly 50%. Additionally, when compared to glucagon-like peptide 1 (GLP-1) receptor agonists, SGLT2is were associated with a modest reduction in new-onset AF, indicating that factors beyond glycemic control contribute to the reduction in atrial arrhythmias^89,92,93. Conversely, the effect of SGLT2is on ventricular arrythmias is conflicting. A large meta-analysis including 60,594 patients noted similar positive results on AF burden but showed no improvement in ventricular fibrillation or cardiac arrest. Among individuals with remote cardiac monitors in place, there was no improvement in ventricular tachycardia (VT) events^94–96. Contrarily, a large meta-analysis with 52,115 patients showed a 27% reduction in VT compared to placebo with use of SGLT2is. This suggests prospective randomized controlled trials are needed to further investigate the effects of SGLT2is on ventricular arrhythmias⁸⁷.

The mechanism by which SGLT2is reduce the risk for incident AF and recurrence is unclear. Hypothesized mechanisms include their effect on reducing cardiac hypertrophy, decreasing inflammation and apoptosis, and activating antioxidant enzymes while reducing hypoxia biomarkers. Given the small amount of SGLT-2 expression in myocardial tissue, direct inhibition of these channels is unlikely to contribute to reduced arrythmogenicity^86,97,98. SGLT2is have also been shown to reduce uric acid, a known activator of the NOD-like receptor protein 3 (NLRP3) inflammasome, and to improve magnesium reabsorption in the kidneys, ultimately preventing the arrhythmogenicity of hypomagnesemia⁹⁹. Additionally, in vitro studies suggest SGLT2is may inhibit a Na⁺/H⁺ exchanger (NHE-1) that normally promotes fibrosis and contributes to electrical remodeling of atrial monocytes. SGLT2is may also enhance the phosphorylation of AMPK, which has previously been shown to improve mitochondrial function and to reduce mitochondrial dysfunction during AF^86,100–103. Further evidence is needed to determine the exact mechanisms reasons behind the anti-arrhythmic properties of SGLT2is.

Preventing ischemia

In recent years, compelling evidence supports the use of SGLT2is for reducing ischemic myocardial injury and consequent cardiac dysfunction. A large meta-analysis demonstrated a statistically significant reduction in the incidence of MI in patients treated with SGLT2is in comparison to placebo, suggesting a direct cardioprotective effect beyond glycemic control¹⁰⁴. Another meta-analysis showed that SGLT2is reduced the occurrence of ischemic events, including those related to coronary artery disease (CAD)¹⁰⁵. SGLT2is also have been proposed to have a direct effect on attenuating the impact of ischemic reperfusion injury after MI. One study showed that non-diabetic rats with induced MI, when treated with empagliflozin, had significant improvements in cardiac function, with reductions in infarct size, improved left ventricular (LV) function, and reduced amount of myocardial fibrosis¹⁰⁶. The underlying mechanism is still unclear, but proposed mechanisms include improved myocardial energetics, reductions in oxidative stress, and enhanced autophagy, all of which contribute to improved preservation of viable myocardium following ischemic reperfusion injury¹⁰⁶. Converging evidence from animal models and large meta-analyses highlight the potential of SGLT2is in reducing the risk for MI, and the deleterious impact of MI on myocardial anatomy and functioning. As such, the anti-ischemic effects of SGLT2is represent a promising avenue for patients for ischemic cardiac disease.

Post-MI

MI remains one of the leading causes of morbidity and mortality affecting adults worldwide. However, identifying new medications that reduce the risk of developing HF post-MI have waned in recent years¹⁰⁷. After demonstrating improved cardiovascular outcomes, SGLT2is were a reasonable target for further investigations in this patient population.

