SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application

Article information

Diabetes Metab J. 2025;49(3):386-402

Publication date (electronic) : 2025 May 1

doi : https://doi.org/10.4093/dmj.2025.0220

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Jae Hyun Bae https://orcid.org/0000-0002-1384-6123 Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail: fermatah@gmail.com

Received 2025 March 18; Accepted 2025 April 23.

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and significantly increases cardiovascular risk and mortality. Despite conventional therapies, including renin-angiotensin-aldosterone system inhibitors, substantial residual risk remains. The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped DKD management. Beyond glycemic control, these agents provide distinct and complementary cardiorenal benefits through mechanisms such as hemodynamic modulation, anti-inflammatory effects, and metabolic adaptations. Landmark trials, including CREDENCE, DAPA-CKD, EMPA-KIDNEY, and FLOW, have demonstrated their efficacy in preserving kidney function and reducing adverse outcomes. SGLT2 inhibitors appear more effective in mitigating glomerular hyperfiltration and lowering heart failure risk, whereas GLP-1 receptor agonists are particularly beneficial in reducing albuminuria and atherosclerotic cardiovascular events. Although indirect comparisons suggest that SGLT2 inhibitors may offer greater protection against kidney function decline, direct head-to-head trials are lacking. Combination therapy holds promise, however further studies are needed to define optimal treatment strategies. This review synthesizes current evidence, evaluates comparative effectiveness, and outlines future directions in DKD management, emphasizing precision medicine approaches to enhance clinical outcomes. The integration of these therapies represents a paradigm shift in diabetes care, expanding treatment options for people with diabetes mellitus at risk of kidney failure.

Keywords: Diabetes mellitus; Diabetic nephropathies; Glucagon-like peptide-1 receptor agonists; Renal insufficiency, chronic; Sodium-glucose transporter 2 inhibitors

KEY FIGURE

Highlights

• SGLT2 inhibitors and GLP-1 receptor agonists provide distinct cardiorenal protection.

• SGLT2 inhibitors slow DKD progression mainly by reducing glomerular hyperfiltration.

• GLP-1 receptor agonists lower albuminuria and ASCVD risk via anti-inflammatory effects.

• Recent trials confirm complementary kidney protection by both drug classes.

• Combined use of the two drug classes may enhance clinical outcomes in DKD.

INTRODUCTION

Diabetic kidney disease (DKD) is one of the most common and debilitating complications of diabetes mellitus, affecting approximately 40% of people with diabetes mellitus and representing the leading global cause of end-stage kidney disease (ESKD) [1]. According to the Global Burden of Disease Study, both type 1 and type 2 diabetes mellitus substantially contribute to chronic kidney disease (CKD)-related disability-adjusted life-years (DALYs). Among CKD causes, type 2 diabetes mellitus is notably the only condition demonstrating a significant increase in age-standardized DALY rates between 1990 and 2017, accounting for one-third of CKD-attributable DALYs [2]. This trend has been observed particularly in aging populations, including Korea, where one in four people with diabetes mellitus is affected by DKD, and the prevalence of ESKD continues to rise in older adults [3].

Beyond its high prevalence and disease burden, DKD markedly increases cardiovascular disease (CVD) risk and mortality [4]. People with CKD stages 1–3 have significantly elevated cardiovascular risks compared to the general population, while nearly half of those with CKD stages 4–5 experience CVD [5]. In these advanced stages, cardiovascular mortality—primarily due to atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and arrhythmias—accounts for approximately 40% to 50% of deaths [5].

Conventional therapies targeting classical risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, confer partial protective effects but do not completely halt DKD progression or sufficiently mitigate its associated cardiovascular risk [6]. Over the past three decades, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) established renin-angiotensin-aldosterone system (RAAS) blockade as the cornerstone of DKD management [7,8]. Although RAAS inhibitors slows estimated glomerular filtration rate (eGFR) decline and reduces the relative risk of kidney failure by approximately 20%, substantial residual risk remains [9]. Several alternative therapeutic strategies have been investigated, including protein kinase C β inhibitors [10], darbepoetin alfa [11], endothelin receptor antagonists (ERAs) [12], direct renin inhibitors [13], nuclear factor erythroid 2-related factor 2 activators [14], and combination of ACE inhibitor and ARB [15]. However, none have demonstrated clinically meaningful cardiorenal improvements. For instance, atrasentan, an ERA, reduced kidney outcome risk by 35% but was also associated with a non-significant increase in hospitalization for HF [16]. Other therapies were linked to increased adverse events such as stroke [11], hyperkalemia [13,15], hypotension [13], acute kidney injury (AKI) [15], and major adverse cardiovascular events (MACE) [14].

