SGLT2 inhibitor role in cardio-metabolic-renal diseases: a narrative review of recent evidence and their pharmacological, clinical and economic implications

Abstract

Cardio-metabolic-renal (CMR) conditions, including type 2 diabetes mellitus, cardiovascular disease and chronic kidney disease, represent some of the most pressing public health challenges of the 21st century. In recent years, sodium–glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) have emerged as promising therapeutic agents across these interconnected disease areas. In Europe, the four currently approved SGLT2is for the treatment of type 2 diabetes mellitus — dapagliflozin, empagliflozin, canagliflozin and ertugliflozin — all have demonstrated cardiovascular and renal benefits in large cardiovascular outcomes trials. Notably, empagliflozin and dapagliflozin have also received approval for the treatment of heart failure and chronic kidney disease. This narrative review provides an overview of the role of SGLT2is in the management of CMR diseases. Overall, SGLT2is have demonstrated consistent cardiovascular safety and clinically meaningful benefits in selected outcomes across CMR conditions, with variations amongst individual agents reflecting differences in trial populations, study design and approved indications. This review summarizes current evidence to support individualized therapeutic decision-making rather than comparative positioning within the class.

PLAIN LANGUAGE SUMMARY

People with type 2 diabetes mellitus often develop other serious health problems over time. These include heart disease, heart failure and chronic kidney disease. These conditions are closely linked and can worsen each other. Together, they are sometimes called cardio-metabolic-renal disease. Treating these conditions early and effectively is important to help people live longer and healthier lives.

This article reviews recent evidence about a group of medicines, called sodium–glucose cotransporter 2 inhibitors, often shortened to SGLT2 inhibitors, that were first developed to lower blood sugar in people with type 2 diabetes mellitus. Over the last decade, large clinical studies have shown that they also protect the heart and kidneys, even in some people who do not have diabetes.

What was studied and why?

The authors reviewed published medical studies on four SGLT2 inhibitors currently approved in Europe. They looked at how these medicines work, how effective they are, how safe they are, and whether they are good value for healthcare systems. The aim was to help doctors understand when and how to use these medicines in people with type 2 diabetes mellitus, heart failure or chronic kidney disease.

What did the review find?

All SGLT2 inhibitors lower blood sugar by helping the kidneys remove excess glucose through the urine. Beyond this effect, they also reduce body weight and blood pressure. More importantly, they lower the risk of being admitted to hospital for heart failure and slow the worsening of kidney disease.

Large studies showed that some agents of this group are effective treatments for heart failure and chronic kidney disease, even in people without diabetes. These medicines reduced the risk of kidney failure, hospital stays and early death. Benefits were seen across many patient groups, including older adults and people taking multiple medications. Side effects were generally mild and manageable. The most common problems were genital infections and dehydration, which usually improved with simple treatment or dose adjustments. Serious side effects were rare. Overall, the benefits of treatment were much greater than the risks for most patients.

Why does this matter?

Heart disease and kidney disease are major causes of illness, hospitalization and healthcare costs. This review shows that SGLT2 inhibitors do more than control blood sugar — they help protect vital organs, improve quality of life and may help people live longer.

Using these medicines earlier in the course of disease may prevent serious complications before they occur. Studies also suggest that SGLT2 inhibitors can reduce long-term healthcare costs by delaying the need for dialysis, hospital care and other expensive treatments.

In summary, SGLT2 inhibitors represent an important advance in the treatment of diabetes, heart failure and chronic kidney disease. They offer a simple, once-daily treatment that benefits the heart and kidneys, as well as blood sugar levels, making them a valuable option for many patients and an important tool for modern healthcare.

Introduction

Type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and chronic kidney disease (CKD) are amongst the most significant public health challenges of the 21st century. A substantial body of evidence from both epidemiological and clinical research highlights a strong interconnection between these conditions, leading to the establishment of the term cardio-metabolic-renal (CMR) disease. These three conditions share common pathophysiological mechanisms and frequently occur together. This overlap supports the implementation of a comprehensive treatment approach that addresses all three diseases simultaneously, including emerging therapies such as the sodium–glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is).1

The development of SGLT2is began with the isolation of phlorizin from apple tree bark in 1835. It was first tested on dogs in 1886, where it was found to cause glucosuria and lower glucose levels.2 By the 1960s, researchers understood that glucose reabsorption in the kidneys was mediated by sodium–glucose co-transporters.3 In 1996, a Japanese research team developed phlorizin analogues,4 leading to the first orally active SGLT2is, which successfully reduced hyperglycaemia in diabetic rats. This paved the way for the approval of SGLT2is.5 Between 2012 and 2015, the EMA and FDA approved three SGLT2is (dapagliflozin, empagliflozin and canagliflozin) for reducing plasma glucose in people with T2DM. In 2008, the FDA raised concerns about the cardiovascular (CV) risks of new antidiabetic drugs, soon followed by the EMA.6,7 Regulators required that new antidiabetic agents demonstrate CV safety to gain approval. Subsequent trials began to report CV and renal protection, driving a significant shift in treatment paradigms, which could be updated according to recent findings.8

SGLT2is are not only glucose-lowering medications, they also reduce the development and progression of heart failure (HF) and prolong life in patients with T2DM with concomitant HF.9–12 SGLT2is improve outcomes in patients with HF irrespective of the presence or absence of T2DM and over a wide range of ejection fractions.13,14 SGLT2is prevent the onset of CKD in patients at risk and slow down the progression of end-stage kidney disease (ESKD) in patients with CKD.15 The benefits of SGLT2i in patients without T2DM are now proven by registered trials in this setting.16,17 All of these activities led to SGLT2is being termed ‘the statin of 21st century’.8

Following their clinical development, SGLT2is available in the market (dapagliflozin, empagliflozin, canagliflozin and ertugliflozin) gained approval across different indications.18–21 All four are indicated in adults with insufficiently controlled T2DM as an adjunct to diet and exercise, as monotherapy (when metformin is inappropriate due to intolerance) or in addition to other antidiabetic agents.18–21 This indication is extended to children aged 10 years and above for empagliflozin and dapagliflozin.18,19 These two agents are also indicated in chronic HF and CKD.18,19

The distinctive cardio-protective and renoprotective effects of SGLT2is set them apart from other oral antidiabetic medications, leading to their inclusion and recommendation in recent guidelines beyond the treatment of T2DM. Notably, SGLT2is are considered across various patient categories in both global and national T2DM, HF and CKD guidelines. The American Diabetes Association’s 2025 Standards of Care in diabetes strongly endorse SGLT2is for patients at CV risk, especially those with comorbidities such as atherosclerotic CVD (ASCVD), HF or CKD, recommending them as first-line therapy in cases of HF, CKD, ASCVD or CV risk factors.22–25 Similarly, the European Society of Cardiology (ESC) guidelines published in 2023 emphasize the central role of SGLT2is in managing T2DM in patients with CV risk, together with the protective effect of SGLT2is for HF.26

SGLT2is also have a pivotal role in other guidelines. The 2021 ESC guidelines for acute and chronic HF, along with their 2023 update, highlighted the addition of SGLT2is in the treatment of chronic HF.27,28 The 2023 update specifically provided recommendations based on a wide range of left ventricular ejection fraction (LVEF) values, including mildly reduced or preserved ejection fractions. It is notable that here, SGLT2is are the only drugs with a class Ia recommendation for HF with preserved ejection fraction (HFpEF) or with mildly reduced ejection fraction (HFmrEF), besides diuretics, for fluid retention; this guideline position covers the important unmet need for treatment for these patients.28

Furthermore, the 2024 KDIGO guidelines recognize the approval of SGLT2is in CKD, recommending their use even in patients without T2DM.29 SGLT2is are the only regimen recommended as first line in the general and diabetic CKD population with a >200 urine albumin-to-creatinine ratio (uACR) 16,17 and could be considered until dialysis or transplantation.

Currently, the body of evidence regarding SGLT2is is growing, with new evidence from clinical trials and real-world data. However, few comprehensive narrative reviews are available summarizing evidence regarding SGLT2is in the three approved indications and highlighting differences between the single SGLT2i agents. This narrative review offers an overview of the role of SGLT2is in CMR disease. Additionally, we will examine subtle differences within the four approved SGLT2is to provide clinical guidance for specialists and general practitioners in selecting and managing this therapeutic class based on the available evidence.

The objective of this narrative review is descriptive and practice-oriented: to summarize the pharmacological characteristics and clinical evidence supporting SGLT2 inhibitor use across the CMR continuum, while highlighting areas where outcomes differ amongst individual agents without implying therapeutic hierarchy.

Methods

A narrative, non-systematic literature search was conducted on MEDLINE (via PubMed), the Cochrane Library and Google Scholar to identify relevant publications on SGLT2is (dapagliflozin, empagliflozin, canagliflozin and ertugliflozin) across CMR conditions. The search covered studies published from January 2010 to December 2024, with the final search performed in December 2024.

Sotagliflozin was not included in our review because it is withdrawn from the European market and had a different indication in type 1 diabetes.

Search terms included combinations of controlled vocabulary and keywords such as: “SGLT2 inhibitors”, “dapagliflozin”, “empagliflozin”, “canagliflozin”, “ertugliflozin”, “type 2 diabetes mellitus”, “heart failure”, “chronic kidney disease”, “cardiovascular outcomes”, “renal outcomes”, “pharmacoeconomics” and “cardio-renal-metabolic”. Example Boolean strategy used in PubMed: (“SGLT2 inhibitors” OR dapagliflozin OR empagliflozin OR canagliflozin OR ertugliflozin) AND (“type 2 diabetes” OR heart failure OR chronic kidney disease OR cardiovascular outcomes OR renal outcomes).

Eligible publications included randomized controlled trials (RCTs), CV outcomes trials (CVOTs), meta-analyses, observational studies, guideline documents and pharmacoeconomic analyses published in English. Articles not directly relevant to the review scope, duplicate records and studies focused exclusively on populations outside the intended clinical context were excluded.

