Using Diabetes Medicines for Chronic Kidney Disease: How SGLT2 Inhibitors and GLP-1 Receptor Agonists Work, Their Benefits, and Safety

The kidney features a unique double capillary system, with glomerular pressure regulated by the balance of tone between the afferent and efferent arterioles [14]. In diabetes, this balance is often disrupted, leading to glomerular hyperfiltration—an early and critical factor in the development and progression of DKD. Hyperfiltration is typically defined as a glomerular filtration rate (GFR) between 120 and 180 mL/min/1.73 m², or a GFR exceeding two standard deviations above the mean for age-matched healthy individuals [7]. It affects approximately 70% of patients with type 1 diabetes (T1DM) and 50% with type 2 diabetes (T2DM) within the first 1–5 years of diagnosis [19,22].

This elevated intraglomerular pressure predisposes nephrons to structural damage, contributing to long-term nephron loss. Mechanistically, glucose reabsorption in the proximal tubule reduces sodium chloride delivery to the macula densa, impairing tubuloglomerular feedback [23]. As a compensatory response, angiotensin II-mediated vasoconstriction of the efferent arteriole further increases glomerular pressure, exacerbating hyperfiltration. Over time, this leads to mesangial and podocyte stretching, glomerulomegaly, and progressive glomerular injury. In T2DM, the pathology is more heterogeneous and can be categorized into three main classes [24,25]:Class I represents typical diabetic glomerulopathy.Class II presents with relatively preserved glomerular structure but prominent vascular and interstitial changes, often showing early GFR decline without albuminuria.Class III includes subclasses IIIa (19% of cases) and IIIb (18%), both lacking significant glomerular basement membrane (GBM) thickening and mesangial expansion. Patients in this group may also experience silent episodes of acute kidney injury (AKI), contributing to gradual functional decline [20].

Exposure of endothelial cells to high glucose levels activates the polyol pathway, leading to increased reactive oxygen species (ROS) production and mitochondrial dysfunction [26]. This oxidative stress upregulates adhesion molecules, promoting immune cell recruitment and inflammation. In the kidneys, glomerular endothelial cells (GEnCs) line the glomerular capillaries and play a vital role in maintaining filtration barrier integrity [27]. These cells are coated with a glycocalyx, a protective layer of polysaccharides that helps regulate vascular permeability. Loss of this glycocalyx, as seen in diabetic models, is closely linked to the development of albuminuria. Animal studies have shown that mitochondrial damage in GEnCs contributes to increased permeability, podocyte injury, proteinuria, and glomerulosclerosis [28]. However, mitochondria-targeted antioxidants can effectively prevent oxidative stress in GEnCs, preserving fenestrations and protecting against glycocalyx degradation, ultimately reducing endothelial dysfunction and albumin leakage [26].

A significantly elevated risk of cardiovascular disease is common in patients with CKD. Patients with CKD consistently experience dyslipidemia, which is defined by elevated serum triglycerides, low HDL cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels [29]. The primary cause of death for people with eGFR < 60 mL/min per 1.73 m² is cardiovascular disease (CVD). Dyslipidemia in nephrotic syndrome (NS) is characterized by elevated LDL and VLDL levels and normal HDL levels [24]. Recent post hoc and meta-analyses of clinical trial data provide evidence that abnormal lipids are linked to a greater loss of GFR and that statin medication may help with both the progression of CKD and the risk of cardiovascular disease [30]. Statins may even delay the course of stage 3 CKD patients. It seems that statins’ positive effects go beyond just decreasing cholesterol [31].

By preferentially widening the efferent arteriole, ACEIs lower glomerular capillary pressure probably due to the suppression of angiotensin II (AngII) [32]. In fact, most experimental research have shown that angiotensin type 1 receptor blockers (ARBs), which lack the ability to enhance bradykinin, do not significantly dilate the efferent arteriole or lower glomerular pressures to the same degree as ACEIs [33]. The combined usage of ARBs and ACEIs appears to have a higher effect in reducing proteinuria which is not related to effects on systemic blood pressure. The protein LRG1, which is primarily produced by GEnCs, enhances endothelial transforming growth factor/activin receptor-like kinase 1 signaling which contributes to angiogenesis and the pathophysiology of DKD [34]. Global LRG1 mutations reduced glomerular angiogenesis, oxidative damage and provided protection against DKD [31].