Recently, two novel therapeutic classes have emerged: sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Initially developed as glucose-lowering therapies, both classes have shown impressive cardiovascular and kidney-protective effects [17,18]. Despite overlapping benefits, growing evidence suggests that these agents have distinct and complementary roles in clinical practice. This review synthesizes current evidence regarding SGLT2 inhibitors and GLP-1 receptor agonists in DKD, examines their mechanisms and clinical outcomes, and highlights future research directions to address ongoing therapeutic needs.

PATHOPHYSIOLOGY OF DKD

DKD arises from a complex interplay of metabolic, inflammatory, and hemodynamic disturbances, differing notably between type 1 and type 2 diabetes mellitus [19,20]. In type 1 diabetes mellitus, DKD typically manifests as diabetic glomerulopathy, characterized by thickening of the glomerular basement membrane, mesangial matrix expansion, and hyalinosis affecting both afferent and efferent arterioles [21,22]. These structural alterations result primarily from chronic hyperglycemia and follow a relatively predictable course. Conversely, DKD in type 2 diabetes mellitus shows greater pathological heterogeneity, with some people developing classical glomerular lesions, while others present with atypical features such as prominent tubulointerstitial damage, vascular abnormalities, or coexisting non-DKD pathology [21,22]. Such variability likely reflects additional factors, including aging, obesity, hypertension, and dyslipidemia, that compound kidney injury and accelerate its progression.

At the cellular level, chronic hyperglycemia initiates several pathogenic mechanisms. Unregulated glucose uptake results in excess reactive oxygen species production [23]. Subsequent oxidative stress damages cellular DNA and organelles, activating repair processes that inadvertently divert glucose metabolism toward harmful pathways [24]. These alternate metabolic routes lead to accumulation of toxic intermediates and advanced glycation end products, promoting inflammation, cellular dysfunction, apoptosis, and fibrosis within kidney tissues [24,25].

Hemodynamic disturbances play a central role in DKD progression. Elevated glucose concentrations activate the RAAS, constricting efferent arterioles and thereby increasing intraglomerular pressure [25]. Initially adaptive, this hyperfiltration response compensates for declining nephron mass but eventually exacerbates glomerular damage. Early podocyte injury, characterized by their effacement and detachment, compromises the filtration barrier integrity and contributes to albuminuria and subsequent glomerulosclerosis [1,19]. Moreover, increased proximal tubular glucose reabsorption disrupts normal tubuloglomerular feedback, further amplifying intraglomerular pressures [25].

Collectively, these intertwined metabolic, inflammatory, and hemodynamic processes underpin the development and progression of DKD (Fig. 1). A comprehensive understanding of these pathways is essential to inform targeted therapeutic strategies.

Fig. 1.

Pathophysiology of diabetic kidney disease and therapeutic targets of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; DKD, diabetic kidney disease; ASCVD, atherosclerotic cardiovascular disease.

SGLT2 INHIBITORS IN DKD

Mechanisms of action

SGLT2 inhibitors primarily act by blocking SGLT2 located on the luminal membranes of proximal renal tubules (S1 and S2 segments). This inhibition reduces reabsorption of filtered glucose and sodium, promoting glycosuria and natriuresis [26]. Glycosuria contributes directly to improved glycemic control, while increased distal sodium delivery restores normal tubuloglomerular feedback, thereby lowering intraglomerular pressure, which is a key mechanism in slowing DKD progression [25,27]. Additionally, these agents favorably impact cardiovascular risk factors, including reductions in blood pressure and body weight, further enhancing kidney protection [27,28].

Recent preclinical data have illuminated additional molecular pathways underlying SGLT2 inhibitor-induced kidney protection. These agents activate AMP-activated protein kinase signaling, leading to suppression of mammalian target of rapamycin complex 1 activity and reduced expression of pro-inflammatory cytokines and adhesion molecules [29]. Such effects help mitigate oxidative stress, inflammation, and subsequent kidney fibrosis [30]. Furthermore, SGLT2 inhibitors may attenuate sympathetic nervous system hyperactivity, a common feature in people with type 2 diabetes mellitus and CKD, potentially through decreasing oxidative stress and inflammation [31,32]. These findings suggest that the effects of SGLT2 inhibitors extend beyond hemodynamic improvements, involving direct modulation of intracellular pathways implicated in kidney injury.