Study selection was performed by the authors through consensus, prioritizing high-quality evidence and landmark trials. A total of 102 articles were ultimately included and grouped into predefined thematic domains (pharmacology and safety, T2DM, HF, CKD and pharmacoeconomics).

Results

Differential pharmacological and safety aspect of approved SGLT2is

Whilst all four SGLT2is share a common mechanism of action, they exhibit differences in pharmacokinetics, selectivity for SGLT2 over SGLT1, metabolism and safety profiles. SGLT2is are rapidly absorbed into the bloodstream and remain in circulation for several hours. After glomerular filtration, they selectively bind to SGLT2 in the luminal membrane of the proximal tubule, reducing glucose reabsorption by 50–60%. This process leads to glucose excretion, thereby lowering plasma glucose and glycosylated haemoglobin levels in patients with T2DM.30 Despite sharing a similar mechanism of action, SGLT2is are not pharmacologically homogeneous, with differences observed during their clinical development.

SGLT2 inhibition in the kidney reduces sodium and glucose reabsorption, leading to urinary excretion of up to 100 g of glucose daily (200–300 kcal).31 This process improves glycaemic control, blood pressure (BP), body weight, lipid profile and renal function.32 SGLT2is also enhance cardiac function by reducing plasma and interstitial fluid volumes, lowering preload without activating the sympathetic nervous system.33,34 Increased sodium delivery to the macula densa triggers tubuloglomerular feedback, reducing hyperfiltration and stabilizing renal function.35 Additional benefits include improved myocardial energy efficiency through a shift to ketone metabolism, glycosuria-induced fasting mimicry activating anti-inflammatory enzymes (SIRT1 and AMPK) and antifibrotic effects, though some mechanisms need further human validation.36,37 However, proposed mechanisms, including haemodynamic modulation, metabolic shifts and potential endothelial effects, remain areas of active investigation and should be interpreted as contributory hypotheses rather than established clinical mechanisms.

Pharmacological differences amongst SGLT2is include variations in dose, absorption, distribution, metabolism, excretion and selectivity for SGLT2 versus SGLT1. Selectivity plays an important role in translating the pharmacological differences amongst SGLT2is in the clinical setting.38 Regarding this aspect, the most selective SGLT2 inhibition is observed with empagliflozin, with a selectivity of 2500-fold higher for SGLT2 versus SGLT1.19

In terms of pharmacokinetics, although the half-life, metabolism and elimination of these drugs are similar, there are notable differences in oral bioavailability. Canagliflozin has the lowest bioavailability (65%), whilst ertugliflozin has the highest (100%). Dapagliflozin is the only agent primarily eliminated through urine, with the others eliminated via faeces.30,38 Ertugliflozin also has the highest bioavailability and the longest half-life.21 These subtle differences may partly explain variations in clinical outcomes. Overall, the pharmacokinetic profile of SGLT2is enables a single daily dose, improving manageability. A detailed comparison of pharmacokinetics and pharmacodynamics is provided in Table 1.

Table 1.

Pharmacodynamic and pharmacokinetic characteristics of four approved SGLT2is.

	Dapagliflozin	Empagliflozin	Canagliflozin	Ertugliflozin
Selectivity SGLT2/SGLT1 inhibition	1400-fold	2500-fold	NR	NR
Absorption (Tmax)	2 hours	1.5 hours	1–2 hours	1 hour
Bioavailability	78%	NR	65%	100%
Fraction bound to protein	91%	86%	99%	93.6%
Volume of distribution	118 L	73.8 L	83.5 L	86 L
T1/2	12.9 hours	12.4 hours	10.6–13.1 hours	17 hours
Metabolism	Glucuronidation	Glucuronidation	Glucuronidation	Glucuronidation
Elimination route	21% faeces	41% faeces	52% faeces	41% faeces
	75% urine	54% urine	33% urine	50% urine

NR, not recorded; SGLT1, sodium–glucose co-transporter 1; SGLT2is, sodium–glucose co-transporter 2 inhibitors; T_1/2, drug half-life.

Adapted from data in ref.18–21

When comparing the four available SGLT2is, a comprehensive view of their safety profiles is crucial to understanding differences and enabling personalized treatment. A recently published study analysed and compared safety results from registered RCTs, including a population of over 78,000 patients for all four agents, alongside data from major pharmacovigilance databases (WHO’s VigiBase, FAERS and EMA’s EudraVigilance).17,16,10,12,39,9,11,40–45 Notably, the number of reported adverse events (AEs) in the pharmacovigilance databases varied due to the differing market availability of the agents: 69,664 events for empagliflozin, 51,172 for dapagliflozin, 59,261 for canagliflozin and 1315 for ertugliflozin.45 Notably, canagliflozin was the first available SGLT2i, approved in 2013 by the FDA, followed by dapagliflozin and empagliflozin (both approved by the FDA in 2014) and ertugliflozin (2017).45 According to these results, the study reports different safety profiles from the four approved SGLT2i, with a discrepancy between AEs reported in clinical trials and those reported in pharmacovigilance databases.45 The most common AEs for dapagliflozin were urinary tract infections (UTIs), in DECLARE-TIMI 58, DELIVER and DAPA-HF, and hypotension in DAPA-HF and DAPA-CKD.9,17,40,41 In reporting databases, diabetic ketoacidosis (DKA) was the most frequently reported side-effect, comprising 11% of events in FAERS, 7% in VigiBase, and 8.8% in EudraVigilance; UTIs followed closely, accounting for 6.3% of reports in VigiBase and 8% in EudraVigilance.45

Regarding empagliflozin, the most common adverse effects were UTIs in EMPA-REG and EMPA-KIDNEY,10,16 and hypotension in EMPEROR-Reduced and EMPEROR-Preserved.43,44 DKA was the most frequently reported AE in all four databases, accounting for 12.4% of empagliflozin-related events in FAERS, 7.9% in VigiBase and 13% in EudraVigilance.45

The most common adverse effects associated with canagliflozin were genital infections in CANVAS and CANVAS-R, and UTI in CREDENCE.12,39 Across databases, for canagliflozin, amputations were the most reported AE, accounting for 17% of events in FAERS, 15.6% in VigiBase, and 32.8% in EudraVigilance. DKA followed, representing 14% of events in FAERS, 13.4% in VigiBase and 21.4% in EudraVigilance.45

Ertugliflozin, the newest SGLT2 inhibitor, has limited data. The VERTIS-CV trial identified UTIs and mycotic genital infections as the most common adverse effects.11 In FAERS and VigiBase, UTIs were the most frequently reported event, whilst EudraVigilance reported DKA as the most common. UTIs accounted for 6.2% of reported events in FAERS and 6% in VigiBase, whilst DKA accounted for 11.6% of events in EudraVigilance. The authors of the review conclude that, unsurprisingly, a higher proportion of AEs was observed in the real world.45

Consequently, several key considerations regarding the most significant AEs associated with SGLT2is can be made. One of the most common AEs with SGLT2is is an increased risk of genital infections in both men and women. However, these agents do not significantly increase the risk of UTIs, including pyelonephritis.45 Most genital infections are not severe, and they typically resolve with brief antifungal treatment.46 Similarly to diuretics, SGLT2is may cause volume depletion but have not been shown to increase the risk of acute kidney injury (AKI). A more serious but uncommon warning associated with SGLT2is is the risk of euglycaemic DKA, which underscores the importance of monitoring ketone levels in suspected cases.30 Nonetheless, large clinical trials, such as CREDENCE, reported only 74 DKA events in 38,702 patients (0.2%).30,39 Additionally, a recent meta-analysis found no increased risk of DKA in patients using SGLT2is compared to those on placebo.47 For canagliflozin specifically, concerns about fractures and amputations have been raised. The CANVAS programme reported a higher incidence of fractures and amputations, particularly affecting the toes and metatarsals, in patients treated with canagliflozin.12 This high incidence could be related to the effect of malabsorption of glucose-galactose and calcium at the intestinal level, where SGLT1 could be more expressed.20 Indeed, other major CVOTs with more selective SGLT2 agents, such as DECLARE-TIMI 58, did not show a significantly increased risk of amputation.9,48 Caution is advised in patients with pre-existing peripheral arterial disease and/or lower extremity ulcers, as the risk of amputation cannot be entirely excluded.48

In CMR diseases, patients are often more vulnerable due to frailty and polypharmacy.1,49 In this case, even if AEs typical for SGLT2is are challenging, the mechanisms of SGLT2 inhibition could help achieve a long-term benefit that could overcome risks due to AEs. Quality of life in older adults is not negatively affected by SGLT2is and may even improve in frail patients with HF, as observed in the DELIVER study, which included patients with HFpEF and HFmrEF.50 Whilst older and frail patients may require closer monitoring and more cautious use of SGLT2is, the benefit–risk balance remains highly favourable, particularly for those at risk of CVD and HF. Another aspect that requires attention in older or frail patients is polypharmacy. A post hoc analysis of the DELIVER trial demonstrated that dapagliflozin provided benefits even in patients taking multiple medications.51 Similarly, a post hoc analysis of the EMPA-KIDNEY study extended the beneficial effects of SGLT2is to frail patients with multimorbidity and polypharmacy.52

Conversely, the SGLT2i tolerability profile could also be applied to healthier patients. Overall data from RCTs, CVOTs and observational studies suggest a reassuring safety profile for SGLT2is in both older and younger patients.49 For example, DECLARE TIMI58 included over 10,000 patients with T2DM and without ASCVD, extending the good safety profile of dapagliflozin to primary prevention patients, with or without ASCVD.9

Moreover, the management of SGLT2is has become increasingly relevant in patients with impaired renal function, especially given that certain agents, such as dapagliflozin and empagliflozin, are now indicated for the treatment of CKD. Every SGLT2i has an estimated glomerular filtration (eGFR) threshold for its initiation: dapagliflozin and empagliflozin should be not started when eGFR falls below 25 and 20 mL/min/1.73 m², respectively.18,19 In contrast, canagliflozin and ertugliflozin have higher eGFR thresholds for initiation: they should not be started when eGFR falls below 30 and 60 mL/min/1.73 m², respectively. Furthermore, canagliflozin and empagliflozin require dose reduction (to 100 mg and 10 mg, respectively) once eGFR decreases below 60 mL/min/1.73 m², whilst ertugliflozin is contraindicated in patients with eGFR <30 mL/min/1.73 m².19–21 Dapagliflozin is the only SGLT2i that does not require dose adjustment in patients with renal impairment.18 A summary of SGLT2i use in the context of renal impairment is provided in Table 2.