Podocytes form the epithelial lining of the glomerulus and are essential for the selective filtration of molecules smaller than 60 kDa. Damage or loss of podocyte foot processes is closely associated with proteinuria and the development of nephrotic syndrome, particularly in advanced stages of DKD [35]. In early DKD, podocyte foot process effacement and widening occur, while significant podocyte loss (>20%) marks an irreversible phase, leading to glomerular scarring and end-stage renal disease (ESRD) [21]. While partial inhibition of the mTOR pathway in podocytes has shown therapeutic benefits, complete loss of mTORC1 activity can worsen kidney damage and promote glomerulosclerosis. In addition to mTOR, podocyte hypertrophy is regulated by key energy-sensing pathways involving LKB1 and AMP-activated protein kinase (AMPK), highlighting their role in maintaining podocyte structure and function under diabetic stress [25].

A range of cytokines and growth factors contribute to the development of glomerular and tubulointerstitial scarring in kidney disease, with their roles varying across different stages of injury [36]. Key mediators include TGF-β, PDGF, Angiotensin II (AngII), basic FGF, endothelin, chemokines, PAI-1, and PPAR-γ, which influence fibrosis through altered gene expression and signaling pathways. Among these, TGF-β is the central driver of renal fibrosis, promoting extracellular matrix (ECM) accumulation. It also induces the expression of PAI-1 and AngII, both of which contribute to fibrotic progression [37]. Elevated PAI-1 levels are associated with both renal and cardiovascular fibrosis. In animal models, transgenic overexpression of TGF-β leads to progressive kidney damage, whereas blocking TGF-β or PDGF-B reduces mesangial matrix expansion, as seen in the anti-Thy1 model [38]. Interestingly, TGF-β deficiency can lead to immune dysregulation and lymphoproliferative disorders, highlighting its dual role in fibrosis and immune modulation. At low concentrations, TGF-β supports podocyte growth arrest and differentiation, indicating its context-dependent effects in kidney pathology [39].

A modest decline in the projected glomerular filtration rate can also be explained by the proximal tubule cell pathway [42]. Remarkably, dapagliflozin treatment reduces the filtration fraction without raising renal vascular resistance. It suggests that post-glomerular vasodilation (not pre-glomerular vasoconstriction) is the cause of SGLT2 inhibition’s lowering outcome for glomerular filtration [43] and explains the renoprotective benefits regardless of the existence of diabetes mellitus by making the well-known SGLT2i action (TGF and glucose-independent) [44].

Beyond glucose control, SGLT2i exhibit notable anti-inflammatory, anti-fibrotic, and anti-hypoxic effects, contributing significantly to their renal and cardiovascular protective benefits in CKD and diabetic nephropathy [45]. These pleiotropic actions are increasingly recognized as key mechanisms behind the favorable outcomes seen in clinical trials. In preclinical studies, phlorizin-mediated SGLT inhibition increased oxygen levels in the renal cortex but reduced medullary pO₂, possibly due to a shift in active transport to the distal nephron [46]. Separately, animal models have shown that dapagliflozin reduces renal injury by enhancing the expression of hypoxia-inducible factor 1 (HIF-1) and related protective proteins in hypoxic kidney cells, suggesting a direct role in mitigating tubulointerstitial hypoxia [47].

SGLT2-mediated glucose uptake in proximal tubular cells is a key driver of oxidative stress and inflammation, contributing to tubular hypoxia and kidney injury [46]. By blocking this pathway, SGLT2i not only improve oxygenation but also reduce cellular stress and injury. Studies in diabetic models have shown that SGLT2 inhibition lowers oxidative, inflammatory, and fibrotic responses—partly by suppressing the AGE–RAGE pathway, a pro-apoptotic cascade triggered by oxidative damage [37]. Moreover, SGLT2i have demonstrated dose-dependent reductions in mesangial expansion, macrophage infiltration, and interstitial fibrosis [44]. These renoprotective effects arise through three primary mechanisms i.e., reduction in hyperfiltration and glomerular stress (potentially independent of glucose levels); improvement in hypoxia (which is strongly glucose-dependent); suppression of inflammatory, fibrotic and apoptotic pathways [48]. Together, these actions explain the broad kidney-protective benefits of SGLT2i, making them effective in managing CKD in both diabetic and non-diabetic populations [14].