The Dapagliflozin Effects on Cardiometabolic Outcomes in Patients With an Acute Heart Attack (DAPA-MI) trial was a recent landmark trial assessing the efficacy of dapagliflozin in reducing the 1-year risk of cardiovascular and metabolic outcomes in patients presenting with acute MI and reduced LV systolic function. The primary outcome was a composite of reduced death, hospitalization for HF, non-fatal MI, AF/AFL event, new DM diagnosis, New York Heart Association (NYHGA) functional classification, and body weight decrease of 5%. The study noted a 34% improvement in cardiometabolic outcomes in patients receiving dapagliflozin. However, the statistical significance fades when outcomes for the body weight decrease, NYHA classification, and new DM are excluded from the composite¹⁰⁸. To further assess the efficacy of SGLT2is post-MI, the Streamlined, Multicentre, Randomised, Parallel Group, Double-blind Placebo-controlled Superiority Trial to Evaluate the Effect of EMPAgliflozin on Hospitalisation for Heart Failure and Mortality in Patients With aCuTe Myocardial Infarction (EMPACT-MI) trial assessed the impact of empagliflozin vs placebo in acute MI and newly developed LVEF <45% or signs of congestion. The trial also required an additional risk factor for HF including: age over 65, LVEF <35%, previous MI, history of AF or DM, eGFR <60, elevated uric acid or natriuretic peptide levels, elevated pulmonary artery pressure or right ventricular systolic pressure, three-vessel CAD, peripheral artery disease, or those who did not undergo revascularization for their index event¹⁰⁹. Results showed no improvement in the composite outcome of reducing the risk for a first hospitalization for HF or all-cause death¹⁰⁹. Limitations to both trials included lower than expected event rates, and both took place during the coronavirus disease pandemic, which may have impacted several different methods used to monitor data.

SGLT-2is, despite their lack of significant impact post-MI in the DAPA-MI and EMPACT-MI trials, have been shown to improve parameters of cardiac remodeling. A meta-analysis of 1343 patients suggested that SGLT2is, in particular empagliflozin, improved several parameters such as heart rate, left atrial volume index, LV mass index, LV end-systolic volume, and LVEF, particularly in patients with HF¹¹⁰. In patients with prior MI, meta-analyses have shown that addition of SGLT2is reduces major adverse cardiovascular events (MACE) and hospitalization due to HF¹¹¹. SGLT2is also improve other parameters including global longitudinal strain, left-ventricular end diastolic volume, and E/e’; However, such evidence was not obtained from individuals in the post-MI setting¹¹². Regardless, these trials may indicate benefits for some cardiac remodeling parameters but so far the lack of translation to clinical trial raises doubts about such efficacy. Future studies are needed to further elucidate the role, if any, that SGLT2is may play in the protection against cardiac remodeling.

Hypertension

In addition to the benefits for DM, CKD, and HF, SGLT2i have been shown to have a modest impact in reducing blood pressure. Several mechanisms have been proposed to explain the anti-hypertensive effects. One proposed mechanism is through osmotic diuresis which is a byproduct of SGLT2i-mediated glucosuria as the SGLT2 couples the transport of both glucose and sodium together. By inhibiting the resorption of glucose and sodium, there is an osmotic diuresis which decreases overall plasma volume, leading to a decrease in systemic blood pressure^113,114. This alone likely does not account for all the anti-hypertensive effects, as patients with CKD, where reduced eGFR limits the effects of osmotic diuresis, still experience some blood pressure reduction¹¹⁵. Additionally, it is proposed that SGLT2is impact the renin–angiotensin–aldosterone system through increased delivery of sodium in the nephrons, however, data has been mixed without consistent support for this theory^116–118. Furthermore, weight loss has long been shown to have a linear association with reductions in blood pressure¹¹⁹. SGLT2is are known to induce weight loss, which has been shown to account for up to 42% of the blood pressure reduction seen with these agents¹²⁰. A final proposed mechanism is the reduction in arterial stiffness, as demonstrated in several studies, though the exact mechanism behind this effect remains unclear¹²¹.

Several trials have quantified the degree of blood pressure reduction with SGLT2is. One large meta-analysis noted a small mean reduction of systolic blood pressure (SBP) of 3.46 mmHg when compared against placebo. Of note, this analysis showed no significant difference in SBP among patients without DM who received SGLT2is¹²². The CREDENCE trial evaluated canagliflozin in patients with DM and renal dysfunction and found a 3.5 mmHg SBP reduction¹²³. Further trials such as the SGLT-2i and ARB Combination Therapy in Patients With T2DM and Nocturnal Hypertension (SACRA Study) and the 12 Week Efficacy and Safety Study of Empagliflozin (BI 10773) in Hypertensive Patients With Type 2 Diabetes Mellitus (EMPA-REG BP) showed mean reduction in SBP of 5.5–10 mm Hg with empagliflozin^124,125. As a comparison, SBP reduction with angiotensin receptor blocking agents has been shown to be ~8 mmHg¹²⁶. Mineralocorticoid receptor antagonists average a reduction of 6.8–9.4 mmHg in SBP^127,128 while beta blockers average a reduction of 10 mmHg¹²⁹. Thiazide diuretics average a SBP reduction of 4–11 mmHg. Despite evidence of similar antihypertensive efficacy in patients with DM, SGLT2is are not currently approved for use as a primary treatment for hypertension¹³⁰.