Table 2.

Approved use of SGLT2is according to eGFR.

SGLT2i	eGFR mL/min/1.73m2
	>90	85	80	75	70	65	60	55	50	45	40	35	30	25	20	15	<15
Dapagliflozin
Empagliflozin
Canagliflozin
Ertugliflozin

Green, use without dose adjustment; orange, use at a lower dosage; yellow, do not start a new therapy with this SGLT2i; red, do not use. eGFR, estimated glomerular filtration rate; SGLT2is, sodium–glucose co-transporter 2 inhibitors.

Adapted from data in ref.18–21

SGLT2i in T2DM: from glycaemic control to CV and renal benefit

All new antidiabetic agents must demonstrate effective glycaemic control to obtain marketing authorization. Glycaemic control is typically assessed through glycated haemoglobin (HbA1c), fasting plasma glucose and postprandial glucose levels. SGLT2is have undergone several phase III, double-blind, placebo-controlled trials to evaluate their glycaemic effects, both in treatment-naive patients and in those already on therapies like metformin, sulfonylureas, thiazolidinediones, DPP4 inhibitors (DPP4is), GLP1 receptor agonists (GLP1RAs) or basal insulin.53

The glycaemic reduction reported in various clinical trials highlights the consistent effectiveness of the currently approved SGLT2is in lowering HbA1c across various doses and patient populations, independently from comorbidity, health status and baseline HbA1c value. The various SGLT2i agents showed similar efficacy in lowering HbA1c.54–65

According to a network meta-analysis on the glucose-lowering efficacy of various glucose-lowering agents, including GLP1RAs, classes based on different end points for HbA1c reduction highlight the superior long-term effectiveness of SGLT2is in managing HbA1c at 104 weeks.66 These findings underscore the importance of SGLT2is as long-term treatment options for T2DM.

The effects of SGLT2is on body weight and metabolic parameters go beyond their impact on HbA1c, with numerous clinical trials and meta-analyses demonstrating their broader benefits. A comprehensive meta-analysis of 424 trials involving 276,336 patients highlighted that SGLT2is, particularly when compared with other glucose-lowering agents, confer significant and sustained reductions in body weight. Alongside semaglutide, SGLT2is showed effective weight reduction over a 1-year period.67 Further analysis of body composition reported that SGLT2is improved various parameters such as body weight, body mass index, waist circumference, visceral and subcutaneous fat areas, and overall fat mass reduction.68 Of note, the weight reduction of SGLT2is seems to be selective of fat mass rather than skeletal muscle mass, as observed in a recent real-world study.69 Amongst the SGLT2is, some showed promising results in reducing fat in areas relevant to CV health. Notably, dapagliflozin constantly reduced weight and fat mass over 102 weeks, without affecting markers of bone turnover or bone mineral density in patients with T2DM inadequately controlled on metformin.59 Moreover, dapagliflozin was associated with a rapid and significant reduction in epicardial fat thickness, an effect that might be independent of overall weight loss. Epicardial fat thickness is an important modifiable risk factor for CVD.70 These clinical findings are echoed by real-world evidence, such as the DARWIN-T2D study, conducted in Italy, where in 735 patients with T2DM, a mean weight loss of 2.7 kg with dapagliflozin was observed.71 Weight loss results between SGLT2i agents were similar, with a mild weight loss for empagliflozin and moderate weight loss with canagliflozin and dapagliflozin, as reported in a systematic review,72 suggesting that SGLT2is not only provide glycaemic control but contribute significantly to body weight and fat mass reduction, potentially improving metabolic and CV outcomes in patients with T2DM.

Interestingly, SGLT2is also exhibit the ability to reduce arterial BP, which is linked to reduced CV morbidity and mortality in patients with T2DM. Weight loss and reduced sympathetic nervous activity also contribute to BP reduction. Moreover, improvements in arterial stiffness may influence BP. Meta-analyses suggest that the BP-lowering effect of SGLT2is is superior to that of other glucose-lowering agents and comparable to the GLP1RA semaglutide.67,73

Regarding CVOT, the DECLARE-TIMI 58 trial involving 17,160 patients with T2DM with or without ASCVD found that dapagliflozin led to a 17% reduction in the composite of CV death or HF hospitalization (HHF) but had no significant effect on major adverse CV events (MACE); however, this reduction was largely due to a decrease in HHF of 27% versus placebo.9 Moreover, it should be considered that only 40.6% of patients had established ASCVD, whilst the remaining 59.4% were patients with T2DM and multiple risk factors. Regarding this population in primary prevention, a post hoc analysis confirmed that the CV benefit was mainly driven by HHF (−36% reduction), reporting a 49% reduction in adverse renal outcomes, with consistent results in the ASCVD population.74 Moreover, this reduction of MACE became significant in the subset of patients with previous myocardial infarction, with a 16% reduction.75 The EMPA-REG OUTCOME trial studied 7020 patients with T2DM and CVD, demonstrating significant CV benefits with empagliflozin over a 3.1-year period, for patients in secondary prevention because all the population enrolled had ASCVD; patients saw a 14% reduction in MACE, 38% reduction in CV death and 35% fewer HHF.10 Similarly, the CANVAS program, with 10,142 patients with T2DM with CV risk factors, confirmed canagliflozin’s efficacy with a 14% MACE reduction and a decrease in HHF, albeit without an impact on mortality.12 In contrast, the CV effects of ertugliflozin were evaluated in a trial involving 8246 patients with T2DM and ASCVD, which showed non-inferiority compared to placebo for MACE, though it had no significant effect on HHF or CV mortality.11 Analysing the different populations between the CVOTs, only DECLARE-TIMI-58 enrolled populations with T2DM with CV risk factors or with ASCVD.9 The expanded population in the CVOT study supports the role of dapagliflozin in both primary and secondary prevention of CVD in patients with T2DM, whereas most other trials predominantly enrolled patients with established ASCVD. Nevertheless, EMPA-REG and CANVAS demonstrated significant reductions in MACE,10,12 further supporting the cardioprotective effects of these agents.

A meta-analysis of 11 CVOTs including more than 75,000 patients reinforced the evidence of SGLT2i benefits, showing sustained reductions in CV mortality, HHF and overall mortality. This class of drugs has shown a particularly robust effect in reducing HF risk, with moderate effects on other CV outcomes.76 Although SGLT2is outperform GLP1RA in some CV benefits, recent evidence suggests that the gap between the two classes is narrowing.77

Large real-world observational trials have confirmed the cardioprotective effects of SGLT2is observed in RCTs. For example, a study across Denmark, Norway and Sweden (CVD-Real Nordics) analysed 22,830 patients with T2DM on SGLT2is (mainly dapagliflozin) versus 68,490 on other glucose-lowering agents. Over a mean follow-up of 0.9 years, SGLT2is were associated with reduced risks of CV mortality, MACE and HHF, though no significant effect on non-fatal myocardial infarction or stroke was noted.78 The benefits were most pronounced in patients with established CVD. A post hoc analysis of this study specifically compared the SGLT2i dapagliflozin with DPP4is, confirming a reduced risk of MACE (−21%), HHF (−41%) and all-cause death (−38%).79 Another real-world study involving 309,056 patients showed similar reductions in HHF and all-cause death.80 Furthermore, the reduction in MACE seems to be higher in the real world. In a large cohort of Korean patients who received dapagliflozin or DPP4is, dapagliflozin showed a higher reduction in MACE compared with DPP4is (the adjusted HR of MACE was 0.69 (95% CI 0.57–0.83)).81 In real-world studies, SGLT2is also extended their cardioprotective action to other CVDs, as reported in a large observational trial on atrial fibrillation onset.82 Dapagliflozin reduced the risk of incidence of atrial fibrillation in patients with T2DM by 17.5 in sensitivity analyses.82

The demonstrated benefit on CV outcomes could also support early introduction of SGLT2is in patients with newly diagnosed T2DM and with poor glycaemic control, as demonstrated by a recent cohort study derived from an Italian registry. In this study, the use of an SGLT2i in the first 3 years after the diagnosis of T2DM eliminated the association of risk of CV outcomes and poor glycaemic control.83

These findings extend the CV benefits of SGLT2i beyond clinical trials to broader, unselected populations. The data suggests that SGLT2i may be valuable for primary prevention and early optimization of T2DM, with benefits applicable to patients with or without existing CVD, as reported in the above-mentioned analysis of DECLARE-TIMI-58 trial.74 These findings project the use of SGLT2is, in particular dapagliflozin, in the context of early initiation to prevent deaths and onset of CVDs such as HF.

SGLT2is provide renoprotection by reducing glomerular pressure and filtration, lowering stress on the filtration barrier and enhancing cortical oxygenation. This improves mitochondrial function, autophagy and tubular glucose toxicity, reducing pro-inflammatory and pro-fibrotic signalling whilst preserving eGFR in the long term.84 Additionally, they may stimulate erythropoiesis, improving oxygen delivery to the kidneys and other organs.85 Before the analysis of large CVOT trials, both empagliflozin and dapagliflozin also demonstrated a positive effect on reducing albuminuria in patients with T2DM.86,87

Prespecified secondary analyses of early CVOTs with SGLT2is reported evidence of kidney protection in patients with T2DM. In the EMPA-REG OUTCOME trial, 7020 patients with T2DM and ASCVD showed significant improvements in albuminuria, with empagliflozin increasing the likelihood of progression from micro-albuminuria to normoalbuminuria (HR 1.43) and from macro-albuminuria to normoalbuminuria (HR 1.82).10,87 CANVAS demonstrated a 40% reduction in the renal composite outcome with canagliflozin,12 whilst DECLARE-TIMI 58 showed a 47% reduction with dapagliflozin.88 VERTIS-CV indicated favourable effects of ertugliflozin on eGFR decline.89 These findings spurred the development of SGLT2is for CKD indications, which are currently available only for dapagliflozin and empagliflozin. Despite the varying reductions in renal composite outcomes, the superiority of an SGLT2i over the others cannot be stated or explained, given the heterogeneity of populations and the different baseline eGFR thresholds.