Interestingly, while glycosuria and natriuresis persist, osmotic diuresis typically diminishes with continued SGLT2 inhibitor treatment. In people with HF, this is accompanied by a metabolic shift toward water and energy conservation [33], resembling estivation, a physiological adaptation observed in animals during prolonged nutrient and water scarcity [34]. This reprogramming may underlie the sustained kidney benefits associated with these agents [34,35].

Clinical evidence: key trials and outcomes

The kidney-protective potential of SGLT2 inhibitors was first identified in cardiovascular outcome trials, including Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) [36], Canagliflozin Cardiovascular Assessment Study (CANVAS) [37], and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) [38]. Although these trials primarily enrolled individuals with relatively low DKD risk and were not designed to evaluate kidney outcomes specifically, exploratory analyses consistently indicated slower kidney disease progression across diverse eGFR and albuminuria levels [39-44].

A subsequent meta-analysis involving six major cardiovascular and kidney outcome trials confirmed these early observations, showing a 36% reduction in composite kidney outcomes regardless of baseline ASCVD status [45]. Notably, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the first dedicated kidney outcome trial evaluating canagliflozin in people with type 2 diabetes mellitus and CKD, demonstrated a substantial reduction in the risk of kidney events [46]. Similarly, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) [47] and the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) [48] trials expanded inclusion beyond diabetes mellitus, showing that dapagliflozin and empagliflozin significantly reduced the risk of kidney outcomes, with consistent benefits across a wide range of eGFR and albuminuria.

CREDENCE

The CREDENCE trial enrolled 4,401 participants with type 2 diabetes mellitus and CKD, with a mean eGFR of 56.2 mL/min/1.73 m² and a median urinary albumin-to-creatinine ratio (UACR) of 927 mg/g (Table 1, Fig. 2) [46]. Canagliflozin reduced the risk of the primary composite outcome (ESKD, doubling of serum creatinine, or renal or cardiovascular death) by 30% compared to placebo, with consistent effects across all prespecified subgroups [46]. Significant risk reductions were also observed for key secondary outcomes (ESKD, doubling of serum creatinine, or renal death) and exploratory outcomes (dialysis, kidney transplantation, or renal death) [46]. Furthermore, pooled analyses from CANVAS and CREDENCE reinforced the kidney protection of canagliflozin in DKD, irrespective of diabetes duration [49] or body mass index [50].

Table 1.

Kidney outcome trials of SGLT2 inhibitors and GLP-1 receptor agonists in people with chronic kidney disease and diabetes mellitus

Fig. 2.

Randomized clinical trials evaluating kidney outcomes of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon- like peptide-1 (GLP-1) receptor agonists in people with chronic kidney disease and diabetes mellitus. CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; EMPA-KIDNEY, Study of Heart and Kidney Protection with Empagliflozin; FLOW, Evaluate Renal Function With Semaglutide Once Weekly; REMODEL, A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People With Type 2 Diabetes and Chronic Kidney Disease (NCT04865770); nsMRA, nonsteroidal mineralocorticoid receptor antagonist; CONFIDENCE, COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint (NCT05254002); GIP, glucosedependent insulinotropic polypeptide; DACRA, dual amylin and calcitonin receptor agonist; TREASURE-CKD, A Study of Tirzepatide (LY3298176) in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes (NCT05536804); Renal Lifecycle, A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe Chronic Kidney Disease (NCT05374291); TRIUMPH-Outcomes, The Effect of Retatrutide Once Weekly on Cardiovascular Outcomes and Kidney Outcomes in Adults (NCT06383390); PRECIDENTD, PREvention of CardIovascular and DiabEtic kidNey Disease in Type 2 Diabetes (NCT05390892). aPhase 2 randomized clinical trials.

DAPA-CKD and EMPA-KIDNEY

Given that the kidney-protective effects of SGLT2 inhibitors are independent of glucose lowering [51], DAPA-CKD and EMPA-KIDNEY have included participants both with and without diabetes mellitus (Table 1, Fig. 2).

In DAPA-CKD, among 4,304 participants (67.5% with type 2 diabetes mellitus and 15.3% with prediabetes at baseline), the mean eGFR was 43.1 mL/min/1.73 m² and the median UACR was 949 mg/g [47,52]. Dapagliflozin reduced the primary composite outcome (sustained ≥50% eGFR decline, ESKD, or death from renal or cardiovascular causes) by 39% compared to placebo [47]. It also reduced a secondary kidney composite outcome (sustained ≥50% eGFR decline, ESKD, or renal death) by 44%. These benefits were consistent regardless of baseline diabetes [47] or glycemic status [52]. Notably, reductions in eGFR slope [53] and UACR [54,55] were more pronounced in people with type 2 diabetes mellitus, suggesting additional kidney-protective mechanisms beyond hemodynamic improvements and albuminuria reduction. Prespecified and post hoc analyses confirmed the consistent effects of dapagliflozin across kidney disease: improving global outcomes (KDIGO) risk categories [56,57].