GLP-1RAs provide notable cardiovascular and renal benefits in patients with type 2 diabetes, particularly those at high cardiovascular risk [50]. Beyond glucose control, they reduce albuminuria and modestly slow the decline in estimated glomerular filtration rate (eGFR), suggesting unique renoprotective effects. GLP-1 is secreted in two phases post-meal—a rapid surge within 15–30 min and a second peak at 90–120 min—regulated by gut-derived neurotransmitters like acetylcholine and gastrin-releasing peptide [38]. This biphasic release is linked to proximal and distal L-cell activation as nutrients transit through the gut. However, native GLP-1 has a short half-life (<2 min) due to rapid cleavage by DPP-IV enzymes, forming inactive GLP-1^{(9−36/9−37)} with low receptor affinity. Both active and inactive forms are quickly cleared by the kidneys, and only 10–15% of GLP-1 reaches systemic circulation. In patients with renal impairment, GLP-1 clearance is delayed, though its initial enzymatic degradation remains unaffected. These dynamics highlight the complexity of GLP-1 biology and its therapeutic potential in renal disease [51,52].

The renoprotective effects of GLP-1RAs are largely attributed to their ability to reduce inflammation, oxidative stress, promote natriuresis, and lower intraglomerular pressure. In early DKD, elevated systemic oxidative stress plays a critical role in disease progression [53]. Recombinant human GLP-1 has been shown to decrease oxidative damage by inhibiting protein kinase C and activating protein kinase A (PKA) in glomeruli and glomerular endothelial cells [54]. GLP-1RAs also suppress the expression of proinflammatory cytokines, adhesion molecules, and profibrotic mediators. Notably, exenatide reduced reactive oxygen species and inflammatory signaling pathways, such as NF-κB, TNF-α, IL-1β, and TLR4, in obese diabetic patients, independent of weight loss [52,55].

GLP-1-induced natriuresis and diuresis are linked to reduced activity of the Na⁺/H⁺ exchanger 3 (NHE3) in proximal tubules, mediated by PKA-dependent phosphorylation. Lower NHE3 activity enhances sodium delivery to the macula densa, triggering afferent arteriolar vasoconstriction and reducing glomerular hyperfiltration. Clinically, agents like liraglutide initially lower eGFR before stabilization, reflecting their role in modulating renal hemodynamics [48].

These drugs specifically block the SGLT2 protein, which is mostly expressed in the kidney’s early proximal convoluted tubule. Normally, about 90% of the glucose that the glomeruli filter is reabsorbed by SGLT2 []. When SGLT2 is inhibited, this reabsorption is decreased, which raises the excretion of glucose in the urine (glucosuria) and lowers plasma glucose levels. ³³

Since sodium and glucose are typically cotransported by SGLT2, its inhibition also reduces sodium reabsorption. Afferent arteriolar constriction results from the restoration of tubuloglomerular feedback brought about by the enhanced sodium transport to the distal nephron []. This leads to osmotic diuresis, which decreases blood pressure, as well as a little decrease in glomerular hyperfiltration, which may halt the course of diabetic nephropathy []. ^{58 37}

A strong, competitive, and specific inhibitor of the sodium glucose transporter SGLT2, empagliflozin regulates glucose reabsorption in the beginning of the proximal tubule and the majority of the kidney’s overall glucose reabsorption. As a result, empagliflozin elevates the excretion of glucose in the urine and leads to decreases in blood glucose levels [61]. These effects are linked to pancreatic cell activity and decrease body weight in normoglycemic obese and non-obese animals regardless of a higher food intake, primarily because of a loss of adipose tissue [62,63]. Empagliflozin decreased blood pressure in diabetic individuals, and alleviated endothelial dysfunction and arterial stiffness in diabetic rats, which slowed the onset of nephropathy in diabetic animal models [61].

Dapagliflozin selectively inhibits SGLT2 in the early proximal tubule, reducing glucose and sodium reabsorption independently of insulin, making it effective even in patients with impaired β-cell function [62]. Beyond glycemic control, it promotes natriuresis, restoring tubuloglomerular feedback, and reducing hyperfiltration and intraglomerular pressure—key contributors to kidney damage in CKD [63]. Clinical trials have shown that dapagliflozin significantly lowers the risk of eGFR decline (≥50%), progression to end-stage kidney disease (ESKD), and cardiorenal mortality, regardless of diabetes status [64].

While its glucosuric effect can increase the risk of urinary tract and genital infections, dapagliflozin is generally well tolerated in CKD patients. Its insulin-independent action, combined with strong renal and cardiovascular benefits, supports its growing use as a key therapeutic option in CKD management, for both diabetic and non-diabetic populations [62,64].

Canagliflozin lowers plasma glucose levels by blocking SGLT2 (irrespective of insulin) which decreases glucose reabsorption and increases glucosuria. Canagliflozin’s natriuretic action (via decreased sodium reabsorption) lowers intraglomerular pressure in addition to lowering hyperglycemia. An important factor in the development of CKD is glomerular hyperfiltration, which is reduced by this restoration of tubuloglomerular feedback [65]. The renoprotective advantages of canagliflozin in CKD patients are thought to be caused by these hemodynamic alterations.