The decline in eGFR is critical for understanding the potential renoprotective role of SGLT2is. A post hoc analysis of the DECLARE-TIMI 58 trial reported that dapagliflozin slowed kidney function decline in patients with T2DM at high CV risk, including those with low KDIGO risk, indicating a key role for dapagliflozin in the early prevention of diabetic kidney disease. A projection of this slope for dapagliflozin is presented in Figure 1, illustrating the possible long-term benefits for patients with normal eGFR, with an approximate delay of 11 years to the decline of kidney function.88

Figure 1. Decline of renal function according to eGFR slope extracted from ref. 88 according to different eGFR levels.

For eGFR 60 or 90 mL/min/1.73 m², the decline was calculated with the eGFR slope of the subgroup with eGFR ≥45 mL/min/1.73 m², while for eGFR of 30 mL/min/1.73 m², the decline was calculated with eGFR slope of the subgroup with GFR ≥45 mL/min/1.73 m². eGFR, estimated glomerular filtration rate. Figure adapted and modified from Madero et al., Kidney Medicine 2024,15 licensed under CC BY 4.0 ( http://creativecommons.org/licenses/by/4.0/).

In a real-world analysis, the eGFR slopes of the three most studied SGLT2is, empagliflozin, dapagliflozin and canagliflozin, were compared. The annual eGFR decline was −1.15 (95% CI −1.33 to −0.96) mL/min/1.73 m² for empagliflozin, −1.14 (−1.32 to −0.96) for dapagliflozin, −1.24 (−1.44 to −1.04) for canagliflozin and −1.06 (−1.18 to −0.94) for other SGLT2is.90 In the international real-world CVD REAL 3 study involving over 65,000 patients with T2DM, initiation of SGLT2i therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs.91

Comparison and association of SGLT2i and GLP1RAs in the T2DM setting

Compared to other antidiabetic classes, the renoprotective effects of SGLT2is are more pronounced. A meta-analysis in patients with T2DM and CKD showed that SGLT2is were associated with a reduced risk of both CV and renal events, whereas amongst GLP1RAs, only injectable semaglutide was shown to significantly decrease renal event risk in patients with T2DM, as demonstrated in the recently published FLOW trial.92,93 A further meta-analysis showed that SGLT2i are the agents with the best probability in preventing the progression of renal composite events in patients with T2DM. Amongst individual molecules, dapagliflozin has the best probability to complement metabolic control in preventing the progression of renal composite outcomes.94 The recently published real-world DARWIN-renal study further demonstrated that, in individuals with T2DM, initiation of dapagliflozin was associated with better preservation of renal function compared to GLP1RAs, as evidenced by a slower decline in eGFR.95 Interestingly, this dapagliflozin benefit is confirmed both in early use and when the eGFR is compromised as in CKD.17,95 These findings further support SGLT2is as preferred agents for renal protection in this patient population, enforcing its early initiation to prevent kidney decline in patients with T2DM, enabling them to have a higher quality of life in the long term.

In summary, SGLT2is present a different protective profile from existing classes of oral antidiabetic agents. The above-mentioned network meta-analysis of 764 trials compared SGLT2is and GLP1RAs in CV, kidney, and mortality outcomes, including mainly trials on T2DM (Table 3).94 Notably, a more evident effect of SGLT2is is present in HHF and hospitalization due to kidney failure.96 Use of GLP1RA could be beneficial for CV and renal outcomes, also in combination with SGLT2is, as demonstrated by a recent meta-analysis of 12 RCTs. The benefits of SGLT2is are consistent with the use of GLP1RA at baseline. Figure 2 and Table 4 report the differences between SGLT2is and GLP1RAs and their possible benefits in combination.97 Another meta-analysis of 12 T2DM CVOTs highlights an additive effect of SGLT2i and GLP1RA combination on CV and renal outcomes.96

Table 3.

Comparison of HR and risk reduction for SGLT2is and GLP1RAs versus placebo according to a network meta-analysis on trials including patients with T2DM.

	SGLT2is		GLP1RAs
Cardio-renal outcomes	RRR	HR (95% CI)	RRR	HR (95% CI)
Death from cardiovascular causes	−17%	0.77 (0.71–0.83)	−14%	0.88 (0.83–0.94)
Cardiovascular disease	−16%	0.84 (0.76–0.92)	−12%	0.88 (0.80–0.96)
Hospitalization due to heart failure	−30%	0.70 (0.63–0.77)	−6%	0.94 (0.85–1.03)
Chronic kidney disease progression	−29%	0.71 (0.57–0.89)	−12%	0.78 (0.67–0.92)
Diabetes outcomes		95% CI
Weight reduction (kg)	−1.92 kg	(−2.23 to −1.62)	−1.45 kg	(−1.72 to −1.18)
HbA1c	−0.60%	(−0.67 to −0.54)	−0.89%	(−0.95 to −0.82)

GLP1RAs, GLP1 receptor agonists; HbA1c, glycated haemoglobin; RRR, relative response rate; SGLT2is, sodium–glucose co-transporter 2 inhibitors; T2DM, type 2 diabetes mellitus.

Adapted from data in ref.94

Figure 2. Comparison of HR and risk reduction for SGLT2is, GLP1RAs and their combination versus placebo according to a meta-analysis of CVOTs.

ACM, all-cause mortality; CKD, chronic kidney disease; CV, cardiovascular; GLP1RA, glucagon-like peptide 1 receptor agonist; HHF, heart failure hospitalization; MACE, major cardiovascular events; RRR, relative risk reduction; SGLT2is, sodium–glucose co-transporter 2 inhibitors.

Adapted from data in ref.97

Table 4.

Comparison of effect of GLP1RAs, SGLT2is and their combination.

	SGLT2is	GLP1RAs	Combined therapy
Effect on HbA1c	↓	↓/↓↓↓	↓↓
Effect on weight	↓	↓/↓↓↓	↓/↓↓
Effect on blood pressure	↓	↓	↓
Effect on mace	↓	↓	↓
Effect on cardiovascular mortality	↓↓	↓	↓ ↓
Effect on non-cardiovascular mortality	↓↓	↓	↓↓↓
Effect on hospitalization due to heart failure	↓↓↓	↓	↓↓↓↓
Effect on renal outcomes	↓↓↓	↓	↓↓↓↓
Gastrointestinal events	/	↑	↑
Genital infections	↑	/	↑

GLP1RAs, GLP1 receptor agonists; HbA1c, glycated haemoglobin; SGLT2is, sodium–glucose co-transporter 2 inhibitors.

The combined use of SGLT2is and GLP1RAs could be a viable extemporaneous or fixed-dose combination in T2DM, as reported in the DURATION-8 trials, which analysed exenatide plus dapagliflozin versus the respective monotherapies and observed synergistic effects between the two agents.98 A recent real-world study confirmed the benefit of the extemporaneous oral combination of dapagliflozin and semaglutide, with a higher reduction of HbA1c and significant changes in various measures in body mass index, fasting plasmatic glucose, BP, total cholesterol, low-density lipoprotein cholesterol and uACR compared with patients taking dapagliflozin alone.99 Regarding possible use of extemporaneous combinations of GLP1RAs and SGLT2is, it is important to consider the safety profile of GLP1RAs and the recent emerging side-effects as doubling the risk of developing non-arteritic anterior ischaemic optic neuropathy, or the misuse of GLP1RAs, such as semaglutide, being widely used in clinical practice for weight reduction.66,100

The presented results underscore the role of SGLT2is in T2DM management. SGLT2i shows several benefits beyond achieving target HbA1c values. SGLT2is not only reduces CV outcomes but also slows eGFR decline, offering considerable renal protection in the primary prevention of T2DM (Figure 3). However, the different outcomes, both in renal and CV protection, should be carefully interpreted, given the different baseline populations and varied designs of the four CVOT trials. Of note, head-to-head randomized controlled studies are lacking, and the superiority of an agent cannot be stated.

Figure 3. Comparison of main outcomes in registered clinical trials between the SGLT2 inhibitors considering primary prevention in cardiovascular outcomes trials for T2DM.

Ertugliflozin and empagliflozin cardiovascular outcomes trials did not include patients with T2DM with multiple risk factors.10–12,74 MACE was defined as the composite of myocardial infarction, stroke and CV death. Composite renal outcomes were defined as the composite of renal worsening, end-stage renal disease or renal death. ^#Sample was not sufficient to have a relevant data. Figures include only agents with available outcome data to improve interpretability and avoid presentation of non-applicable comparisons. *In CANVAS study an increased risk of amputation and fractures was observed with canagliflozin.12 CV, cardiovascular; HHF, heart failure hospitalization; MACE, major cardiovascular events; NA, not available; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus.

Adapted from data in ref.12,74

The Italian diabetes guidelines categorize SGLT2is across different patient groups, including those with HF, ASCVD and renal impairment, which is unsurprising given their broad benefits. However, their most promising application could be in relatively ‘healthy’ patients with T2DM.101 This is supported by their well-documented ability to prevent CV events, particularly in patients with high-risk factors for CV. Moreover, their impact on slowing eGFR decline may help prevent the progression of kidney disease, thereby improving renal outcomes. The cardio-renal benefits may be independent of glycaemic reduction, and early intervention could enhance reaching these outcomes. The reduction in cardio-renal events may not only lead to significant health benefits but also allow patients to have a longer and better life, reducing all-cause mortality, improving patient quality of life and offering additional advantages in terms of pharmacoeconomic and healthcare outcomes.