The EMPA-KIDNEY trial enrolled a larger proportion of participants without diabetes mellitus and included individuals with lower mean eGFR (37.3 mL/min/1.73 m²) and median UACR (329 mg/g) compared to DAPA-CKD. Among 6,609 participants, 46% had diabetes (96.4% with type 2 diabetes mellitus), and approximately 31% had DKD [48]. Empagliflozin reduced the primary outcome (kidney disease progression or cardiovascular death) by 28% compared with placebo. Similar benefits were observed for kidney disease progression alone and for a composite of ESKD and cardiovascular death. These effects were consistent regardless of diabetes status, underlying kidney disease, or baseline eGFR [48,53]. Importantly, empagliflozin also slowed kidney disease progression in participants with minimal albuminuria [54].

Both DAPA-CKD and EMPA-KIDNEY demonstrated substantial kidney protection irrespective of diabetes status. However, the magnitude of long-term eGFR preservation [48,58] and absolute risk reduction in kidney outcomes [59] appeared greater in individuals with diabetes mellitus. In EMPA-KIDNEY, a prespecified subgroup analysis showed smaller relative risk reductions among participants with lower baseline albuminuria, likely due to a lower event rate [48]. This pattern aligns with findings from CANVAS [42], CREDENCE [60], and DAPA-CKD [58], in which greater absolute eGFR preservation was noted in participants with higher baseline albuminuria. Nevertheless, empagliflozin consistently slowed eGFR decline compared with placebo across all subgroups [48]. Additional studies are needed to determine whether SGLT2 inhibitors can meaningfully delay kidney disease progression in people with non-albuminuric or non-proteinuric DKD.

GLP-1 RECEPTOR AGONISTS IN DKD

Mechanisms of action

GLP-1 receptor agonists lower blood glucose levels primarily by stimulating insulin and somatostatin secretion and suppressing glucagon release from pancreatic islets, thereby improving glycemic control [61]. In addition, they promote weight loss, reduce blood pressure, and improve postprandial lipid profiles [62].

In the kidney, GLP-1 receptors are predominantly expressed on vascular smooth muscle cells of the afferent arteriole [63]. Their activation acutely increases renal blood flow and glomerular filtration rate via nitric oxide-mediated vasodilation [18]. Interestingly, in people with type 2 diabetes mellitus, who often exhibit glomerular hyperfiltration, GLP-1 receptor agonists stabilize or modestly reduce eGFR, an effect reminiscent of the initial declines observed with RAAS and SGLT2 inhibitors [64]. However, they dose not substantially alter long-term eGFR trajectories [65]. Short-acting agents may induce transient natriuresis, though this effect diminishes with continued use [66,67].

GLP-1 receptor agonists also exert antioxidant, anti-inflammatory, and antifibrotic effects by downregulating pro-inflammatory pathways (e.g., nuclear factor-κB), cytokines (e.g., transforming growth factor β), and T-cell proliferation [18]. Preclinical studies suggest that these properties attenuate kidney inflammation and fibrosis, thus delaying the progression of albuminuria [18,63]. Emerging clinical evidence supports these findings, although the underlying mechanisms remain to be fully elucidated [18,62].

Clinical evidence: key trials and outcomes

GLP-1 receptor agonists have shown kidney benefits in cardiovascular safety trials, primarily by reducing the onset and progression of albuminuria [62]. Post hoc analyses from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) and Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) trials demonstrated that liraglutide and semaglutide significantly reduced albuminuria and slowed eGFR decline in people with type 2 diabetes mellitus, especially those with baseline eGFR <60 mL/ min/1.73 m² or preexisting albuminuria [68]. Mediation analyses suggested that these effects were partly attributable to improvements in glycosylated hemoglobin (HbA1c; 25%–26%) and systolic blood pressure (9%–22%), supporting both direct and indirect mechanisms of kidney protection [69]. In addition, an exploratory analysis from the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial showed a 15% reduction in a composite kidney outcome (new-onset macroalbuminuria, sustained ≥30% eGFR decline, or chronic renal replacement therapy [RRT]), predominantly driven by reductions in macroalbuminuria [70].

