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.

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].

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 align 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.

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

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.

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.

REFERENCES

• 1. Thomas MC, Brownlee M, Susztak K, Sharma K, JandeleitDahm KA, Zoungas S, et al. Diabetic kidney disease. Nat Rev Dis Primers 2015;1:15018.PubMedPMC
• 2. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020;395:709-33.PubMedPMC
• 3. Kim NH, Seo MH, Jung JH, Han KD, Kim MK, Kim NH. 2023 Diabetic kidney disease fact sheet in Korea. Diabetes Metab J 2024;48:463-72.ArticlePubMedPMCPDF
• 4. Zoccali C, Mallamaci F, Adamczak M, de Oliveira RB, Massy ZA, Sarafidis P, et al. Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association. Cardiovasc Res 2023;119:2017-32.ArticlePubMedPMCPDF
• 5. Jankowski J, Floege J, Fliser D, Bohm M, Marx N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 2021;143:1157-72.ArticlePubMedPMC
• 6. Agrawal L, Azad N, Emanuele NV, Bahn GD, Kaufman DG, Moritz TE, et al. Observation on renal outcomes in the Veterans Affairs Diabetes Trial. Diabetes Care 2011;34:2090-4.ArticlePubMedPMCPDF
• 7. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62.ArticlePubMed
• 8. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.ArticlePubMed
• 9. Fioretto P, Pontremoli R. Expanding the therapy options for diabetic kidney disease. Nat Rev Nephrol 2022;18:78-9.ArticlePubMedPDF
• 10. Tuttle KR, McGill JB, Haney DJ, Lin TE, Anderson PW; PKCDRS, and PKC-DRS 2 Study Groups. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2007;2:631-6.ArticlePubMed
• 11. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-32.PubMed
• 12. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010;21:527-35.ArticlePubMedPMC
• 13. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-13.ArticlePubMed
• 14. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369:2492-503.ArticlePubMedPMC
• 15. Mann JF, Anderson C, Gao P, Gerstein HC, Boehm M, Ryden L, et al. Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens 2013;31:414-21.PubMed
• 16. Heerspink HJ, Parving HH, Andress DL, Bakris G, CorreaRotter R, Hou FF, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 2019;393:1937-47.PubMed
• 17. van der Aart-van der Beek AB, de Boer RA, Heerspink HJ. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol 2022;18:294-306.ArticlePubMedPDF
• 18. Muskiet MH, Tonneijck L, Smits MM, van Baar MJ, Kramer MH, Hoorn EJ, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017;13:605-28.ArticlePubMedPDF
• 19. Naaman SC, Bakris GL. Diabetic nephropathy: update on pillars of therapy slowing progression. Diabetes Care 2023;46:1574-86.ArticlePubMedPMCPDF
• 20. van Raalte DH, Bjornstad P, Cherney DZ, de Boer IH, Fioretto P, Gordin D, et al. Combination therapy for kidney disease in people with diabetes mellitus. Nat Rev Nephrol 2024;20:433-46.ArticlePubMedPDF
• 21. Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD atlas of renal pathology: diabetic nephropathy. Am J Kidney Dis 2015;66:e37-8.ArticlePubMed
• 22. Fiorentino M, Bolignano D, Tesar V, Pisano A, Biesen WV, Tripepi G, et al. Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies. Nephrol Dial Transplant 2017;32:97-110.ArticlePubMed
• 23. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C: dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000;49:1939-45.ArticlePubMedPDF
• 24. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20.ArticlePubMedPDF
• 25. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol 2021;17:319-34.ArticlePubMedPDF
• 26. Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia 2018;61:2079-86.ArticlePubMedPMCPDF
• 27. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752-72.ArticlePubMed