SGLT2is in HF: a manageable first-line therapy across an ejection fraction range

SGLT2is exhibit favourable pleiotropic effects that extend beyond their primary role in glycaemic control. Due to their unique pathophysiological profile, these agents have revolutionized the management of HF, and ongoing research suggests that they may also play a role in treating conditions other than T2DM. Currently, empagliflozin and dapagliflozin are the only two SGLT2is approved for HF, and their indications have expanded over time with new trials covering various ranges of LVEF values.102

Although the initial evidence for HF benefits stemmed from data on reduced HHF observed in CVOTs, such as DECLARE-TIMI and EMPA-REG, dedicated HF trials were pivotal in expanding the use of SGLT2is for this indication.9,10 Across HF trials, SGLT2is consistently reduce HHF, whilst effects on CV mortality are more variable and depend on study population, end point definition and statistical power. Pooled analyses suggest potential mortality benefits for some agents; however, reductions in HHF represent the most consistent class effect.

The DAPA-HF study demonstrated that dapagliflozin significantly reduced the risk of first and recurrent HHF by 30% and the risk of CV death by 18% in patients with HFrEF, regardless of T2DM status.40,103 Similarly, the EMPEROR-Reduced trial showed that empagliflozin 10 mg reduced the composite risk of HHF and CV death by 31% over a median follow-up period of 16 months in patients with HF (NYHA class II, III or IV) and an ejection fraction of 40% or less, regardless of T2DM status.43 However, CV death risk reduction did not reach superiority over placebo in this study, reducing by 8%. The benefits observed in both studies were consistent independently of any guideline-recommended therapies for HF, including sacubitril-valsartan.43 Subsequent trials expanded the use of SGLT2is to patients with HFpEF and HFmrEF. The EMPEROR-Preserved trial demonstrated that empagliflozin 10 mg was superior to placebo in improving outcomes in patients with HF and an ejection fraction >40%. This SGLT2i significantly reduced the composite risk of HHF and CV death by 21% (the two components of the primary end point were reduced by 29% and 9%, respectively), regardless of T2DM status, but with an attenuation of effect at an ejection fraction of ≥60%.44 Finally, the DELIVER study reported that introducing dapagliflozin reduced the risk of HF exacerbation (unplanned HHF or urgent visits for HF) and CV mortality (the two components of the primary end point were reduced by 21% and 12%, respectively), compared to placebo in patients with HFmrEF or HFpEF. Dapagliflozin also provided additional benefits to patients whose ejection fraction had improved from a previously lower value to >40%. The effect of dapagliflozin was consistent amongst patients with or without T2DM, those with ejection fractions ≤60% or >60%, and those with improved ejection fractions, without any attenuation of the effect.41 Based on current evidence, dapagliflozin is the first and only SGLT2i to demonstrate a proven benefit in HF, with reductions in both CV mortality and HHF irrespective of ejection fraction. Specifically, the risk of CV death was significantly lowered (−18%) with dapagliflozin, as was the risk of all-cause mortality (−17%), though no significant CV mortality benefit was observed with empagliflozin.13 On the other hand, empagliflozin has also shown significant benefits on HHF in both the EMPEROR-Reduced and EMPEROR-Preserved trials, successfully meeting their respective primary end points. However, a direct head-to-head randomized clinical trial comparing dapagliflozin and empagliflozin is lacking, and thus superiority of one agent over the other cannot be established.

Both empagliflozin and dapagliflozin are currently used for HF management due to their broad efficacy across various LVEFs. Their effectiveness becomes even more significant when analysing pooled analyses of studies on HFrEF and HFpEF. In the pooled analysis of the DAPA-HF and DELIVER trials, dapagliflozin reduced the risk of CV death, all-cause mortality, total HHF and MACE.13 Notably, dapagliflozin’s effect remained consistent across a wide range of ejection fractions. In this analysis, covering the full range of ejection fractions in patients with HF, dapagliflozin significantly reduced the risk of CV death and HHF.13 Similarly, an analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials was conducted.14 Empagliflozin reduced the composite risk of CV death or HHF, primarily through a reduction in hospitalizations but not in CV mortality, but its effect on risk of hospital reduction was reduced in patients with an ejection fraction of ≥65%. Conversely, the effect on CV death reduction was modest and not always consistent between the different ejection fractions. No evidence was reported for all-cause mortality in this pooled analysis. Whilst empagliflozin’s effects were clinically meaningful and consistent across patients with ejection fractions from <25% to <65%, they were attenuated to those with an ejection fraction ≥65%.14 This attenuation begins around an ejection fraction ≥60% (Figure 4).13 The detailed summary of the main results of the clinical development programmes of both SGLT2i approved for HF and the meta-analyses of these trials across ejection fraction are presented in Table 5.

Figure 4. Composite outcome of cardiovascular death or hospitalization due to heart failure across left ventricular ejection fraction from the two pooled analyses of heart failure randomized clinical trials13,14 for A) dapagliflozin and B) empagliflozin.

The dashed line indicates when empagliflozin loses effect around an ejection fraction of 60–65%. Panel A adapted from Jhund et al., Nat Med, 2022,13 licensed under CC BY 4.0 ( http://creativecommons.org/licenses/by/4.0/). Panel B adapted from Butler et al., Eur Heart J. 2022,14 distributed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0, http://creativecommons.org/licenses/by-nc/4.0/). This material is not covered by the Creative Commons license applied to this article and remains subject to the original license terms.

Table 5.

Main outcomes from RCTs of SGLT2is in HF.

Outcome	Dapagliflozin			Empagliflozin
	DAPA-HF	DELIVER	Pooled analysis across LVEF spectrum	EMPEROR Reduced	EMPEROR Preserved	Pooled analysis across LVEF spectrum
Number of patients with the study drug and conditions	2373 HFrEF	3131 HFmrEF, HFpEF and ≥40 years of age	5504 HF	1863 HFrEF	2997 HFmrEF; HFpEF	4860 HF
Primary end point	Composite of worsening HF or death from cardiovascular causes	Composite of worsening HF or death from cardiovascular causes	Composite of HHF or death from cardiovascular causes	Death from cardiovascular causes or HHF	Death from cardiovascular causes or HHF	Death from cardiovascular causes or HHF
HR (95% CI)	RRR: 26% 0.74 (0.65–0.85) p<0.0001	RRR: 18% 0.82 (0.73–0.92) p<0.001	RRR: 22% 0.78 (0.72–0.86) p≤0.001	RRR: 25% 0.75 (0.65–0.86) p<0.001	RRR: 21% 0.79 (0.69–0.90) p<0.001	EF <25%	RRR: −23% 0.77 (0.60–0.98)
						EF 25–34%	RRR: −28% 0.72 (0.59–0.87)
						EF 35–44%	RRR: −18% 0.82 (0.63–1.05)
						EF 45–54%	RRR: −26% 0.74 (0.61–0.91)
						EF 55–64%	RRR: −22% 0.78 (0.62–0.97)
						EF ≥65%	RRR: −2% 0.98 (0.68–1.40)
Cardiovascular death HR (95% CI)	RRR: 18% 0.82 (0.69–0.98) p=0.0294	RRR: 12% 0.88 (0.74–1.05) p=0.1678	RRR: 14% 0.86 (0.76–0.97) p=0.01	RRR: 8% 0.92 (0.75–1.12) p=0.2951	RRR: 9% 0.91 (0.76–1.09) p=0.2951	EF 25–34%	RRR: −7% 0.93 (0.65–1.32)
						EF 35–44%	RRR: −5% 0.95 (0.72–1.24)
						EF 45–54%	RRR: +7% 1.07 (0.76–1.51)
						EF 55–64%	RRR: −23% 0.77 (0.58–1.02)
						EF ≥65%	RRR: −1% 0.99 (0.70–1.40) ì)
All-cause death HR (95% CI)	RRR: 17% 0.83 (0.71–0.97) p=0.0217	RRR: 6% 0.94 (0.83–1.07) p=0.3425	RRR: 10% 0.90 (0.82–0.99) p=0.03	RRR: 8% 0.92 (0.77–1.10) p=0.9893	RRR: 0 1.00 (0.87–1.15) p=0.9893	Not available
HHF HR (95% CI)	RRR: 30% 0.70 (0.59–0.83) p<0.0001	RRR: 23% 0.77 (0.67–0.89) p=NA	RRR: 29% 0.71 (0.65–0.78) p<0.001	RRR: 31% 0.69 (0.59–0.81) p=0.0003	RRR: 29% 0.71 (0.60–0.83) p=0.0009	EF 25–34%	RRR: −26% 0.74 (0.50–1.07)
						EF 35–44%	RRR: −37% 0.67 (0.51–0.87)
						EF 45–54%	RRR: −21% 0.79 (0.55–1.12)
						EF 55–64%	RRR: −44% 0.56 (0.42–0.76)
						EF ≥65%	RRR: −19% 0.81 (0.59–1.10)

EF, ejection fraction; HF, heart failure; HFpEF, HF with preserved EF; HFrEF, HF with reduced EF; HFmrEF, HF with mildly reduced EF; HHF, hospitalization due to HF; LVEF, left ventricular EF; RCT, randomized controlled trial; RRR, relative risk reduction; SGLT2is, sodium–glucose co-transporter 2 inhibitors.