The Cardiovascular and Renal Outcomes With Efpeglenatide in Type 2 Diabetes (AMPLITUDE-O) trial evaluated efpeglenatide in people with type 2 diabetes mellitus and either CVD or CKD. The study demonstrated a 32% reduction in a secondary composite kidney outcome, which included incident macroalbuminuria, >30% increase in UACR, sustained >40% decline in eGFR, sustained eGFR <15 mL/min/1.73 m², or the need for RRT lasting >30 days [71]. Among the 4,076 participants, 80% were receiving ACE inhibitors, ARBs, or angiotensin receptor-neprilysin inhibitors, and 15.2% were on SGLT2 inhibitors. Notably, kidney-protective effects and reductions in UACR were observed regardless of concomitant SGLT2 inhibitor use [72]. A recent meta-analysis of randomized controlled trials (RCTs), including AMPLITUDE-O, examining six GLP-1 receptor agonists (lixisenatide, liraglutide, subcutaneous semaglutide, exenatide, dulaglutide, and efpeglenatide) reported a 21% reduction in a composite kidney outcome (macroalbuminuria, doubling of serum creatinine or ≥40% eGFR decline, RRT, or death from kidney disease), corresponding to a number needed to treat of 47 [73].

FLOW

The Evaluate Renal Function With Semaglutide Once Weekly (FLOW) trial is the first dedicated kidney outcome study specifically designed to assess the effect of a GLP-1 receptor agonist (once-weekly subcutaneous semaglutide) in people with type 2 diabetes mellitus and CKD at high-risk of progression (Table 1, Fig. 2) [74]. Eligible participants had CKD defined as either an eGFR of 50–75 mL/min/1.73 m² with UACR 300–5,000 mg/g, or an eGFR of 25 to <50 mL/min/1.73 m² with UACR 100–5,000 mg/g. At baseline, 75.3% of the 3,533 participants were receiving ACE inhibitors or ARBs, and 15.6% were using SGLT2 inhibitors. Over a median follow-up of 3.4 years, semaglutide reduced the risk of the primary outcome (kidney failure [initiation of chronic RRT, kidney transplantation, or sustained GFR <15 mL/min/1.73 m²], sustained ≥50% eGFR decline, or kidney-related or cardiovascular death) by 24% compared to placebo [75]. These benefits were consistent across prespecified subgroups, including participants on concurrent SGLT2 inhibitors (P for interaction=0.109) [76]. Semaglutide also significantly reduced the kidney-specific component of the primary outcome and slowed the annual rate of eGFR decline [75].

COMPARATIVE EFFECTIVENESS IN DKD

Network meta-analyses of RCTs

Currently, no RCTs have directly compared SGLT2 inhibitors with GLP-1 receptor agonists for kidney outcomes in DKD. However, several network meta-analyses have provided indirect comparisons in people with type 2 diabetes mellitus across a range of cardiovascular and kidney risk profiles [77-79].

A comprehensive network meta-analysis of 31 trials involving 98,234 participants with type 2 diabetes mellitus receiving various glucose-lowering therapies showed that both drug classes significantly reduced the risk of kidney failure (eGFR <15 mL/min/1.73 m² or RRT) compared to placebo. However, no significant differences were observed between SGLT2 inhibitors and GLP-1 receptor agonists in absolute risk reductions for kidney failure [77]. In contrast, a separate analysis involving 32,949 individuals with type 2 diabetes mellitus and CKD, restricted to placebo-controlled trials of either SGLT2 inhibitors or GLP-1 receptor agonists, reported a 21% greater reduction in a composite kidney outcome (ESKD, decline in kidney function, albuminuria, and renal or cardiovascular death) with SGLT2 inhibitors compared to GLP-1 receptor agonists [78]. Another network meta-analysis also suggested the superiority of SGLT2 inhibitors over GLP-1 receptor agonists for kidney outcomes, independent of baseline albuminuria status [79].

Observational studies

Observational studies have produced mixed results. In a large PCORnet cohort study, SGLT2 inhibitors and GLP-1 receptor agonists showed comparable effectiveness for a composite kidney outcome, including sustained ≥40% eGFR decline, ESKD, or mortality [80]. Similarly, a target trial emulation using U.S. healthcare databases found no significant difference between the two classes in a composite kidney outcome of >50% eGFR decline, ESKD, or all-cause mortality [81]. Baseline eGFR and UACR values in these studies suggest that participants were not predominantly at high-risk for CKD progression [80,81]. In contrast, a multicenter retrospective cohort study, including a higher-risk population (23% with CKD) reported slower eGFR decline and lower risks of CKD progression and doubling of serum creatinine among SGLT2 inhibitor users compared with GLP-1 receptor agonist users. Notably, no significant difference in albuminuria was observed [82].