In individuals with type 2 diabetes and CKD, canagliflozin has been demonstrated in clinical trials like the CREDENCE research to lower the risk of unfavorable kidney outcomes, such as a persistent fall in eGFR, progression to end-stage kidney disease and renal death [65]. Canagliflozin’s most common adverse effects include urinary tract infections and vaginal mycotic infections, both of which are linked to elevated urine glucose levels [66]. Potential hazards include bone fractures and, in certain assessments, an increased likelihood of lower limb amputations. An overview of different SGLT2i is depicted in Table 1.

The effectiveness and safety of incorporating canagliflozin versus a placebo into standard care for patients with CKD and T2DM has been assessed in the CREDENCE trial (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy, i.e., T2DM patients with DKD (eGFR 30–<90 mL/min/1.73 m²; severe albuminuria) [58]. When compared to a placebo, canagliflozin significantly decreased either the composite endpoint of renal death, serum creatinine doubling or end-stage kidney disease (ESKD). The results showed that, in patients with established DKD, SGLT2 inhibition can decrease the progression of renal disease [52,64].

In a new trial, patients with albuminuria (eGFR 25–<75 mL/min/1.73 m²) and chronic renal disease (with or without type 2 diabetes) were randomly assigned to receive dapagliflozin (with or without saxagliptin) or a placebo. This study assessed the number of patients who reached a 30% reduction in UACR over the trial period, as well as the percentage change in UACR between dapagliflozin 10 mg + saxagliptin 2.5 mg and placebo and between dapagliflozin 10 mg and placebo during a 24-week period [64]. Comparing dapagliflozin to a placebo, the results showed that the former reduced the probability of an integrated renal endpoint (≥50% drop in eGFR, progression to ESKD, or renal/cardiovascular death). Even in those with non-diabetic CKD, dapagliflozin exhibits strong renoprotective effects, extending the potential utility of SGLT2i in kidney disease [52,58].

The EMPEROR-Preserved and EMPEROR-Reduced trials are evaluating the safety and efficacy of empagliflozin in patients with heart failure, either with preserved or reduced ejection fraction, as an add-on to standard therapy. Meanwhile, the EMPA-KIDNEY trial is assessing empagliflozin’s impact on kidney disease progression and cardiovascular death in patients with CKD, regardless of diabetes status and down to an eGFR of 20 mL/min/1.73 m² [67]. These studies build upon the landmark EMPA-REG OUTCOME trial, which showed that empagliflozin significantly reduced the risk of cardiovascular death and renal disease progression. Collectively, these trials reinforce empagliflozin’s potential as a versatile agent in managing both cardiorenal complications in diabetic and non-diabetic populations [68].

The RCT results have been corroborated by observational studies (e.g., CVD-REAL 3 studies from the Japan CKD Database) which show that starting SGLT2i is linked to a slower drop in eGFR and a decreased risk of ESKD in standard clinical practice. According to subgroup analysis, these advantages hold true regardless of proteinuria levels and the previous rate at which kidney function declined [69]. In addition to enhancing glycemic management, it offers significant cardiovascular and renal protection, lowering the chance of developing end-stage kidney disease and other negative consequences. These advantages seem to hold true for different patient groupings, suggesting that they could be used more widely in CKD populations with and without diabetes [70]. SGLT2i are crucial for reducing kidney and cardiovascular hazards in this high-risk patient population. The key findings of major randomized clinical trials are summarized in Table 2.

According to pooled investigations, SGLT2i lower the risk of a composite renal outcome by about 30–40% when compared to a placebo. This composite renal outcome is usually defined as a prolonged fall in estimated glomerular filtration rate (eGFR), progression to end-stage kidney disease (ESKD), or renal death. For example, a well-known meta-analysis found that trials using drugs like canagliflozin, dapagliflozin, and empagliflozin had a hazard ratio (HR) for renal outcomes of approximately 0.66 [,,]. ^{69 70 71}

Regardless of beginning kidney function or baseline albuminuria levels, the renoprotective effects of the various SGLT2i are consistent. This implies that these medications slow down the course of DKD in a wide range of patients, including those with lower initial eGFR []. ⁶⁵

Along with potential direct anti-inflammatory and anti-fibrotic effects on the kidney, the advantages are ascribed to hemodynamic changes, including decreased intraglomerular pressure through natriuresis as well as better glycemic management []. All things considered, these meta-analyses support the use of SGLT2i as a crucial part of DKD management in clinical practice and validate that they are successful in slowing the progression of kidney disease in diabetic patients. They also support the results of individual landmark trials, such as CREDENCE and DAPA-CKD [,,,]. ^{71 58 64 65 66}