Adapted from data in ref.13,14,40,41,43,44

The two agents were also compared in a meta-analysis of 11 RCTs.104 A significant decrease in mortality for dapagliflozin (OR 0.80, 95% CI 0.66–0.98) was observed compared with empagliflozin in all-cause death, regardless of ejection fraction, as well as in CV deaths (OR of dapagliflozin 0.78, 95% CI 0.65–0.92; OR of empagliflozin 0.90; 95% CI 0.78–1.03). Dapagliflozin could be favoured for this comprehensive effect on all-cause and CV death and its ability to improve prognosis in patients with HF.104 This effect on mortality was also reported in the ESC guidelines on HF and their update, recognizing the unique dapagliflozin results on CV and all-cause reduction.27,28

The benefits of SGLT2is were measured not with regard to hospitalization and mortality but also on improvement of all domains of health status. A pooled analysis of DAPA-HF and DELIVER trials confirmed that dapagliflozin improved health status in all domains in the Kansas City Cardiomyopathy Questionnaire (KCCQ), regardless of LVEF.105 Further analysis demonstrated sustained improvement of empagliflozin in KCCQ, regardless of baseline status, both in EMPEROR-Reduced and EMPEROR-Preserved trials; however, the effect of ejection fraction on this outcome is unknown.106,107 A meta-analysis compared dapagliflozin and empagliflozin in patients with HFpEF and HFrEF with different outcomes with regard to quality of life (measured with the KCCQ) and 6-min walking tests.108 Patients with HFpEF experienced greater benefits from SGLT2i administration, particularly dapagliflozin, as evidenced by improved 6-min walk distances, compared with patients with HFrEF. In this meta-analysis, dapagliflozin demonstrated clinical and overall improvements in KCCQ scores across the range of LVEF, and it was more effective in reducing weight than the placebo.108 Recently, a new randomized study in Japan (Effect of Dapagliflozin on Volume of Epicardial Adipose Tissue in Asymptomatic Heart Failure (DAPA-EAT)) demonstrated the metabolic benefits of dapagliflozin in patients with subclinical HF. A treatment of 24 weeks of dapagliflozin was able to reduce epicardial adipose fat, together with left ventricular myocardial fibrosis and myocardial volume, and this effect was accompanied by an improvement in left ventricular diastolic function.109

A further perspective on HF is the clinical development in acute HF. EMPULSE and DICTATE-HF are the first RCTs that observed benefit in this setting. Early initiation of dapagliflozin and empagliflozin achieved the goals of decongestion and guideline-directed medical therapy optimization.110,111 In the DICTATE-HF trial, dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1–Q3: 260–1150 mg] versus 800 mg [Q1–Q3: 380–1715 mg]; p=0.006) and fewer intravenous diuretic up-titrations (p≤0.05) to achieve weight loss equivalent to that experienced with usual care; however, the dapagliflozin arm did not reach the primary end point.110 Larger RTCs will be necessary to warrant approval for SGLT2is in this setting. A recent consensus by the American College of Cardiology, recognizing the central role of SGLT2is in both chronic and acute cases, considered the decongestive effect on hospitalization achieved in the DICTATE-HF trial.112 Recently, a meta-analysis of RCTs demonstrated the positive effect of early administration of SGLT2is after an acute phase of HF.113 This early administration improved key outcomes for conditions such as the incidence of AKI or the readmission for HF. Overall, this meta-analysis confirmed the decongestant effect observed in the DICTATE-HF and EMPULSE trials.113

Given the significant burden of HF, SGLT2is have become a valuable guideline-directed therapy offering reductions in both mortality and HHF. Their efficacy across the full range of ejection fractions is emphasized in the 2023 updates of the ESC HF guidelines.28 Their early initiation is considered in the recent American College of Cardiology consensus, any time after admission in haemodynamically stable patients with eGFRs of ≥20 mL/min/1.73 m².112 Notably, two distinguishing features of SGLT2is in HF treatment are their fixed dosage without the need for titration and their consistent effectiveness across all LVEF ranges. Moreover, SGLT2is could also improve tolerability to other guideline-directed therapies, such as angiotensin receptor-neprilysin inhibitors or mineralocorticoid receptor agonists, reducing the risk of hyperkalaemia and slowing EGFR decline, and with minimal effect on BP, which can also avoid discontinuation of those treatments in patients.114 These characteristics, along with the robust results from RCTs (Figures 5 and 6), have positioned SGLT2is as a cornerstone of pharmacological treatment for HF.

Figure 5. Comparison of the main outcome in registered clinical trials of patients with HFrEF treated with different SGLT2 inhibitors.

ACM, all-cause mortality; CV, cardiovascular; HHF, heart failure hospitalization; HFrEF, heart failure with reduced ejection fraction; RRR, relative risk reduction.

Adapted from data in ref.40,43

Figure 6. Comparison of the main outcomes in registered clinical trials in patients with HFpEF treated with different SGLT2 inhibitors.

ACM, all-cause mortality; CV, cardiovascular; HHF, heart failure hospitalization; HFpEF, heart failure with preserved ejection fraction; RRR, relative risk reduction.

Adapted from data in ref.41,44

SGLT2is in CKD: an important option in a new armamentarium

The renoprotective effect of SGLT2is in T2DM has led to the development of clinical programmes targeting patients with CKD. Both empagliflozin and dapagliflozin gained approval for CKD treatment, supported by the results of the DAPA-CKD and EMPA-KIDNEY trials.16,17 In 2020, the DAPA-CKD study enrolled 4304 patients with CKD who were treated with either dapagliflozin or placebo. The trial was stopped early due to significant efficacy, showing that the primary renal outcome was 39% lower in the dapagliflozin group compared to placebo (HR 0.61; 95% CI 0.51–0.72; p<0.001), regardless of whether patients had T2DM.17 A sub-analysis of 293 patients with stage 4 CKD and albuminuria demonstrated that dapagliflozin was safe and effective even at lower eGFR levels; in this group, dapagliflozin reduced the primary composite end point by 27%, renal end points by 29%, CV events by 17% and mortality risk by 32% compared with placebo.17 A sub-analysis of mortality in the DAPA-CKD population revealed that dapagliflozin extended survival regardless of baseline patient characteristics; the reduction in all-cause death was 31% versus placebo and the survival benefits were primarily attributed to a significant reduction in non-CV deaths, underscoring the renoprotective effects of the treatment.115

Although experience with renal benefits in patients with eGFR <20 mL/min/1.73 m² remains limited, SGLT2is can be continued even in patients on dialysis. The EMPA-KIDNEY trial enrolled 6609 adults, with or without T2DM, who had CKD (eGFR >20 mL/min/1.73 m² but <45 mL/min/1.73 m², or who had an eGFR >45 but <90 mL/min/1.73 m² with a uACR of at least 200 mg/g) to assess the effects of empagliflozin on renal disease progression or CV death. The trial was also stopped early in March 2022 due to positive results, suggesting that patients with CKD and without albuminuria can also benefit from SGLT2is. Empagliflozin reduced the risk of renal disease progression or CV death by 28% compared to placebo, without significant safety concerns. Additionally, the number of hospital admissions for any cause was lower in the empagliflozin group (HR 0.86; 95% CI 0.78–0.95; p=0.003).16 A summary of results from the two pivotal clinical trials on CKD is provided in Table 6. When considering the primary end points, it is important to emphasize the discrepancy in their definitions. In EMPA-KIDNEY, the primary end point comprised progression of kidney disease (defined by several outcomes, including ESKD, a decline in eGFR to <10 mL/min/1.73 m², a ≥40% reduction in eGFR from baseline, or death from renal causes) and death from CV causes. By contrast, in DAPA-CKD, the primary end point included a ≥50% reduction in eGFR, ESKD and death from renal or CV causes. These differences may contribute to inconsistencies in the reported primary outcomes, and therefore, the results should be interpreted with caution.17

Table 6.

Main outcomes from the EMPA-KIDNEY and DAPA-CKD studies.

Outcome	DAPA-CKD (N=4304)	EMPA-KIDNEY (N=6609)
	Dapagliflozin	Empagliflozin
Primary end point: EMPA-KIDNEY: composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 mL/min/1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes DAPA-CKD: composite of a sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes	39% RRR NNT=19 HR 0.61 (95% CI 0.51–0.72) p<0.001	28% RRR NNT=27 HR 0.72 (95% CI 0.64–0.82) p<0.001
All-cause mortality	31% RRR HR 0.69 (95% CI 0.53–0.88) p=0.004	13% RRR HR 0.87 (95% CI 0.70–1.08) p=0.21
Composite of death or HHF	29% RRR HR 0.71 (95% CI 0.55–0.92) p=0.009	16% RRR HR 0.84 (95% CI 0.67–1.07) p=0.15
All cause hospitalization	Post-hoc 22% RRR HR 0.78 (95% CI 0.70–0.87)	14% RRR HR 0.86 (95% CI 0.78–0.95) p=0.003

eGFR, estimated glomerular filtration rate; HHF, hospitalization due to heart failure; NNT, number needed to treat; RRR, relative risk reduction.

Adapted from data in ref.16,17

A meta-analysis of both trials confirmed the ability of SGLT2is to slow eGFR decline, particularly in patients without T2DM.116 Specifically, data from DAPA-CKD and other populations of patients with CKD were used in a meta-analysis to evaluate the outcome-based clinical benefits of dapagliflozin in patients with CKD through a time-to-event analysis. The results indicated that treatment with dapagliflozin over a lifetime horizon could significantly delay the occurrence of adverse clinical outcomes, even for patients at a modest risk of progression. Notably, in the DAPA-CKD population, dapagliflozin extended the time to kidney failure by an average of 6.6 years (dapagliflozin: 25.2 years, 95% CI 19.0–31.5; standard therapy: 18.5 years, 95% CI 14.7–23.4). In the pooled CKD population, dapagliflozin delayed kidney failure by 6.3 years (dapagliflozin: 36.0 years, 95% CI 31.9–38.3; standard therapy: 29.6 years, 95% CI 25.5–34.7).117

Another key development in the use of SGLT2is for CKD is the incorporation of the albuminuria threshold in current KDIGO guidelines.29 Further evidence of the effectiveness of SGLT2is in CKD without T2DM comes from recent real-world studies. In the OPTIMISE-CKD study, which included 1480 patients without T2DM, dapagliflozin demonstrated similar kidney protection, cardiorenal benefits and reduced all-cause mortality risk across different uACR levels.117 This suggests that the efficacy observed in clinical trials is applicable to real-world patients with CKD, regardless of albuminuria levels.15

The benefits observed in patients with T2DM and CKD also appear to extend to patients with CKD without T2DM. The results in clinical trials,16,17 corroborated later from real-world evidence,117 underscore the beneficial effect of SGLT2is. Notably, dapagliflozin is the only SGLT2i with evidence of a statistically significant all-cause mortality reduction, reaching a 31% risk reduction versus placebo, with a reduction of −26% in the population with T2DM.118 Additionally, empagliflozin showed a trend of all-cause mortality reduction, albeit not statistically significant due to the limited sample size.16 The approval of dapagliflozin and empagliflozin for use in patients with CKD and without T2DM provides this population with an effective treatment option, often used in conjunction with RAS inhibitors or as an alternative in patients for whom RAS inhibitors are contraindicated due to hyperkalaemia or hypotension.117 The results of empagliflozin and dapagliflozin in trials for CKD are summarized in Figure 7.

Figure 7. Comparison of the main outcomes in registered clinical trials in patients with CKD treated with SGLT2 inhibitors.

ACM, all-cause mortality; CKD, chronic kidney disease; CV, cardiovascular; HHF, heart failure hospitalization; RRR, relative risk reduction.

Adapted from data in ref.16,17

The KDIGO guidelines have recognized SGLT2is as a groundbreaking therapy, helping to slow the progression of kidney function decline towards end-stage renal disease.29 Moreover, KDIGO guidelines recommend early diagnosis and treatment of CKD in patients with a high risk for CKD, including those with hypertension, T2DM and CVD.29 This early detection could help exploit the benefit of SGLT2is on slowing eGFR decline progression. Moreover, SGLT2is may also produce benefit at the CV level or for metabolic syndrome, which could benefit patients with kidney injury.119

Further advances in this setting could be represented for CKD stages 4 and 5, with very recent results presented at the American Society of Nephrology Congress on the study DAPA-advKD, showing that dapagliflozin could reduce eGFR slope (a difference of 1.06 from placebo) and improve renal outcomes even in this critical group of patients.120 However, preliminary findings presented at congresses should be interpreted cautiously until peer-reviewed publications are available.

Pharmacoeconomic data and their implications in SGLT2is across the approved settings

Pharmacoeconomic evidence is expanding for multiple SGLT2is, though the volume of published analyses varies by agent and indication. The expanding use of SGLT2is in nephrology, cardiology and diabetology represents not only a clinical paradigm shift but also a significant opportunity to improve the economic sustainability of healthcare systems. Initially developed for glycaemic control in T2DM, SGLT2is, particularly dapagliflozin and empagliflozin, have demonstrated consistent benefits in HF and CKD regardless of T2DM status.

Pharmacoeconomic evaluation in CKD: emerging evidence

Amongst the various approved indications, the use of SGLT2is in CKD likely presents the most pronounced pharmacoeconomic impact. This is due to both the high disease burden and the substantial costs associated with advanced stages of CKD, such as dialysis, transplantation and hospitalizations. A recent Italian study121 employed a lifetime Markov model from the perspective of the Italian National Health Service (Servizio Sanitario Nazionale) to assess the cost effectiveness and budget impact of early dapagliflozin use in patients with mild-to-moderate CKD and low albuminuria (uACR <200 mg/g). Dapagliflozin emerged as a dominant strategy, yielding both better clinical outcomes and lower overall costs compared to standard of care (SoC) without SGLT2is. Specifically, it provided an incremental gain of 0.934 quality-adjusted life years (QALYs) and 1.045 life years whilst saving €2,580.80 per patient.

Budget impact and avoided costs

The associated budget impact analysis over a 5-year horizon estimated cumulative net savings of over €1.3 million, with notable cost savings evident as early as the first year of implementation (~€252,000). These savings were largely attributable to reductions in dialysis initiation, HHF and AKI, all of which are high-cost events that commonly occur in advanced CKD.

These findings are aligned with large-scale clinical trials such as DAPA-CKD,17 in which dapagliflozin significantly reduced the risk of CKD progression, CV death and hospitalizations, independently of baseline T2DM. Furthermore, real-world data from the OPTIMISE-CKD trial122 and the Italian ENDORSE model123 have confirmed the translatability of clinical trial results into routine practice, particularly in patients with early-stage CKD with preserved renal function and low albuminuria.

System-level value in high-prevalence settings

In Italy, where CKD affects an estimated 5–7.5% of the adult population,124 early pharmacological interventions that delay disease progression can have transformational implications for both patient outcomes and healthcare resource management. Given that the average cost of dialysis exceeds €50,000 per patient per year, even modest reductions in the progression to renal replacement therapy can translate into substantial systemic savings. A recent legislative proposal by the Italian Chamber of Deputies (2024) emphasized CKD as an urgent public health and financial priority, reinforcing the need for sustainable and preventive models of care.125

CKD is an area where costs are projected to rise. A microsimulation model estimated that, in 31 countries/regions, the annual direct costs of diagnosed CKD and kidney replacement therapy would increase by 9.3% between 2022 and 2027, from US$372.0 billion to US$406.7 billion; SGLT2is emerged as promising agents in this setting based on cost-effectiveness analyses.126 Several cost-effectiveness studies are available for SGLT2is in the CKD setting. A recent analysis using a Markov model based on the DAPA-CKD trial, but applied to a broader population, showed that dapagliflozin may be cost effective for patients across a wide spectrum of eGFR and albuminuria, with or without T2DM, in healthcare systems in the UK, Spain, Italy and Japan.127 In comparison of costs per outcome, a simulation using data from the DAPA-CKD and EMPA-KIDNEY trials found that, amongst patients with CKD, empagliflozin provides better monetary value for preventing renal and CV events in diabetic patients, whilst dapagliflozin offers better value for patients without T2DM. Dapagliflozin was also more cost effective in preventing CVD, whilst empagliflozin provided better value in preventing CKD progression.127

A comparative cost-determination framework evaluated the outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year period based on the DAPA-CKD trial.128 The model estimated incidence rates of ESKD, HHF, AKI and all-cause mortality for a population of 100,000 patients. Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7221 vs 10,767), HHF (2370 vs 4684), AKI (4110 vs 5819), and all-cause mortality (6383 vs 8874) compared to those on standard therapy alone. Across 31 countries, these reductions in clinical events were associated with a 33% reduction in total costs, resulting in cumulative mean medical care cost savings of US$264 million per 100,000 patients over 3 years. Based on the DAPA-CKD trial, treatment with dapagliflozin could prevent cardio-renal events at a population level, potentially having a positive impact on healthcare systems worldwide.128 Regarding the Italian setting, a comparative micro-simulation model estimated the outcome-related costs of dapagliflozin plus SoC versus SoC alone over a 3-year horizon based on the DAPA-CKD trial.129 Reductions (−35.6%) in clinical events (ESKD, HHF and AKI) with dapagliflozin treatment were associated with a 34.4% reduction in total costs (€170 million) over 3 years, in line with the reduction for global analysis, estimating a positive impact on the Italian Health System.129

Overall, a meta-analysis of 13 cost-utility studies (including eight on dapagliflozin, three on empagliflozin and two on canagliflozin) reported that all SGLT2is were cost-saving when added to SoC in patients with CKD without T2DM, and cost effective when added to SoC in patients with CKD and T2DM.130 With regard to empagliflozin, several studies informed by the EMPA-KIDNEY trial demonstrated cost-utility benefits in terms of QALYs gained and reduced healthcare resource utilization compared to SoC in both UK and East Asian healthcare settings.131,132 Nonetheless, dapagliflozin currently appears to have a broader body of pharmacoeconomic evidence in CKD. A systematic comparative review would be valuable to determine whether meaningful differences exist between the two agents, or whether both can be considered cost effective within today’s fragmented economic landscape.

The potential of SGLT2is is further enhanced by improved diagnosis of CKD. The ENDORSE project evaluated the clinical and economic impact of targeted training for practitioners to increase CKD awareness and early diagnosis.123 The training led to increased use of eGFR (+44.7%) and uACR (+95.2%) tests. A budget impact analysis projected cumulative 5-year savings of €1.7 million for the study cohort. When extrapolated to the entire Italian CKD population, potential savings were estimated at €106.6 million, indicating significant cost savings for the national healthcare system.123 In the USA, reinforced CKD screening followed by treatment with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and SGLT2is has been shown to be cost effective for the general population aged 35 and above.133

Cost-effectiveness data in the HF setting also shows promising results for SGLT2is. A global study comparing direct and indirect costs of HF across 197 countries estimated the total economic burden of HF in 2012 at US$108 billion, with direct costs accounting for 60% (US$65 billion) and indirect costs for 40% (US$43 billion).134 For both HFrEF and HFpEF, cost effectiveness has been demonstrated for empagliflozin and dapagliflozin, with solid comparisons across the spectrum of ejection fractions.135–138 In the specific context of HFrEF, both agents are supported by systematic reviews demonstrating broad cost effectiveness across diverse healthcare settings, though some differences between them were observed.139,140 The cost-effectiveness data on dapagliflozin and empagliflozin in HF also supported their approval in the NICE guidelines from the UK.141,142

A Markov model analysis for HFrEF indicated that dapagliflozin, when added to SoC, was a cost-effective strategy, in comparison with empagliflozin–SoC.143 When compared to SoC alone, dapagliflozin–SoC and empagliflozin–SoC had incremental cost-effectiveness ratios (ICER) of US$56,782 and US$89,258 per QALY, respectively. Dapagliflozin–SoC cost US$5524 more but provided 0.20 additional QALYs than empagliflozin–SoC, with an ICER of US$27,861 per QALY. Efficacy on mortality could have hindered the QALY calculated for dapagliflozin, partly explaining these results.143 Another Markov model analysis, simulating patients with HFpEF, showed that dapagliflozin had an incremental expected lifetime cost of US$29,896 compared to empagliflozin, resulting in an ICER of US$36,902/QALY.144 To further support these findings, a UK analysis based on pooled data from the DAPA-HF to DELIVER trials demonstrated that adding dapagliflozin to usual care was likely to be cost-effective across the full range of LVEF.145

Implications for health policy and reimbursement

In the current healthcare landscape, particularly within the framework of the National Recovery and Resilience Plans in the EU, economic evaluation tools such as cost-utility analysis and budget impact analysis have become essential to guide reimbursement decisions and therapeutic access policies.146 Treatments that provide multi-dimensional value, clinical efficacy, safety, patient quality of life and system-level cost savings are prioritized for integration into chronic care pathways. SGLT2is largely fulfil these criteria, with the dapagliflozin advantage that dose adjustments are not required as kidney function declines, as well as the potential for high long-term adherence, which is a key driver of real-world effectiveness and cost-efficiency. These characteristics position SGLT2is as ideal candidates for integration into population health strategies, particularly those aiming to promote early intervention and disease modification.