• 28. Thomas MC, Cherney DZ. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 2018;61:2098-107.ArticlePubMedPDF
• 29. Schaub JA, AlAkwaa FM, McCown PJ, Naik AS, Nair V, Eddy S, et al. SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes. J Clin Invest 2023;133:e164486.ArticlePubMedPMC
• 30. Tuttle KR. Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors. J Clin Invest 2023;133:e167700.ArticlePubMedPMC
• 31. Herat LY, Magno AL, Rudnicka C, Hricova J, Carnagarin R, Ward NC, et al. SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl Sci 2020;5:169-79.PubMedPMC
• 32. Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep 2019;21:70.ArticlePubMedPDF
• 33. Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, et al. Water conservation overrides osmotic diuresis during SGLT2 inhibition in patients with heart failure. J Am Coll Cardiol 2024;83:1386-98.ArticlePubMed
• 34. Marton A, Kaneko T, Kovalik JP, Yasui A, Nishiyama A, Kitada K, et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol 2021;17:65-77.ArticlePubMedPDF
• 35. Packer M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis. Circulation 2022;146:1383-405.ArticlePubMedPMC
• 36. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.ArticlePubMed
• 37. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.ArticlePubMed
• 38. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.ArticlePubMed
• 39. Levin A, Perkovic V, Wheeler DC, Hantel S, George JT, von Eynatten M, et al. Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories: post hoc analysis of a randomized, double-blind, placebo-controlled, multinational trial. Clin J Am Soc Nephrol 2020;15:1433-44.PubMedPMC
• 40. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6:691-704.ArticlePubMed
• 41. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation 2018;138:1537-50.ArticlePubMedPMC
• 42. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Effect of canagliflozin on renal and cardiovascular outcomes across different levels of albuminuria: data from the CANVAS program. J Am Soc Nephrol 2019;30:2229-42.ArticlePubMedPMC
• 43. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Relative and absolute risk reductions in cardiovascular and kidney outcomes with canagliflozin across KDIGO risk categories: findings from the CANVAS program. Am J Kidney Dis 2021;77:23-34.e1.ArticlePubMed
• 44. Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019;7:606-17.ArticlePubMed
• 45. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZ, Dagogo-Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021;6:148-58.ArticlePubMed
• 46. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJ, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.ArticlePubMed
• 47. Heerspink HJ, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.ArticlePubMed
• 48. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023;388:117-27.ArticlePubMed
• 49. Tobe SW, Mavrakanas TA, Bajaj HS, Levin A, Tangri N, Slee A, et al. Impact of canagliflozin on kidney and cardiovascular outcomes by type 2 diabetes duration: a pooled analysis of the CANVAS program and CREDENCE trials. Diabetes Care 2024;47:501-7.ArticlePubMedPMCPDF
• 50. Yu J, Sweeting AN, Gianacas C, Houston L, Lee V, Fletcher RA, et al. The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: insights from the CANVAS program and CREDENCE trial. Diabetes Obes Metab 2023;25:3724-35.PubMed
• 51. Cherney DZ, Dekkers CC, Barbour SJ, Cattran D, Abdul Gafor AH, Greasley PJ, et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol 2020;8:582-93.ArticlePubMed
• 52. Persson F, Rossing P, Vart P, Chertow GM, Hou FF, Jongs N, et al. Efficacy and safety of dapagliflozin by baseline glycemic status: a prespecified analysis from the DAPA-CKD trial. Diabetes Care 2021;44:1894-7.ArticlePubMedPMCPDF
• 53. EMPA-KIDNEY Collaborative Group. Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPAKIDNEY trial. Lancet Diabetes Endocrinol 2024;12:51-60.PubMed