Overall, indirect comparisons suggest that SGLT2 inhibitors may offer greater preservation of eGFR than GLP-1 receptor agonists in a broader population of people with type 2 diabetes mellitus and CKD. However, direct head-to-head trials are needed to confirm these findings across diverse clinical settings.

CLINICAL PRACTICE CONSIDERATIONS

Cardiovascular-kidney-metabolic traits

The choice between SGLT2 inhibitors and GLP-1 receptor agonists for managing DKD should be guided by a comprehensive assessment of an individual’s cardiovascular-kidney-metabolic (CKM) health [83]. Current guidelines recommend either class for people with type 2 diabetes mellitus and established ASCVD, high cardiovascular risk, HF, or CKD [84,85]. However, specific clinical contexts may inform treatment selection. SGLT2 inhibitors are preferred in people with HF or at high-risk for HF, whereas GLP-1 receptor agonists are favored for those requiring significant weight loss, ASCVD risk reduction, CKD management, or in whom mitigation of metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis is a clinical priority [84].

SGLT2 inhibitors provide substantial benefits for people with type 2 diabetes mellitus and either established HF or elevated HF risk [86]. CKD and HF commonly coexist and exacerbate each other, as CKD increases the risk of HF, while HF accelerates kidney function decline [17]. Notably, SGLT2 inhibitors improve anemia [87,88] and hyperkalemia [89,90], both prevalent complications in CKD and HF. In a recent RCT, ertugliflozin improved left ventricular global longitudinal strain in people with type 2 diabetes mellitus and pre-HF, effects associated with increased ACE2 and angiotensin (1–7) levels, suggesting a potential underlying mechanisms [91]. Based on such findings, guideline-directed medical therapy currently recommends SGLT2 inhibitors for people with type 2 diabetes mellitus who are at risk for HF, have pre-HF, or have established HF [92].

GLP-1 receptor agonists are particularly beneficial for individuals requiring significant weight loss and metabolic improvements. The Semaglutide Treatment Effect in People with Obesity and Heart Failure with Preserved Ejection Fraction and Diabetes Mellitus (STEP-HFpEF DM) trial demonstrated that semaglutide significantly reduced body weight and improved HF-related symptoms and physical limitations in people with obesity-related HF with preserved ejection fraction and type 2 diabetes mellitus [93]. These benefits were independent of baseline HbA1c and occurred without an increased risk of hypoglycemia [94]. Although the underlying mechanisms are not fully understood, proposed contributors include reductions in N-terminal pro–B-type natriuretic peptide levels [95], improvements in cardiac remodeling [96], and anti-inflammatory effects [97]. GLP-1 receptors also hold promise for people with MASLD, a common chronic liver disease linked to increased risk of type 2 diabetes mellitus, CKD, or other cardiometabolic complications [98-100]. Ongoing trials are evaluating their potential benefits in populations with type 2 diabetes mellitus and either CKD or MASLD [101,102].

Safety and limitations

SGLT2 inhibitors are generally well tolerated but are associated with an increased risk of genital infections [103,104] and, rarely, euglycemic diabetic ketoacidosis [105-107]. An initial decline in eGFR is common after treatment initiation but typically stabilizes over time, contributing to long-term preservation of kidney function [108]. A meta-analysis of RCTs and cohort studies showed that SGLT2 inhibitors reduce the risk of AKI across diverse cardiovascular risk profiles [59,109], and are associated with lower mortality, major adverse kidney events, and MACE in acute kidney disease [110]. Importantly, although their glucose-lowering efficacy diminishes in advanced CKD, cardiovascular and kidney benefits remain preserved [111]. Nevertheless, careful patient selection and ongoing monitoring are essential to mitigate potential risks.

GLP-1 receptor agonists are commonly associated with gastrointestinal adverse events, which may lead to dehydration in some people [112]. However, a post hoc analysis of semaglutide trials found no increased risk of kidney-related adverse events compared with active comparators [113]. The FLOW trial further demonstrated that semaglutide reduced cardiovascular risk regardless of baseline CKD severity [114]. Practical considerations include cost and route of administration, as most formulations are injectable, although oral preparations are emerging. In a U.S. cohort study, the 2-year discontinuation rate for GLP-1 receptor agonists was 64.1% among people with type 2 diabetes mellitus, driven by factors such as older age, low income, gastrointestinal adverse events, and insufficient weight loss [115]. Notably, metabolic benefits often diminish after treatment discontinuation [116], underscoring the importance of long-term planning in therapeutic decision-making.

FUTURE PERSPECTIVES

Long-term outcomes

While strong evidence supports the kidney-protective effects of both SGLT2 inhibitors and GLP-1 receptor agonists, the long-term durability of these benefits remains uncertain (Table 2). Most large-scale trials have had relatively short follow-up periods (typically 2 to 4 years), and the sustained efficacy of these therapies beyond this timeframe has not been fully established.

Table 2.

Research gaps and future directions for SGLT2 inhibitors and GLP-1 receptor agonists in diabetic kidney disease

Post-trial follow-up data from EMPA-KIDNEY suggest that cardiorenal benefits may persisted for up to 1 year after treatment cessation, highlighting the importance of continued therapy for long-term effectiveness [117]. Based on findings from the FLOW trial, recent guidelines have elevated GLP-1 receptor agonists to the same level of recommendation as SGLT2 inhibitors for people with CKD [84]. However, dedicated kidney outcome trials for GLP-1 receptor agonists remain limited, and further long-term studies are needed to better define their role in CKD management.

Combination therapies

Combination therapy with SGLT2 inhibitors and GLP-1 receptor agonists offers a promising approach to enhance cardiovascular and kidney protection in people with type 2 diabetes mellitus, particularly those at high risk [9,20]. These agents exert their effects through distinct yet complementary mechanisms that target key pathways involved in the development and progression of DKD (Fig. 1). Evidence from RCTs has shown that the benefits of each agent are maintained regardless of concomitant use [118,119], without a significant increase in the risk of hypoglycemia or AKI [120,121].

Mechanistic studies further support the rationale for combination therapy. Co-administration leads to greater reductions in albuminuria and more pronounced initial declines in eGFR, indicative of reduced intraglomerular pressure [122,123]. Imaging and single-cell transcriptomic analyses demonstrate that SGLT2 inhibitors and GLP-1 receptor agonists improve kidney tissue oxygenation and perfusion, respectively [124], and act on distinct kidney cell types [125,126], reinforcing a biological basis for additive or synergistic effects.

This combination also provides a practical strategy for reducing residual cardiometabolic risk. Stratification based on CKM profiles may help identify individuals most likely to benefit [83]. In clinical practice, SGLT2 inhibitors are often initiated first due to their oral administration and broader reimbursement, with GLP-1 receptor agonists subsequently added to address persistent hyperglycemia, excess body weight, or residual albuminuria [84,85]. Although early combination therapy may increase initial costs, it has the potential to reduce long-term healthcare expenditures by lowering the need for interventions and hospitalizations [127,128]. Further economic analyses are warranted to support sustainable implementation.

In addition to SGLT2 inhibitors and GLP-1 receptor agonists, finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has demonstrated significant cardiovascular and kidney-protective effects in people with type 2 diabetes mellitus and CKD or HF [129-132]. Along with RAAS inhibitors, these therapies are increasingly regarded as foundational components of DKD management [19,133]. Ongoing trials are evaluating the optimal sequencing and combination of these agents to further improve outcomes (Fig. 2).

Research gaps

Despite considerable progress, important research gaps remain. These include elucidating underlying mechanisms, identifying reliable predictors of therapeutic response, and defining benefits in populations underrepresented or excluded from clinical trials [134,135]. Addressing these gaps will facilitate precision medicine by enabling treatment strategies tailored to individual profiles [136], ultimately improving clinical outcomes (Table 2).

CONCLUSIONS

The emergence of SGLT2 inhibitors and GLP‑1 receptor agonists represents a major advancement in the management of DKD. These drug classes have consistently demonstrated substantial benefits in slowing kidney function decline, reducing cardiovascular events, and improving clinical outcomes in people with type 2 diabetes mellitus. Treatment selection should be guided by their mechanisms of action, safety profiles, and person-specific characteristics. Combination therapy may offer additive or synergistic effects, further enhancing cardiovascular and kidney protection. Despite these advances, important questions remain regarding the long-term durability of benefits, the degree of kidney protection independent of glycemic and weight effects, and the optimal integration of these therapies into routine care. As evidence from ongoing clinical trials and real-world studies accumulates, future guidelines are expected to evolve toward more personalized and comprehensive strategies for DKD management.

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None

ACKNOWLEDGMENTS

None

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	CREDENCE, 2019 [46]	DAPA-CKD, 2020 [47]	EMPA-KIDNEY, 2022 [48]	FLOW, 2024 [75]
Medication	Canagliflozin	Dapagliflozin	Empagliflozin	Semaglutide
Mode of action	SGLT2 inhibitor	SGLT2 inhibitor	SGLT2 inhibitor	GLP-1 receptor agonist
No. of participants	4,401	4,304	6,609	3,533
Women	1,494 (33.9)	1,425 (33.1)	2,192 (33.2)	1,069 (30.3)
Age, yr	63.0±9.2	61.8±12.1	63.8±13.9	66.6±9.0
Key inclusion criteria	T2DM (HbA1c 6.5%–12.0%); eGFR 30–<90 mL/min/1.73 m² and UACR >300–5,000	eGFR 25–75 mL/min/1.73 m² and UACR 200–5,000	eGFR 45–<90 mL/min/1.73 m² and UACR ≥200 or eGFR 20–<45 mL/min/1.73 m²	T2DM (HbA1c ≤10%); eGFR 50–75 mL/min/1.73 m² and UACR >300–<5,000 or eGFR 25–<50 mL/min/1.73 m² and UACR >100–<5,000
DM	4,401 (100)	2,906 (67.5)	3,040 (46.0)	3,533 (100)
HbA1c, %	8.3±1.3	7.1±1.7	6.3±1.2	7.8±1.3
BMI, kg/m²	31.3±6.2	29.5±6.2	29.7±6.8	32.0±6.3
eGFR, mL/min/1.73 m²	56.2±18.2	43.1±12.4	37.3±14.5	47.0±15.2
UACR, median	927	949	329	568
RAAS inhibitor use	4,395 (99.9)	4,224 (98.1)	5,628 (85.2)	3,367 (95.3)
Duration of treatment, yr	2.6	2.4	2.0	3.4
Primary endpoint	Composite of ESKD, doubling of serum creatinine, or renal or cardiovascular death	Composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death	Progression of kidney disease (ESKD, sustained eGFR <10 mL/min/1.73 m², sustained eGFR decline ≥40%, or renal death) or cardiovascular death	Composite of kidney failure, sustained eGFR decline ≥50%, or kidney-related or cardiovascular death
Outcome, HR (95% CI)	0.70 (0.59–0.82)	0.61 (0.51–0.72)	0.72 (0.64–0.82)	0.76 (0.66–0.88)
NNT, n (95% CI)	22 (15–38)	19 (15–27)	28 (19–53)	20 (14–40)
Between-group difference in eGFR slope, mL/min/1.73 m²/yr (95% CI)^a	1.52 (1.11–1.93)	0.93 (0.61–1.25)	0.75 (0.54–0.96)	1.16 (0.86–1.47)
Between-group difference in UACR reduction, % (95% CI)^a	31 (26–35)	29 (25–33)	19 (15–23)	32 (25–38)

Topic	Current evidence gap	Future research directions
Underlying mechanisms	Incomplete understanding of the mechanistic, metabolic, and molecular basis underlying cardiorenal benefits beyond glycemic control	Conduct preclinical and clinical studies to elucidate mechanisms, including effects on kidney bioenergetics and tissue-specific pathways
Predictors of response	Lack of validated predictors, including biomarkers or clinical characteristics, to identify responders and guide treatment selection	Develop and validate precision tools to predict treatment response using genomic, metabolic, and biomarker-based data
High-risk populations	Limited evidence in high-risk or underrepresented groups (e.g., advanced CKD, dialysis, kidney transplant, or multimorbidity)	Conduct dedicated and inclusive trials to evaluate efficacy and safety in high-risk and underrepresented populations
Long-term outcomes	Insufficient data on the durability, long-term safety, and consequences of treatment discontinuation	Establish long-term registries and follow-up studies to assess outcomes and treatment sustainability
Therapeutic strategies	Uncertainty regarding the optimal use and integration with existing therapies, including combination regimens	Define evidence-based approaches to combining novel agents with standard-of-care therapies
Clinical implementation	Gaps between clinical evidence and real-world practice, resulting in suboptimal adoption	Conduct implementation research and quality improvement initiatives to enhance uptake and guideline adherence
Economic and preventive implications	Lack of data supporting preventive use in early CKD or high-risk populations	Perform health economic evaluations and assess early intervention strategies for kidney and cardiovascular prevention