Final pharmacoeconomic considerations

The growing body of evidence surrounding the use of SGLT2is in patients with CKD reflects a significant evolution in how clinicians and policy-makers approach chronic, multi-system diseases. No longer viewed solely through the lens of glycaemic control in T2DM, SGLT2i are now recognized as disease-modifying agents with broad organ-protective benefits, spanning nephrology, cardiology and internal medicine.

Dapagliflozin currently has a large pharmacoeconomic evidence base, but available analyses for empagliflozin and canagliflozin similarly support cost effectiveness across several healthcare settings. This is particularly important in CKD, where the disease burden is high, progression is often silent and irreversible, and late-stage interventions, such as dialysis and transplantation, are amongst the most expensive services within public health systems. The ability of dapagliflozin to delay or avoid these end points, whilst improving quality of life and survival, marks a critical turning point in chronic disease management.

In broader healthcare system terms, the favourable cost–utility profile of dapagliflozin, alongside real-world effectiveness in both diabetic and non-diabetic populations, supports its prioritization in formulary inclusion, clinical guidelines and early access programmes. National and regional health authorities, particularly those operating under constrained budgets or value-based care frameworks, can leverage these pharmacoeconomic insights to justify the upstream allocation of resources towards therapies with high downstream returns. In doing so, they not only reduce future expenditures but also align with principles of preventive and precision medicine.

Furthermore, the use of dapagliflozin in early-stage CKD responds to a critical unmet need in clinical practice: the lack of effective, low-risk therapies for patients with mildly impaired renal function and normal or low-grade albuminuria. Traditional therapeutic approaches often reserve intervention for more advanced stages of disease, by which time significant and sometimes irreversible damage has occurred. By shifting this paradigm towards early intervention, SGLT2is open the door to a more proactive and holistic model of care that aligns with modern chronic disease strategies.

On a regulatory and policy level, the mounting clinical and economic data supporting SGLT2i use in CKD may catalyse reimbursement revisions and label extensions, particularly for non-diabetic indications. Given that this class of agents has already demonstrated benefit across multiple patient phenotypes, its potential to bridge specialties from nephrology to cardiology to endocrinology makes it uniquely well-suited for inclusion in integrated care pathways and multidisciplinary disease management programmes. Importantly, the favourable safety profile, ease of use (fixed-dose oral regimen), and lack of need for dose titration in renal impairment of SGLT2is (and specifically of dapagliflozin) further enhance their real-world applicability and patient adherence — critical factors that influence not only individual outcomes but also system-wide cost-efficiency.

In the context of ageing populations, rising multimorbidity and increasing demand for value-based care, therapies like dapagliflozin and empagliflozin represent more than a clinical advance; they embody a strategic lever for healthcare systems seeking to balance clinical excellence, cost containment and equity of access.

In conclusion, dapagliflozin, with its body of pharmacoeconomic evidence, exemplifies a new generation of therapeutic agents that deliver simultaneous gains in patient outcomes and system sustainability. Similarly, promising results could support empagliflozin in such a role. As such, their integration into early CKD management should be seen not as an incremental step but as a system-wide innovation — one capable of transforming the trajectory of CKD and the way we value, deliver and fund care across the CMR continuum.

Discussion

In this review, we highlighted a portion of the available evidence on SGLT2is across approved therapeutic settings, offering a broad overview of their applications to help guide practitioners in choosing SoC therapies for T2DM, HF or CKD. Whilst slight differences exist between SGLT2is, these may be attributed to pharmacodynamic or pharmacokinetic variations, and outcomes in clinical trials across the different indications present heterogeneous results in terms of efficacy and safety. As reported in this narrative review, SGLT2is have unique characteristics and data that can assist prescribers in making informed decisions. Box 1 summarizes the main key aspects reported in this review.

Box 1. Key aspects of SGLT2is across different indications .

SGLT2is (dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) emerged as therapies with benefits beyond glucose control, including cardiovascular and renal protection

All SGLT2is inhibit glucose reabsorption in the kidney, improving glycaemia, weight, blood pressure and renal function

Pharmacological differences: bioavailability, selectivity for SGLT2 over SGLT1, metabolism and elimination

Genital infections are the most common adverse effects related to SGLT2is; risk of diabetic ketoacidosis is rare; canagliflozin uniquely associated with amputation risk in some trials

SGLT2is were generally safe in both young and older/frail patients, but renal function thresholds for initiation differ amongst agents

Guidelines (American Diabetes Association, European Society of Cardiology, KDIGO) strongly recommend SGLT2is for patients with type 2 diabetes mellitus + CV risk, HF or chronic kidney disease — even independent of HbA1c

SGLT2is show effectiveness in lowering HbA1c and reducing fat mass, blood pressure and weight. Benefits observed in both primary and secondary prevention populations

SGLT2is show stronger effects than GLP1RAs on HF and kidney outcomes; GLP1RAs may complement them in CV prevention

SGLT2is provide consistent reduction in HF hospitalizations and mortalities in both HFpEF and HFrEF. Dapagliflozin showed mortality and HF hospitalization benefit across all ejection fraction ranges

Combination therapy (SGLT2i + GLP1RA) shows additive benefits on HbA1c, weight and cardiorenal outcomes

SGLT2is (notably dapagliflozin and empagliflozin) slow chronic kidney disease progression and reduce risk of renal and CV death, with proven benefit even in patients without type 2 diabetes mellitus

Cost-effectiveness studies favour early initiation of SGLT2is due to reduced hospitalizations, mortality and disease progression

CV, cardiovascular; GLP1RAs, GLP1 receptor agonists; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; SGLT2is, sodium–glucose co-transporter 2 inhibitors.

Recent evidence emphasizes the importance of early initiation of SGLT2is to achieve better clinical outcomes and a favourable impact on healthcare systems. A key insight supporting early initiation comes from a recent meta-analysis by Maddaloni et al., which suggests that the greatest kidney protection benefits may be achieved when SGLT2is are initiated early in individuals with preserved eGFRs.147 The rapid decline in kidney and heart function, particularly in patients with T2DM, underscores the need for effective cardioprotective and renoprotective therapies.148

Across the different indications of SGLT2is, early intervention and treatment are well recognized in the guidelines, and it could participate in a paradigm shift towards a global benefit on survival, quality of life, and a decrease in economic burden on national health systems of cardiometabolic and renal diseases. According to the available evidence, it is time to start considering the early initiation of SGLT2is as another paradigm in the treatment of CMR diseases.

Amongst SGLT2is, dapagliflozin is supported by a consistent body of evidence, favouring its early initiation in patients with T2DM and CKD, and demonstrating a unique benefit in reducing CV death in HF irrespective of ejection fraction.143 Empagliflozin also has extensive evidence showing statistically significant CV and renal benefits in patients with and without T2DM; however, important gaps remain, including limited data in primary prevention for T2DM, inconsistent results across ejection fraction subgroups in HF trials, and modest evidence regarding all-cause mortality in CKD populations.10,16,106,107 Nevertheless, dapagliflozin is not without limitations, as reflected by the modest reduction in MACE observed in the DECLARE-TIMI 58 trial.9 These variations should be interpreted in the context of trial heterogeneity rather than as evidence of comparative superiority. In the absence of head-to-head randomized trials, treatment selection should be guided by patient characteristics, regulatory indications and guideline recommendations.

Moreover, the position of dapagliflozin’s selectivity (in the middle between the highly selective SGLT2is ertugliflozin and empagliflozin, and the low selectivity of canagliflozin and sotagliflozin) seems to favour its effect on renal function, even if more data are required.149 Data on dapagliflozin suggests that this agent could decrease a range of adverse outcomes, whilst decreasing related costs, accounting also for a longer time horizon. Moreover, dapagliflozin showed a benefit on CV death reduction in HF across LVEF. The dapagliflozin benefits on kidney function decline are also consistent in patients with CKD without T2DM. Aside from these minor yet detectable differences, rigorously conducted meta-analyses and head-to-head clinical trials are required to clarify whether clinically meaningful differences exist within the class.

Importantly, this review is limited by its narrative design and by the evolving nature of the evidence base, which may influence interpretation of intra-class differences over time. The heterogeneity across trials, absence of head-to-head randomized comparisons, and evolving indications limit direct comparative interpretation. Clinical decisions should therefore prioritize patient phenotype, comorbidities, regulatory indications and local guideline recommendations rather than perceived intra-class hierarchy. Interpretation of outcomes should remain aligned with regulatory indications, particularly those defined by the EMA, which are based on agent-specific evidence from dedicated trials.

Conclusion

In summary, SGLT2is represent a foundational therapeutic class across the CMR continuum. Evidence supports consistent CV safety and meaningful reductions in selected outcomes, particularly HF events and kidney disease progression. Differences amongst individual agents reflect the current evidence landscape rather than definitive superiority, underscoring the importance of individualized treatment strategies and ongoing comparative research. These favourable effects may also be mediated by direct protective action on the vascular endothelium, positioning SGLT2is as a new class of endothelium-protective agents, capable of improving vascular function and modulating chronic inflammatory states. However, the mechanistic pathways beyond the various SGLT2i effects are still being clarified in clinical settings. Future head-to-head studies and comprehensive meta-analyses will likely clarify further differences between SGLT2is, both within the class and in comparison with other SoC agents. It would not be surprising if new indications for this class of drugs emerge in the near future.