Zelniker et al.’s (2019) meta-analysis showed that, in comparison to a placebo, SGLT2i significantly lower the risk of composite renal endpoints, such as doubling of serum creatinine, renal death, or progression to end-stage kidney disease and offered solid proof of SGLT2is’ renoprotective benefits in diabetic renal disease []. ⁶⁶

Heerspink et al.’s (2020), meta-analysis demonstrated the dual benefits of SGLT2i, highlighting their role in comprehensive diabetes care by confirming that they significantly reduce the progression of kidney disease and cardiovascular events in addition to improving glycemic control []. Neuen et al.’s (2019) meta-analysis supports the argument for SGLT2i as crucial tools in slowing the progression of DKD and was reinforced by pooled data from several trials, which showed that SGLT2 lower albuminuria and halt the decline in estimated glomerular filtration rate (eGFR) []. ^{58 52}

Jamil et al. (2022) [] implicated that patients on SGLT2i had a significantly decreased risk of MACE and all-cause mortality. Furthermore, the SGLT2 inhibitor group showed a much higher change in Hb1AC. The SGLT2 inhibitor group had a considerably decreased incidence of acute renal damage, major adverse events, and hyperkalemia in terms of safety outcomes. In individuals with diabetes and CKD, the SGLT2i dramatically reduced the incidence of severe cardiovascular events and all-cause mortality. Additionally, SGLT2i work well to lower patients’ Hb1Ac levels []. ^{67 67}

In Brendon et al.’s (2019) study [], SGLT2i significantly decreased the probability of dialysis, kidney disease-related death, or transplantation. Additionally, SGLT2i consistently improved acute renal damage and end-stage kidney disease across investigations. There was distinct, unambiguous evidence of benefit for all eGFR subgroups, including those with a baseline eGFR of 30–45 mL/min per 1.73 m. Additionally, renoprotection was constant across studies, regardless of RAS blockade use and baseline albuminuria. ⁵² 2

Ning Li et al.’s (2020) [] recent trials were the first to show how sodium–glucose cotransporter-2 (SGLT2) inhibitors affected renal outcomes in patients with CKD. Patients with eGFR < 60 mL/min/1.73 mand those with UACR > 300 mg/g had a 30% and 43% lower risk of the major renal outcome, respectively, while using SGLT2i. Patients with CKD who also had type 2 diabetes showed a similar effect []. ^{52 52} 2

However, SGLT2 reduced the risk of major renal outcomes by 46% in individuals with macroalbuminuria (defined as UACR > 300 mg/g) and atherosclerotic cardiovascular disease. In CKD patients with heart failure, SGLT2i did not significantly lower the risk of serious renal outcomes. In patients with CKD, SGLT2i dramatically decreased the probability of the primary outcome. However, the renal protective effect varies for patients with diverse characteristics and underlying conditions []. ⁶⁶

Although SGLT2 inhibitor use has been linked in multiple trials to a higher relative risk of euglycemic DKA, the absolute risk is still minimal. DKA is uncommon in people with type 2 diabetes (and consequently in many with diabetic renal impairment), according to meta-analyses that include data from randomized studies [72]. Instead of being a direct pharmacological consequence of the drug itself, the majority of occurrences happen under particular triggering factors (such as severe illness, low insulin doses, or perioperative states).

When compared to a placebo, the combined data consistently demonstrate that SGLT2i are linked to an increased incidence of genital mycotic infections. Usually mild to moderate in severity, these infections—which are most frequently caused by Candida species—respond well to standard antifungal treatment and infrequently result in treatment cessation [73].

Although SGLT2i considerably raise the risk of genital infections, the absolute number of occurrences is low and controllable with the right therapy, according to meta-analyses that aggregate data from several RCTs, including those that concentrate on patients with DKD. Despite having a higher relative risk, euglycemic DKA is still uncommon overall, especially in people with type 2 diabetes and significant CKD [74].

In the LEADER trial, diabetic patients with recognized cardiovascular conditions or significant risk were randomized to either the liraglutide or placebo group [83]. The liraglutide group experienced a mean decrease of 2.3 kg in body weight and 0.4% in HbA1c after an average follow-up of 3.8 years [84]. According to the primary endpoint, the liraglutide group experienced a lower incidence of MACEs (13%) than the placebo group (14.9%). The recurrence of nephropathy was 22% lower in the liraglutide group compared to the placebo group and was particularly beneficial for macroalbuminuria. This effect was most noticeable in subgroups of individuals with moderate (eGFR 30–59 mL/min/1.73 m²) or severe (eGFR < 30 mL/min/1.73 m²) CKD. The eGFR fall was lower in the liraglutide group.