• 54. EMPA-KIDNEY Collaborative Group. Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-kidney trial. Lancet Diabetes Endocrinol 2024;12:39-50.PubMed
• 55. Jongs N, Greene T, Chertow GM, McMurray JJV, Langkilde AM, Correa-Rotter R, et al. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:755-66.ArticlePubMed
• 56. Chertow GM, Vart P, Jongs N, Toto RD, Gorriz JL, Hou FF, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol 2021;32:2352-61.ArticlePubMedPMC
• 57. Waijer SW, Vart P, Cherney DZ, Chertow GM, Jongs N, Langkilde AM, et al. Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial. Diabetologia 2022;65:1085-97.ArticlePubMedPMCPDF
• 58. Heerspink HJ, Jongs N, Chertow GM, Langkilde AM, McMurray JJ, Correa-Rotter R, et al. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:743-54.ArticlePubMed
• 59. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022;400:1788-801.PubMedPMC
• 60. Jardine M, Zhou Z, Lambers Heerspink HJ, Hockham C, Li Q, Agarwal R, et al. Kidney, cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria: a CREDENCE secondary analysis. Clin J Am Soc Nephrol 2021;16:384-95.PubMedPMC
• 61. McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the complexity of GLP-1 action from sites of synthesis to receptor activation. Endocr Rev 2021;42:101-32.ArticlePubMedPDF
• 62. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes: state-of-the-art. Mol Metab 2021;46:101102.ArticlePubMed
• 63. Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol 2023;19:201-16.ArticlePubMedPDF
• 64. Tonneijck L, Smits MM, Muskiet MH, Hoekstra T, Kramer MH, Danser AH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, doubleblind, placebo-controlled trial. Diabetes Care 2016;39:2042-50.ArticlePubMedPDF
• 65. von Scholten BJ, Persson F, Rosenlund S, Hovind P, Faber J, Hansen TW, et al. The effect of liraglutide on renal function: a randomized clinical trial. Diabetes Obes Metab 2017;19:239-47.ArticlePubMedPDF
• 66. Tonneijck L, Muskiet MH, Smits MM, Hoekstra T, Kramer MH, Danser AH, et al. Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: an 8-week, randomised, open-label trial. Diabetes Obes Metab 2017;19:1669-80.ArticlePubMedPDF
• 67. Lovshin JA, Barnie A, DeAlmeida A, Logan A, Zinman B, Drucker DJ. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care 2015;38:132-9.ArticlePubMedPDF
• 68. Shaman AM, Bain SC, Bakris GL, Buse JB, Idorn T, Mahaffey KW, et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation 2022;145:575-85.ArticlePubMed
• 69. Mann JF, Buse JB, Idorn T, Leiter LA, Pratley RE, Rasmussen S, et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab 2021;23:2058-66.ArticlePubMedPMCPDF
• 70. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019;394:131-8.PubMed
• 71. Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;385:896-907.ArticlePubMed
• 72. Lam CS, Ramasundarahettige C, Branch KR, Sattar N, Rosenstock J, Pratley R, et al. Efpeglenatide and clinical outcomes with and without concomitant sodium-glucose cotransporter-2 inhibition use in type 2 diabetes: exploratory analysis of the AMPLITUDE-O trial. Circulation 2022;145:565-74.PubMed
• 73. Sattar N, Lee MM, Kristensen SL, Branch KR, Del Prato S, Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653-62.ArticlePubMed
• 74. Rossing P, Baeres FM, Bakris G, Bosch-Traberg H, Gislum M, Gough SC, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 2023;38:2041-51.ArticlePubMedPMCPDF
• 75. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JF, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med 2024;391:109-21.ArticlePubMed
• 76. Mann JF, Rossing P, Bakris G, Belmar N, Bosch-Traberg H, Busch R, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med 2024;30:2849-56.ArticlePubMedPMCPDF
• 77. Palmer SC, Tendal B, Mustafa RA, Vandvik PO, Li S, Hao Q, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network metaanalysis of randomised controlled trials. BMJ 2021;372:m4573.PubMedPMC