Anti-inflammatory effects

DM is associated with increased levels of systemic inflammation which factor into negative downstream complications such as renal disease and CVD¹³¹. Another significant benefit of SGLT2is includes their anti-inflammatory properties, which may play a role in their overall organ-protective impact. SGLT2is’ impacts on inflammatory biomarkers such as C-reactive protein (CRP), ferritin, leptin, adiponectin, and others have been studied in randomized controlled trials. One large meta-analysis including 34 studies and over 6000 patients showed significant reductions in CRP levels compared to placebo but not when compared to other DM medications. Furthermore, ferritin was shown to decrease with SGLT2is when compared to placebo and other DM medications. SGLT2is also demonstrated reduction in leptin leptin levels, but not when compared to other DM medications¹³². These effects indicate that while controlling hyperglycemia through any means reduces overall inflammation, SGLT2is also possess independent anti-inflammatory properties. Some proposed mechanisms include an AMPK-dependent inhibition of the release of inflammatory cytokines^133,134, modulation of the inflammasome NLRP3¹³⁵, upregulation of autophagy¹³⁶, and increased conversion of macrophages to anti-inflammatory subtypes¹³⁷. Beyond molecular reduction of inflammation, SGLT2is have demonstrated beneficial alterations to the human microbiota leading to reduction in systemic toxin production³⁵. Additional studies are in progress which may aid in the understanding of other pathways and better explain anti-inflammatory effects in patients without DM.

Liver anti-steatotic effects

Hepatic steatosis, the accumulation of fat in the liver, is a hallmark of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). DM and obesity are both strongly associated with NAFLD, posing the highest risk for its progression to NASH with advanced hepatic fibrosis^138,139. Due to SGLT2i efficacy in reducing insulin resistance and improving glycemic control, they have potential to be a promising treatment option for NASH/NAFLD by reduction of hepatic fat accumulation¹⁴⁰. SGLT2is also have the potential to improve other metabolic parameters such as body weight, blood pressure, and serum uric acid which can all contribute to improved liver health¹⁴¹. Using magnetic resonance imaging (MRI), the extent to which SGLT2is such as dapagliflozin, empagliflozin, and canagliflozin can treat NAFLD/NASH has been assessed in the following trials on patients with DM. Latva-Rasku et al. treated patients with dapagliflozin over 8 weeks and noted a 13% relative reduction in liver fat content¹⁴². Similarly, Kahl et al. reported a 22% reduction in liver fat after 24 weeks of empagliflozin treatment¹⁴³, and Gaborit et al. observed a 25% reduction after 12 weeks of therapy¹⁴⁴. Cusi et al.’s study on canagliflozin also showed an 18% reduction in hepatic triglyceride content over 24 weeks¹⁴⁵. All of these trials exhibited a statistically significant reduction in liver steatosis with SGLT2is when compared to placebo (Table 3).

Table 3.

Reduction in steatosis with SGLT2is vs placebo

Study	Agent	Duration (weeks)	Reduction of steatosis (%)
Latva-Rasku et al.	Dapagliflozin	8	13
Kahl et al.	Empagliflozin	24	22
Gaborit et al.	Empagliflozin	12	25
Elhini et al.	Empagliflozin	24	31

These reductions in hepatic fat content were often accompanied by improvements in other metabolic parameters, including weight (around 2–7%), liver function tests, and glycemic control. However, there is currently a shortage of placebo-controlled trials analyzing the histological outcomes of SGLT2i treatment in NAFLD/NASH. Nevertheless, MRI-based quantification suggests that SGLT2is are a promising therapeutic option for managing NAFLD/NASH, particularly in patients with DM¹³⁸.

Vascular function

DM is also highly associated with the development micro- and macrovascular disease, which can lead to further complications including retinopathy, neuropathy, nephropathy, as well as atherosclerosis and CVD¹⁴⁶. Given this range of complications, another important impact of SGLT2is beyond blood glucose control is their role in improving vascular function. This effect has been demonstrated in a meta-analysis of 11 studies and 868 patients showing significant improvement in flow-mediated vasodilation, a marker of vascular function¹⁴⁷. Furthermore, an analysis of 24 preclinical studies showed similar improvement in endothelial dysfunction and shed some light on the mechanism of glucose-independent endothelial benefit¹⁴⁸. SGLT2is have also been shown to increase the amount of circulating nitric oxide (NO) as hyperglycemia decreases endothelial nitric oxide synthase expression. SGLT2is, through glucosuria, increase NO release that allows for improved vasodilation, and anti-inflammatory activity of endothelial tissues^149–151. Another important impact includes the anti-inflammatory effects of SGLT2is in the endothelium^133–137. They have been shown to decrease the production of endothelial reactive oxygen species (ROS)^152,153. This reduces ROS-mediated endothelial damage and improves vascular function. SGLT2is have also been shown to be protective of the endothelial lining called the glycocalyx¹⁵⁴. The glycocalyx is created from proteoglycans, among other molecules, and when present, decreases vascular permeability and susceptibility to circulating inflammatory cells¹⁵⁵. Furthermore, SGLT2is have exhibited the ability to reduce the impact of DM on the progression of arterial stiffness seen through arterial pulse pressure and pulse wave velocity^121,156. While some of these mechanisms primarily impact patients with DM, others may be present in all patients receiving SGLT2is, potentially explaining part of their cardioprotective and renoprotective benefits.

While there have been consistent cardioprotective and renoprotective vascular effects, some signals towards negative vascular effects have been noted in literature. Specifically, a 30% increase in the risk for non-fatal stroke had been noted in a 2016 meta-analysis with a proposed possible mechanism of hemoconcentration¹⁵⁷. The effect, however, has not been sustained as a recent meta-analysis by Pasqualotto et al. found no significant difference in the incidence of all types of strokes (relative risk (RR) 0.96; 95% CI 0.89–1.04)¹⁵⁸. As a further evidence of benefit in neurologic vascular health, SGLT2is are associated with a pronounced 31% decreased risk in the development of vascular dementia¹⁵⁹. In spite of the physiologic mechanisms for vascular protection, there does appear to be an 83% increased risk of peripheral artery disease in long-term (>100 weeks) treatment groups, with a 68% increase in the risk of amputation in long-term treatment groups¹⁶⁰.

Malignancy

Early concerns were raised about signals towards an increased risk of bladder cancer in males and breast cancer in females in those treated with dapagliflozin, which had been attributed to impaired diagnosis prior to randomization rather than a true causal effect¹⁶¹. Since then conflicting evidence has been found regarding SGLT2is and cancer risk. In a 2017 systematic review, no association with overall cancer had been found, however there were increased odds of developing bladder (odds ratio (OR) 3.87; 95% CI 1.48–10.08) while no statistical significance in breast cancer was isolated (OR 1.68; 95% CI 0.87–3.22)¹⁶¹. A later 2024 meta-analyses continued to show no change in the overall incidence of cancer, with a contradictory 47% decrease in the risk of bladder cancer with dapagliflozin use (RR 0.53; 95% CI 0.35–0.81, p = 0.003)¹⁶². Mendelian randomization studies performed with the intent to alleviate the controversy ultimately demonstrated mixed effects within cancer subgroups, with a 1.8% increased risk of bladder cancer, a 195.6% increased risk of prostate cancer, a 2.8% decrease in bronchial and lung cancer, among other findings¹⁶³.

Mechanistically, glycemic control affecting cell proliferation ascribes the main overall reduction in cancer effects, while sub-group specific environments such as dysplastic urothelial changes may explain the potential increase demonstrated by mendelian studies¹⁶³. Given the contradictory findings of specific cancer types with SGLT2i treatment and mendelian randomization studies demonstrating possible causality, further long-term investigations are warranted.

Cost-efficacy

The widespread use of SGLT2is has led to investigations into their overall cost effectiveness. For use in HFpEF, an incremental cost effectiveness ratio (ICER) of $141,200 per quality-adjusted life-year (QALY) was found, giving the medication an intermediate-to-low score by the ACC/AHA value framework^164,165. For use of dapagliflozin in HFrEF, there is an ICER of $68,300 per QALY gained over standard of care, which would give the intervention an intermediate score by ACC/AHA standards¹⁶⁶. Across the spectrum of LVEF, dapagliflozin demonstrated an ICER of $85,554 per QALY for use in HF with any LVEF when utilizing the full Medicare cost¹⁶⁷. However, in China the ICER is significantly lower, averaging about $124.03 per QALY gained for use of dapagliflozin or empagliflozin in HFrEF¹⁶⁸. The discrepancy in United States cost effectiveness against effectiveness in other countries spans the breadth of SGLT2i indications (Supplementary Table 1). This exemplifies that despite the demonstrated efficacy of SGLT2is in HF, the cost of the medications in the United States may limit their overall potential value.

The cost-effectiveness of SGLT2is is, however, improved when used for the population with DM rather than the population with HF. There is widespread evidence for the use of SGLT2is as a second-line medication in the use of DM¹⁶⁹. For United States payers, there is an ICER of $6967 per QALY in the use of empagliflozin as second line therapy for DM over sitagliptin. The cost effectiveness was further improved when stratified for patients with and without CVD (ICER $3,589/QALY vs $12,577/QALY respectively)¹⁷⁰. Similar results are demonstrated with the investigation of SGLT2is over sulfonylureas. However, there is no cost-effectiveness advantage for the use of SGLT2is over metformin for first-line therapy in DM. An analysis found an ICER of $478,000 per QALY for the use of SGLT2is over metformin as first-line therapy, noting that SGLT2i costs would need to be reduced by 70% to meet a willingness to pay threshold of $150,000 per QALY¹⁷¹. For use in CKD, SGLT2is have demonstrated themselves to be cost-effective options to the addition to standard of care in the United States. This has been demonstrated in patients with both diabetic CKD ($25,974 per QALY) and in patients with non-diabetic CKD ($60,000 per QALY)^172,173.

With the significant cost burden of empagliflozin and dapagliflozin under full Medicare, the medications have been selected for the first ever round of cost negotiations by the Medicare Drug Price Negotiation program for the year of 2026. However, more policy changes would be required to match the cost-effectiveness demonstrated by countries like the UK, Japan, Australia, and China (Supplementary Table 1).

Side effects and adverse events

SGLT2is are generally well tolerated and associated with mild adverse effects. The predominant risk of SGLT2is is the association with genitourinary tract infections, typically secondary to the increase in glucosuria^65,174. The odds ratio of contracting a genitourinary infection with SGLT2i use over placebo has been shown to range between three and six depending on population and medication selection^65,174,175. There does not seem to be a significant difference in genitourinary infection risk between individual SGLT2is such as dapagliflozin, empagliflozin, and canagliflozin¹⁷⁵.

One of the more rare but serious adverse events reportedly associated with SGLT2is is Fournier’s gangrene¹⁷⁶. Fournier’s gangrene refers to a rare necrotizing infection of the genitalia, perineal, and perianal regions¹⁷⁷ However, a large case-control study found no statistically significant association between SGLT2is and Fournier’s gangrene, consistent with findings from the DECLARE-TIMI 58 trial, raising doubts to the suspected association^6,178. A second severe side effect frequently discussed with SGLT2is is the risk for diabetic ketoacidosis (DKA). The classic example of an SGLT2i-associated DKA is a euglycemic or mildly hyperglycemic DKA, with glucose levels often <200 mg/dL. The suspected mechanism is threefold: increased ketone body formation due to lower blood glucose, increased ketone body formation secondary to lipolysis, and increased ketone body reabsorption¹⁷⁹. However, recent meta-analyses have not found an increased risk of DKA with SGLT2i use¹⁸⁰. Similarly, there has been a suggested association between SGLT2i and amputations and fractures, noted predominantly in the CANVAS program; however, this relationship has not been supported in meta-analyses^7,181.

Future directions

As aforementioned, recent meta-analyses have consistently demonstrated the cardiovascular and renal benefits of SGLT2is beyond diabetic populations. Tsai et al. highlighted their efficacy in non-diabetic patients, showing reductions in cardiovascular death, HF hospitalizations, and improved renal outcomes¹⁸². Ali et al. reinforced these findings, confirming significant reductions in cardiovascular and all-cause mortality, MACE, HF hospitalizations, and kidney composite outcomes¹⁸³. Karakasis et al. reviewed 36 systematic analyses, demonstrating improved cardiovascular outcomes and enhanced quality of life in patients with HFpEF or HFrEF¹⁸⁴. Similarly, Giugliano et al. analyzed 11 cardiovascular outcome trials and reported consistent benefits in reducing cardiovascular death, HF hospitalizations, and renal complications in both diabetic and non-diabetic patients⁴². Collectively, these studies underscore the broad therapeutic potential of SGLT2 inhibitors beyond glycemic control.

Despite robust evidence and guideline endorsements, the underutilization of SGLT2is remains a concern, particularly among non-diabetic populations. A survey targeting nephrologists revealed that only 37% prescribed SGLT2is to more than half of their non-diabetic CKD patients with proteinuria¹⁸⁵. Barriers identified include concerns about potential adverse effects, such as mycotic genital infections and euglycemic diabetic ketoacidosis, as well as a lack of familiarity with the indications for SGLT2is in non-diabetic patients.

To enhance the appropriate prescription of SGLT2 inhibitors, especially in non-diabetic individuals, clinicians can adopt a structured decision-making framework. Patient assessment should begin with identifying high-risk individuals, including those with HF or CKD, regardless of DM status, while also considering comorbidities such as CVD, hypertension, or proteinuria that may benefit from SGLT2 inhibition. The next step involves a thorough risk-benefit analysis, evaluating the low absolute risk of adverse events, such as genital infections and euglycemic ketoacidosis, while also considering contraindications like recurrent urinary tract infections or severe hypersensitivity reactions. Effective implementation requires targeted education for healthcare providers on the expanded indications and safety profiles of SGLT2is, fostering collaboration among primary care physicians, cardiologists, nephrologists, and endocrinologists to optimize patient selection and management. Additionally, patient engagement through education and shared decision-making is essential to dispel misconceptions and enhance adherence.

There is also significant potential for precision medicine to further aid in patient selection for SLGT2i therapy. Precision medicine aims to tailor treatments based on based on genetic, metabolic, and clinical patient factors. For instance, genetic profiling may identify variants in certain genes related to glucose metabolism or transport that may allow prediction of individual responses, while pharmacogenomic testing could assess drug metabolism pathways and potential risks like euglycemic diabetic ketoacidosis. Biomarker-guided therapy using circulating markers may help stratify patients who would derive the most cardiovascular and renal benefits, with personalized dosing based on renal function. Additionally, artificial intelligence-driven predictive models integrating electronic health records and real-world data could refine risk stratification and optimize patient selection, particularly in non-diabetic populations. Additionally, precision medicine could help identify non-diabetic HF and CKD patients who would benefit most from SGLT2is based on hemodynamic profiles. Moreover, microbiome-driven approaches may reveal how gut microbiota composition influences drug response, enabling microbiome-based interventions to improve efficacy. By integrating genetics, biomarkers, artificial intelligence, and novel clinical applications, precision medicine could further refine the role of SGLT2is, ensuring their optimal use in diverse patient populations.

In addition to combating underutilization of SGLT2is in clinical practice, the medical community should continue to investigate SGLT2i uses beyond DM, CKD, NAFLD, and HF. For instance, SGLT2is are being explored as adjuncts in weight management for obesity, particularly benefiting patients without DM. Moreover, their effects on insulin resistance and weight reduction make them potentially beneficial for polycystic ovary syndrome. In addition, given their cardiovascular benefits, SGLT2is are being considered for peripheral artery disease as well, where they could improve functional outcomes. Additionally, preliminary evidence hints at neuroprotective effects that may lower stroke risk and cerebral inflammation, especially in DM patients, as well as reducing risk of developing dementia and Alzheimer disease¹⁵⁹. There is even speculation that SGLT2is could reduce certain cancer risks, such as breast and colon cancer, by lowering hyperglycemia and insulin levels, though this area requires further research. Investigations into SGLT2i and GLP-1 agonists in the treatment of NAFLD are underway as well¹⁸⁶. Preliminary studies suggest that SGLT2is may even have benefits in conditions such as kidney stone prevention, anemia, and possibly in non-cardiometabolic disorders like sepsis and cirrhotic ascites^187,188. Collectively, these effects could make SGLT2 inhibitors a valuable part of future therapeutic strategies for a broader range of conditions.

Conclusion

In conclusion, SGLT2is have emerged as a transformative class of medications with broad clinical utility for DM, HF, and CKD. Initially developed for blood glucose management, these medications have demonstrated benefits beyond glycemic control, including cardioprotective and nephroprotective effects. Contemporary clinical trials have consistently shown their efficacy in reducing hospitalizations for HF and slowing the progression of CKD, making them the standard of care (Supplementary Table 2). Ongoing research continues to explore their potential in additional therapeutic areas. Despite their proven benefits, SGLT2i remain under prescribed, partly due to cost and clinicians’ familiarity with these medications. As evidence grows, it is crucial for healthcare providers to consider SGLT2is as a component of GDMT for patients with DM, HF, CKD, and associated comorbidities.

Author contributions

P.M., J.B., E.T.W., S.C., N.N., and M.K. wrote the main manuscript text and prepared figure. Y.M., A.R., R.S., Y.B., C.J.L., S.V., K.E.H., W.H.W.T., T.A., S.I., and C.K. critically reviewed and extensively edited the manuscript. All authors reviewed the manuscript.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s44324-025-00068-z.