Liraglutide’s effectiveness in controlling body weight in overweight or obese diabetes individuals was assessed in the SCALE study. Patients were randomized to receive either a placebo or 3 mg or 1.8 mg of liraglutide. Both liraglutide arms experienced a significant decrease in weight at the end of the 56-week research period; however, their urine albumin/creatinine ratios (UACR) were lower than those of the placebo group [85]. Liraglutide turned out to be unsuccessful in improving renal functions in a sample of 279 diabetic patients with intermediate CKD (eGFR 30–59 mL/min/1.73 m²), in contrast to the LEADER and SCALE trials [86].

Ten randomized controlled trials in the “SUSTAIN” series are designed to assess the impact of weekly administration of subcutaneous semaglutide on glycemic management in individuals with type 2 diabetes. The most widely prescribed medications for type 2 diabetes (T2DM) (sitagliptin, exenatide, insulin glargine, dulaglutide, canagliflozin, and liraglutide) were compared with semaglutide administered either alone or combined with insulin, metformin, sulfonylurea, and/or insulin [87]. Semaglutide treatment does not raise the chance of adverse renal events when compared to other antidiabetic treatments [85]. After 2.1 years of follow-up, the semaglutide arm outperformed the placebo for MACEs (6.6% versus 8.9%), glycemic control (mean HbA1c −1.1% versus −1.4%), weight loss (−3.6 vs. −4.9 kg), and the onset or worsening of nephropathy (3.8% versus 6.1%).

The purpose of the randomized, double-blind, parallel-group ELIXA research was to examine the effects of lixisenatide and a placebo on cardiovascular risk in individuals with diabetes who had recently experienced an episode of acute coronary syndrome [86]. The incidence of MACEs was one of the key composite endpoints that were evaluated for superiority and non-inferiority. According to the study, lixisenatide’s cardiovascular safety is no worse or better than that of a placebo. Lixisenatide avoids the development of macroalbuminuria in participants who were initially normoalbuminuric (−1.69%) and lowers the UACR variance in both microalbuminuric (−21%) and macroalbuminuric (−39%) patients at baseline [88].

In the EXSCEL trial, diabetic subjects were randomly assigned to receive exenatide LAR at a dose of 2 mg weekly versus placebo for a 3.2-year observation period. The findings demonstrated that exenatide is not superior in terms of efficacy in averting MACEs and is comparable to placebo in terms of safety across every group of patients with CKD of varying degrees [89]. Subsequent analysis of the data modified for baseline demographics and comorbidities showed an important improvement in the renal composite outcome, mainly explained by a lower incidence of macroalbuminuria, even though exenatide did not significantly enhance the decline in eGFR, the incidence of ESRD, or renal-related death in the EXSCEL trial [81,89].

In the AWARD-7 study, diabetic patients with CKD stages G3 and G4 were recruited and randomly assigned. HbA1c changes at 26 weeks were the main outcome [87]. The results showed that dulaglutide safely and efficiently improves glycemic control in diabetic patients with advanced renal disease after 52 weeks of monitoring. Although there were no statistically significant variations in the reduction of UACR, dulaglutide was more effective than insulin glargine in reducing the decline in renal function in terms of secondary endpoints. These findings obliquely support the idea that weight reduction in GLP-1RA-treated patients is due to a decrease in fat mass rather than muscle mass [90].

In the multicenter, double-blind, placebo-controlled REWIND trial, diabetic individuals with cardiovascular medical conditions or a history of cardiovascular events were randomized. The prevalence of MACEs using an intention-to-treat strategy was the main result [91]. The percentages of eGFR fall ≥ 30% and the requirement for dialysis revealed a trend that was nearly identical in both groups, despite the fact that the incidence of macroalbuminuria was 8.9% compared to 11.3% in the placebo group [86]. The meta-analysis GLP-1RAs do not just lower the incidence of MACEs, heart failure hospitalization, and all-cause mortality, but they also improve the composite renal consequence in terms of eGFR decline over time [85,91].