• 78. Yamada T, Wakabayashi M, Bhalla A, Chopra N, Miyashita H, Mikami T, et al. Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis. Cardiovasc Diabetol 2021;20:14.ArticlePubMedPMCPDF
• 79. Kawai Y, Uneda K, Yamada T, Kinguchi S, Kobayashi K, Azushima K, et al. Comparison of effects of SGLT-2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus patients with/without albuminuria: a systematic review and network meta-analysis. Diabetes Res Clin Pract 2022;183:109146.ArticlePubMed
• 80. Edmonston D, Mulder H, Lydon E, Chiswell K, Lampron Z, Shay C, et al. Kidney and cardiovascular effectiveness of SGLT2 inhibitors vs GLP-1 receptor agonists in type 2 diabetes. J Am Coll Cardiol 2024;84:696-708.ArticlePubMed
• 81. Xie Y, Bowe B, Gibson AK, McGill JB, Maddukuri G, Yan Y, et al. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: emulation of a target trial using health care databases. Diabetes Care 2020;43:2859-69.ArticlePubMedPDF
• 82. Fadini GP, Longato E, Morieri ML, Bonora E, Consoli A, Fattor B, et al. Comparative renal outcomes of matched cohorts of patients with type 2 diabetes receiving SGLT2 inhibitors or GLP-1 receptor agonists under routine care. Diabetologia 2024;67:2585-97.ArticlePubMedPMCPDF
• 83. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 2023;148:1606-35.ArticlePubMed
• 84. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2025. Diabetes Care 2025;48(Supplement 1):S181-206.
• 85. Choi JH, Lee KA, Moon JH, Chon S, Kim DJ, Kim HJ, et al. 2023 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association. Diabetes Metab J 2023;47:575-94.PubMedPMC
• 86. Marx N, Federici M, Schutt K, Muller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J 2023;44:4043-140.PubMed
• 87. Mazer CD, Hare GM, Connelly PW, Gilbert RE, Shehata N, Quan A, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation 2020;141:704-7.ArticlePubMed
• 88. Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, et al. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol 2020;8:903-14.ArticlePubMed
• 89. Neuen BL, Oshima M, Perkovic V, Agarwal R, Arnott C, Bakris G, et al. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur Heart J 2021;42:4891-901.ArticlePubMedPDF
• 90. Neuen BL, Oshima M, Agarwal R, Arnott C, Cherney DZ, Edwards R, et al. Sodium-glucose cotransporter 2 inhibitors and risk of hyperkalemia in people with type 2 diabetes: a meta-analysis of individual participant data from randomized, controlled trials. Circulation 2022;145:1460-70.ArticlePubMed
• 91. Lim S, Bae JH, Oh H, Hwang IC, Yoon YE, Cho GY. Effect of ertugliflozin on left ventricular function in type 2 diabetes and pre-heart failure: the Ertu-GLS randomized clinical trial. Cardiovasc Diabetol 2024;23:373.ArticlePubMedPMCPDF
• 92. Bozkurt B. Contemporary pharmacological treatment and management of heart failure. Nat Rev Cardiol 2024;21:545-55.ArticlePDF
• 93. Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med 2024;390:1394-407.
• 94. Davies MJ, van der Meer P, Verma S, Patel S, Chinnakondepalli KM, Borlaug BA, et al. Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA1c levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2025;13:196-209.Article
• 95. Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, Shah SJ, et al. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF program. J Am Coll Cardiol 2024;84:27-40.PubMed
• 96. Solomon SD, Ostrominski JW, Wang X, Shah SJ, Borlaug BA, Butler J, et al. Effect of semaglutide on cardiac structure and function in patients with obesity-related heart failure. J Am Coll Cardiol 2024;84:1587-602.ArticlePubMed
• 97. Verma S, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, et al. Inflammation in obesity-related HFpEF: the STEPHFpEF program. J Am Coll Cardiol 2024;84:1646-62.PubMed
• 98. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASDEASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.ArticlePubMed
• 99. Bae J, Han E, Lee HW, Park CY, Chung CH, Lee DH, et al. Metabolic dysfunction-associated steatotic liver disease in type 2 diabetes mellitus: a review and position statement of the fatty liver research group of the Korean Diabetes Association. Diabetes Metab J 2024;48:1015-28.ArticlePubMedPMCPDF
• 100. Targher G, Tilg H, Byrne CD. Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol 2021;6:578-88.ArticlePubMed
• 101. Bea S, Ko HY, Bae JH, Cho YM, Chang Y, Ryu S, et al. Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease. Gut 2025;74:284-94.ArticlePubMed
• 102. Bae JH, Cho YM. Incretin hormones: revolutionizing the treatment landscape for kidney and liver diseases in type 2 diabetes and obesity. J Diabetes Investig 2025;16:183-6.ArticlePubMed
• 103. Lin DS, Lee JK, Chen WJ. Clinical adverse events associated with sodium-glucose cotransporter 2 inhibitors: a meta-analysis involving 10 randomized clinical trials and 71 553 individuals. J Clin Endocrinol Metab 2021;106:2133-45.ArticlePubMedPDF
• 104. Moon JS, Kim NH, Na JO, Cho JH, Jeong IK, Lee SH, et al. Safety and effectiveness of empagliflozin in Korean patients with type 2 diabetes mellitus: results from a nationwide postmarketing surveillance. Diabetes Metab J 2023;47:82-91.ArticlePubMedPDF
• 105. Musso G, Saba F, Cassader M, Gambino R. Diabetic ketoacidosis with SGLT2 inhibitors. BMJ 2020;371:m4147.ArticlePubMed
• 106. Baek HS, Jeong C, Yang Y, Lee J, Lee J, Lee SH, et al. Diabetic ketoacidosis as an effect of sodium-glucose cotransporter 2 inhibitor: real world insights. Diabetes Metab J 2024;48:1169-75.ArticlePubMedPMCPDF
• 107. Gao FM, Ali AS, Bellomo R, Gaca M, Lecamwasam A, Churilov L, et al. A systematic review and meta-analysis on the safety and efficacy of sodium-glucose cotransporter 2 inhibitor use in hospitalized patients. Diabetes Care 2024;47:2275-90.ArticlePubMedPDF
• 108. Cherney DZ, Cosentino F, Dagogo-Jack S, McGuire DK, Pratley R, Frederich R, et al. Ertugliflozin and slope of chronic eGFR: prespecified analyses from the randomized VERTIS CV trial. Clin J Am Soc Nephrol 2021;16:1345-54.PubMedPMC
• 109. Htoo PT, Tesfaye H, Schneeweiss S, Wexler DJ, Everett BM, Glynn RJ, et al. Effectiveness and safety of empagliflozin: final results from the EMPRISE study. Diabetologia 2024;67:1328-42.ArticlePubMedPDF
• 110. Pan HC, Chen JY, Chen HY, Yeh FY, Huang TT, Sun CY, et al. Sodium-glucose cotransport protein 2 inhibitors in patients with type 2 diabetes and acute kidney disease. JAMA Netw Open 2024;7:e2350050.ArticlePubMedPMC
• 111. Butler J, Packer M, Siddiqi TJ, Bohm M, Brueckmann M, Januzzi JL, et al. Efficacy of empagliflozin in patients with heart failure across kidney risk categories. J Am Coll Cardiol 2023;81:1902-14.ArticlePubMed
• 112. Drucker DJ. Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity. Diabetes Care 2024;47:1873-88.ArticlePubMedPDF
• 113. Mann JF, Hansen T, Idorn T, Leiter LA, Marso SP, Rossing P, et al. Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials. Lancet Diabetes Endocrinol 2020;8:880-93.ArticlePubMed
• 114. Mahaffey KW, Tuttle KR, Arici M, Baeres FM, Bakris G, Charytan DM, et al. Cardiovascular outcomes with semaglutide by severity of chronic kidney disease in type 2 diabetes: the FLOW trial. Eur Heart J 2025;46:1096-108.ArticlePubMedPDF
• 115. Rodriguez PJ, Zhang V, Gratzl S, Do D, Goodwin Cartwright B, Baker C, et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among US adults with overweight or obesity. JAMA Netw Open 2025;8:e2457349.ArticlePubMedPMC
• 116. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;325:1414-25.PubMed
• 117. EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Agrawal N, Wanner C, Green JB, et al. Long-term effects of empagliflozin in patients with chronic kidney disease. N Engl J Med 2025;392:777-87.ArticlePubMed
• 118. Apperloo EM, Neuen BL, Fletcher RA, Jongs N, Anker SD, Bhatt DL, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2024;12:545-57.ArticlePubMed
• 119. Neuen BL, Fletcher RA, Heath L, Perkovic A, Vaduganathan M, Badve SV, et al. Cardiovascular, kidney, and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis. Circulation 2024;150:1781-90.ArticlePubMed
• 120. Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2016;4:1004-16.ArticlePubMed
• 121. Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2019;7:356-67.ArticlePubMed
• 122. van Ruiten CC, van der Aart-van der Beek AB, IJzerman RG, Nieuwdorp M, Hoogenberg K, van Raalte DH, et al. Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: a prespecified secondary analysis of a randomized controlled clinical trial. Diabetes Obes Metab 2021;23:1851-8.PubMedPMC
• 123. van der Aart-van der Beek AB, Apperloo E, Jongs N, Rouw DB, Sjostrom CD, Friedli I, et al. Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: a randomized cross-over clinical study. Diabetes Obes Metab 2023;25:1758-68.ArticlePubMedPDF
• 124. Gullaksen S, Vernstrom L, Sorensen SS, Ringgaard S, Laustsen C, Funck KL, et al. Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial. Diabetologia 2023;66:813-25.ArticlePubMedPDF
• 125. Wu H, Gonzalez Villalobos R, Yao X, Reilly D, Chen T, Rankin M, et al. Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies. Cell Metab 2022;34:1064-78.e6.ArticlePubMedPMC
• 126. Sourris KC, Ding Y, Maxwell SS, Al-Sharea A, Kantharidis P, Mohan M, et al. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int 2024;105:132-49.ArticlePubMed
• 127. Schousboe JT, Landsteiner A, Drake T, Sultan S, Langsetmo L, Kaka A, et al. Cost-effectiveness of newer pharmacologic treatments in adults with type 2 diabetes: a systematic review of cost-effectiveness studies for the American College of Physicians. Ann Intern Med 2024;177:633-42.ArticlePubMedPDF
• 128. Global Health & Population Project on Access to Care for Cardiometabolic Diseases (HPACC). Expanding access to newer medicines for people with type 2 diabetes in low-income and middle-income countries: a cost-effectiveness and price target analysis. Lancet Diabetes Endocrinol 2021;9:825-36.ArticlePubMed
• 129. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020;383:2219-29.ArticlePubMed
• 130. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021;385:2252-63.ArticlePubMed
• 131. Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022;43:474-84.ArticlePubMedPDF
• 132. Vaduganathan M, Filippatos G, Claggett BL, Desai AS, Jhund PS, Henderson A, et al. Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes. Nat Med 2024;30:3758-64.ArticlePubMedPMCPDF
• 133. Banerjee M, Maisnam I, Pal R, Mukhopadhyay S. Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis. Eur Heart J 2023;44:3686-96.ArticlePubMedPDF
• 134. Kutz A, Kim DH, Wexler DJ, Liu J, Schneeweiss S, Glynn RJ, et al. Comparative cardiovascular effectiveness and safety of SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors according to frailty in type 2 diabetes. Diabetes Care 2023;46:2004-14.ArticlePubMedPMCPDF
• 135. Hanlon P, Butterly E, Wei L, Wightman H, Almazam SA, Alsallumi K, et al. Age and sex differences in efficacy of treatments for type 2 diabetes: a network meta-analysis. JAMA 2025;333:1062-73.ArticlePubMedPMC
• 136. Dennis JM, Young KG, Cardoso P, Gudemann LM, McGovern AP, Farmer A, et al. A five-drug class model using routinely available clinical features to optimise prescribing in type 2 diabetes: a prediction model development and validation study. Lancet 2025;405:701-14.ArticlePubMed

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Bae JH. SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application. Diabetes Metab J. 2025;49(3):386-402.

Received: Mar 18, 2025; Accepted: Apr 23, 2025

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

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