The impact of semaglutide vs. placebo on the development of renal impairment in participants with type 2 diabetes and CKD (FLOW trial) was initiated in 2019 in order to assess semaglutide’s efficacy to lower the incidence of the composite primary endpoint (eGFR decline ≥ 50% from baseline, requirement for dialysis, death from renal causes, and death from cardiovascular disease) in comparison to a placebo [92]. The study found the true function of GLP-1RAs as medications that can prevent the progression of DKD in individuals with type 2 diabetes, as depicted in Table 4.

Tirzepatide, a dual GLP-1/GIP agonist, is a new treatment option for those with type 2 diabetes and DKD. Despite the fact that tirzepatide was first created to help with weight loss and glycemic control, new evaluations of the SURPASS trials have revealed encouraging results for renal outcomes. In particular, tirzepatide has been linked to slower eGFR decline and decreases in albuminuria indicating possible renoprotective actions in addition to its metabolic advantages. Whether tirzepatide alone or in conjunction with other medications, such as SGLT2i, can further improve kidney outcomes in comparison to monotherapy is now being investigated in ongoing combination therapy trials [98]. The rationale behind these studies depends on the complementary mechanisms of action: SGLT2i lower intraglomerular pressure and offer strong cardiovascular and renal protection, while tirzepatide enhances glycemic control and has anti-inflammatory effects through dual incretin receptor activation. These actions could work in concert to decrease the evolution of diabetic nephropathy [99].

Tirzepatide has been shown to enhance glycemic control, lower albuminuria, and lessen renal inflammation and fibrosis in animal models of diabetic nephropathy. According to these preclinical results, dual incretin receptor activation may slow the progression of kidney injury by lowering inflammation and oxidative stress. According to preclinical evidence, tirzepatide may directly affect renal tissue, possibly improving tubular repair and lowering glomerular hyperfiltration, in addition to improving systemic metabolic parameters [100].

The main goals of the SURPASS clinical trial series were weight loss and glycemic management in individuals with type 2 diabetes. Secondary analyses, however, have revealed encouraging kidney signs: Reduced albuminuria levels, which may indicate a slowing of diabetic kidney damage. Trends toward a slower decline in eGFR in patients with pre-existing kidney impairment. Continuous analyses are assessing whether the enhancements in metabolic regulation result in long-term renoprotection, even though strong, specialized kidney outcome trials for tirzepatide are still being developed.

Since tirzepatide has just recently hit the market, empirical data pertaining to DKD is starting to surface. Confirming the persistence of renoprotective effects and comprehending its influence on hard kidney endpoints, such as the rate of decline in eGFR and the progression to end-stage kidney disorders, would require post-marketing observation. The long-term relationship between GIP and GLP-1 receptor signaling is one area of study [96]. The unresolved questions will presumably be clarified by the introduction of GLP-1 receptor antagonists (exendin (9–39]) and, more recently, GIP receptor agonists (GIP (3–30] NH₂), as well as, ideally, longer-acting GIP receptor agonists for human usage.

This groundbreaking study showed that empagliflozin dramatically slowed the deterioration of kidney function and decreased major renal endpoints (e.g., progression to end-stage kidney disease and renal death) in a large population with CKD, including a considerable proportion of non-diabetic patients. Hemodynamic effects (such as natriuresis and decreased intraglomerular pressure) account for a major portion of its advantages, and they work regardless of diabetes status [108].

The FLOW study, on the other hand, assesses the effectiveness of a GLP-1 receptor agonist (such as semaglutide), mainly in diabetic CKD. When opposed to SGLT2i, GLP-1 RAs appear to have fewer direct renoprotective advantages, particularly in non-diabetic CKD populations, despite their strong glycemic control, weight loss and small reductions in albuminuria. Furthermore, GLP-1 RAs may not adequately address the hemodynamic stress observed in advanced CKD due to their reliance on anti-inflammatory and metabolic enhancement mechanisms [109].

EMPRISE focused specifically on empagliflozin versus DPP-4 inhibitors, but secondary comparisons with GLP-1 RAs were also evaluated. These studies showed that SGLT2i provided superior renal protection, especially in reducing hospitalizations for heart failure and slowing CKD progression, even in patients with existing DKD [108,109].

The GRADE trial, while primarily designed to assess glycemic durability, provided some insights into cardiovascular and renal outcomes among multiple drug classes. Although GLP-1 RAs and SGLT2i were not directly compared, subgroup analyses suggested favorable weight and albuminuria reduction with GLP-1 RAs, and stronger hemodynamic and renal filtration benefits with SGLT2is, supporting their complementary roles [112].

A network meta-analysis comparing cardiovascular and renal outcomes across major trials concluded that both drug classes significantly reduce major adverse cardiovascular events (MACE) and progression of kidney disease. However, SGLT2i were more effective in reducing hospitalization for heart failure and progression to end-stage renal disease, whereas GLP-1 RAs showed slightly stronger effects on reducing stroke and non-fatal cardiovascular events [112,113].

Observational comparative studies from registries (e.g., Scandinavian National Diabetes Registries, U.S. Optum and Medicare claims databases) have demonstrated that SGLT2i are associated with more consistent reductions in ESKD risk, while GLP-1 RAs show stronger effects on macrovascular outcomes and weight loss, particularly in obese or high-risk patients. Furthermore, SGLT2i were associated with a significantly lower risk of serious renal events (HR 0.76), while MACE rates were similar. Notably, combined use of both classes has shown additive benefits in recent retrospective analyses, though prospective confirmation is ongoing [114].

While definitive randomized controlled trials are still lacking, real-world data consistently show SGLT2i outperform GLP-1 RAs in renal outcomes, whereas GLP-1 RAs may offer additional cardiometabolic benefits, such as weight loss and improved endothelial function. These findings support a phenotype-driven or comorbidity-guided treatment approach in DKD/CKD management.

SGLT2i have continuously demonstrated advantages in lowering cardiovascular events and delaying the deterioration of kidney function. Additionally, GLP-1 RAs help with weight loss, glycemic control, and inflammation reduction, all of which may indirectly safeguard renal function. When these two groups are combined, kidney function preservation may result in additive or even synergistic effects.

It is probable that CKD patients, whether diabetic or not, are being recruited and categorized based on their initial albuminuria and eGFR results. The change in the eGFR slope (rate of decline), which offers a sensitive indicator of the preservation of renal function, is frequently the main endpoint. Safety profiles, changes in albuminuria, and cardiovascular outcomes are examples of secondary objectives.

A paradigm shift in the treatment of patients at high risk for progressive renal disease may result if combined therapy shows a noticeably slower drop in eGFR than monotherapy. The results might lend credence to the inclusion of dual therapy in CKD clinical guidelines, providing a more thorough method of renoprotection. With the goal of utilizing the unique mechanisms of both drug classes to improve long-term results for patients with CKD, this trial is a part of the changing landscape of combination medicines in the nephrology sector [112,113,114,115].

TCF7L2 gene variants are one of the most potent genetic risk factors for type 2 diabetes, and new research indicates they may also affect how the body reacts to GLP-1 RAs. Specifically, decreased incretin impact and impaired insulin secretion have been associated with risk alleles like the T allele of the rs7903146 variation. In certain patients, this could result in a decreased therapeutic response or resistance to GLP-1 RA treatment. Genotyping TCF7L2 can assist in identifying individuals who may be less likely to benefit from GLP-1 RA monotherapy in a biomarker-driven tailored strategy. To improve glycemic and renal outcomes, those with these risk alleles may be eligible for alternative or combination therapy (such as SGLT2i) []. TCF7L2 genotyping has the potential to be used in clinical practice to customize diabetes therapy according to a patient’s genetic profile, but more investigation and confirmation are needed. ¹¹⁵

Emerging perspectives in the combined application of SGLT2i and GLP-1 RAs for CKD and DKD, highlighting advances in biomarker discovery, personalized treatment strategies, and novel therapeutic indications are depicted in. Figure 6

The combination makes use of complimentary mechanisms: GLP-1 RAs enhance glycemic control and aid in weight loss, while SGLT2i lower intraglomerular pressure and provide cardiovascular and renal protection. This collaboration has the potential to cut long-term healthcare expenses by reducing problems (such as hospitalizations and the advancement of renal disease).

According to economic assessments, SGLT2i and GLP-1 agonists may save money overall, even though their initial prices are higher since they can avoid expensive issues. For example, lower hospitalization rates and postponed end-stage kidney disease development can compensate for increased drug procurement expenses. These evaluations, however, frequently rely on data from high-income nations, and local pricing structures in low-income environments might vary greatly [117].

Government-led agreements and tiered pricing models can assist in reducing costs in low-income settings, improving access and making cost-effective medications more accessible to more patients.

Including these combo treatments in programs for vital medications can help to lower costs by promoting local producers to create generic versions and facilitating subsidized access.

Combining cutting-edge treatments with effective chronic care and preventative care management in low-income environments can optimize clinical benefits while distributing expenses over a larger healthcare plan [117].

By utilizing digital technology and local healthcare support, telemedicine guidelines for monitoring CKD in remote areas seek to close the gap in specialist care and enhance long-term results. The following essential elements are typically included in these protocols, which were created with cost-effectiveness and health equity in mind: