Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia and has emerged as a global health crisis. The International Diabetes Federation (IDF) estimated that 537 million adults were living with diabetes in 2021, with projections reaching 643 million by 2030 (IDF, 2021). Chronic hyperglycemia in diabetes leads to both microvascular and macrovascular complications, significantly increasing morbidity and mortality. Among the microvascular complications, Diabetic Kidney Disease (DKD) is one of the most devastating, accounting for nearly 50% of End-Stage Renal Disease (ESRD) cases worldwide (Thomaset al., 2015). Affecting approximately 20-40% of individuals with diabetes, DKD remains a leading cause of Chronic Kidney Disease (CKD) and ESRD (Alicicet al., 2017). In India, the burden is particularly concerning due to the rising prevalence of Type 2 Diabetes Mellitus (T2DM) across both urban and rural populations. Beyond its clinical impact, DKD imposes considerable psychosocial and economic strain on patients and caregivers (Jhaet al., 2013) and markedly increases the risk of cardiovascular events, underscoring the importance of early and effective intervention (Pálsson and Patel, 2014).

Despite advances in glycemic control and blood pressure management, DKD progression often continues unabated. Conventional therapies, such as Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs), reduce albuminuria and slow renal decline but fail to halt disease progression in many cases (Brenner et al., 2001). Furthermore, intensive glycemic control may increase the risk of hypoglycemia, particularly in elderly patients or those with comorbidities (ADVANCE Collaborative Group, 2008). These limitations highlight the need for more targeted and multifaceted treatment approaches.

Given the multifactorial pathophysiology of DKD, encompassing hemodynamic, metabolic, inflammatory, and fibrotic pathways, effective nephroprotection is likely to require a combination of agents with complementary mechanisms of action. Telmisartan, beyond its antihypertensive effects, exhibits partial Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ) agonism, which may provide additional anti-inflammatory and antifibrotic benefits (Schuppet al., 2004). Dapagliflozin, a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor, offers renal protection through both glucose-dependent and glucose-independent mechanisms, including reductions in intraglomerular pressure, oxidative stress, and inflammation (Heerspinket al., 2020). Their complementary pharmacological actions suggest a potential synergistic benefit in preserving renal function and improving overall outcomes in patients with DKD.

This review aims to comprehensively evaluate the dual nephroprotective role of dapagliflozin and telmisartan in the management of diabetic kidney disease. It synthesizes evidence from preclinical studies, clinical trials, and real-world practice to assess their individual and combined efficacy, mechanisms of action, and safety profiles, while also identifying gaps in current knowledge to guide future research.

Chronic hyperglycemia in diabetes mellitus leads to increased glucose reabsorption by SGLT2 in the kidney, exacerbating hyperglycemia initiating metabolic disturbances that lead to glomerular and tubular injury and causing direct kidney damage. This damage includes elevated TGF-β expression, ROS production, and AGE formation. Additionally, hyperglycemia-induced HIF-1α expression in the mesangium promotes fibrotic factors, while insulin resistance contributes to dyslipidaemia and lipotoxicity in tubular epithelial cells, further advancing diabetic kidney disease (Mazzieriet al., 2024). Hyperglycemia increases the production of Advanced Glycation End products (AGEs), which promote mesangial expansion, basement membrane thickening, and podocyte dysfunction (Brownlee, 2005). Additionally, glucose overload in renal tubular cells leads to glucotoxicity, which impairs mitochondrial function and induces apoptosis (Vallon and Thomson, 2017).

In the incipient phase of Diabetic Kidney Disease (DKD), glomerular hyperfiltration is primarily attributed to an increased Single-Nephron Glomerular Filtration Rate (SNGFR) coupled with elevated intraglomerular hypertension, culminating in hypertrophic remodelling of the renal parenchyma and proximal tubular segments. The Renin-Angiotensin-Aldosterone System (RAAS), notably via angiotensin II and aldosterone, exerts a critical pathogenic influence by mediating vasoconstriction, stimulating Reactive Oxygen Species (ROS) generation, and activating downstream profibrotic signalling cascades. Concurrently, upregulated Sodium-Glucose Cotransporter 2 (SGLT2) expression in the proximal tubule diminishes sodium chloride delivery to the macula densa, abrogating Tubuloglomerular Feedback (TGF), thereby inducing afferent arteriolar vasodilation and exacerbating intraglomerular pressure. These synergistic hemodynamic perturbations and molecular mechanisms initiate and perpetuate glomerulosclerosis and interstitial fibrosis, driving the progression of DKD (Yang and Xu, 2022).

It is an early hemodynamic abnormality in DKD, resulting from afferent arteriole dilation and efferent arteriole constriction. This hemodynamic stress causes mechanical injury to podocytes and glomerular capillaries (Hostetter, 2003). Non-hemodynamic factors-such as metabolic imbalances, lipotoxicity, and hormonal dysregulation-amplify this damage, contributing to renal fibrosis and functional decline (Cooper, 2001).

The pathogenesis of Diabetic Kidney Disease (DKD) is largely driven by immune-mediated inflammatory processes initiated through the activation of Nuclear Factor-kappa B (NF-κB), which upregulates the expression of endothelial adhesion molecules such as Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) within the renal microvasculature. These adhesion molecules facilitate the extravasation and accumulation of leukocytes and macrophages into renal tissues, leading to the secretion of pro-inflammatory cytokines and chemokines that contribute to injury of glomerular and tubular compartments. Both resident and infiltrating immune cells, including T lymphocytes and macrophages, coordinate complex innate and adaptive immune responses that intensify local inflammation and promote fibrogenesis. Moreover, a skewed immune profile characterized by predominance of pro-inflammatory Th1 and Th17 subsets alongside diminished regulatory T cell function exacerbates renal damage and accelerates progression of DKD (Navarro-González and Mora-Fernández, 2008). The pathophysiology also involves a complex interaction between oxidative stress and the accumulation of Advanced Glycation End Products (AGEs) resulting from chronic hyperglycemia. Elevated generation of Reactive Oxygen Species (ROS), predominantly mediated by NADPH oxidase activity, induces oxidative damage to cellular macromolecules including lipids, proteins and DNA. In parallel, the buildup of AGEs and their engagement with the receptor for Advanced Glycation End products (RAGE) potentiate oxidative stress and inflammatory signalling cascades. This vicious cycle of enhanced oxidative and inflammatory mediators drives progressive renal cell injury, extracellular matrix deposition, and architectural remodelling characteristic of DKD progression (Mazzieriet al., 2024).

The imbalance between ROS production and antioxidant defences accelerates renal fibrosis via activation of TGF-β and extracellular matrix accumulation (Ha and Lee, 2000). Tubulointerstitial fibrosis in diabetic kidney disease results from sustained hyperglycemia triggering the release of profibrotic factors like TGF-β, ET-1, fibronectin, collagen-1, and CTGF. TGF-β plays a central role by promoting epithelial-mesenchymal transition and stimulating extracellular matrix deposition, while ET-1 induces vasoconstriction and enhances inflammatory and fibrotic signalling. Accumulation of fibronectin and collagen-1 further disrupts tissue architecture, and elevated CTGF exacerbates glomerulosclerosis and fibrosis. Together, these mechanisms drive tubular atrophy, interstitial matrix expansion, and progressive kidney dysfunction (Xuet al., 2023).

The RAAS plays a pivotal role in the pathogenesis of DKD. Hyperglycemia and mechanical stress stimulate intrarenal RAAS activation, particularly angiotensin II, which promotes vasoconstriction, sodium retention, and aldosterone secretion (Remuzziet al., 2002). Angiotensin II also stimulates inflammatory and profibrotic pathways, including TGF-β and Connective Tissue Growth Factor (CTGF), leading to glomerulosclerosis and tubulointerstitial fibrosis (Andersonet al., 1993).

Patients exhibiting albuminuria primarily demonstrate structural modifications of the glomerular filtration barrier, characterized by podocyte loss and increased thickness of the glomerular basement membrane. These pathological changes lead to increased permeability, permitting the passage of albumin into the urinary space. The presence of filtered albumin in the tubular lumen subsequently activates tubular epithelial cells, triggering inflammatory responses and the secretion of profibrotic mediators, including Transforming Growth Factor-beta (TGF-β). These processes facilitate tubulointerstitial fibrosis, characterized by excessive extracellular matrix deposition, tubular atrophy, and scarring, ultimately resulting in progressive renal functional decline (Naaman and Bakris, 2023; Pagtalunanet al., 1997). Podocytes are particularly susceptible to injury from AGEs, oxidative stress, and angiotensin II. Tubular injury occurs due to increased glucose and protein load, which triggers epithelial-to-mesenchymal transition (EMT), tubular atrophy, and interstitial fibrosis (Gilbert, 2004). This progressive tubular damage contributes significantly to the decline in estimated Glomerular Filtration Rate (eGFR) and advancement toward ESRD.

Telmisartan is a long-acting, selective angiotensin II type 1 receptor (AT1) blocker with a unique pharmacological profile among Angiotensin Receptor Blockers (ARBs). It has high lipophilicity and a prolonged terminal half-life of approximately 24 hr, allowing for once-daily dosing (Stangieret al., 2000). Telmisartan exhibits high binding affinity and slow dissociation from AT1 receptors, contributing to sustained Blood Pressure (BP) reduction and receptor blockade (Michelet al., 2013).

As an ARB, telmisartan inhibits the vasoconstrictive and sodium-retentive effects of angiotensin II by selectively blocking AT1 receptors. This leads to vasodilation, reduced aldosterone secretion, and decreased sodium and water retention, which together lower systemic and intraglomerular pressure (Burnier, 2001). The blockade of RAAS by telmisartan also attenuates the downstream inflammatory and fibrotic responses involved in DKD progression (Remuzziet al., 2002).

Unlike other ARBs, telmisartan acts as a partial agonist of peroxisome Proliferator-Activated Receptor-Gamma (PPAR-γ), a nuclear receptor that regulates glucose and lipid metabolism, inflammation, and oxidative stress (Schuppet al., 2004). This dual action enhances insulin sensitivity, reduces pro-inflammatory cytokine production, and inhibits mesangial cell proliferation-factors implicated in the pathogenesis of DKD (Bensonet al., 2004). Thus, telmisartan exerts metabolic benefits beyond RAAS blockade, positioning it as a pleiotropic agent in diabetes care.

On-target and Transcend trials found that telmisartan exhibited comparable efficacy to ramipril in influencing key renal endpoints, including the doubling of serum creatinine levels and progression to end-stage renal disease. The TRANSCEND trial’s subgroup analyses indicated that telmisartan may confer renal protective effects in patients presenting with microalbuminuria or macroalbuminuria alongside decreased estimated Glomerular Filtration Rate (eGFR); however, no significant renal advantages were observed in participants with maintained renal function (Tobeet al., 2011).

The AMADEO study rigorously compared telmisartan and losartan in hypertensive type 2 diabetic patients with overt nephropathy using a randomized, double-blind design over one year. Results demonstrated that telmisartan achieved a significantly greater reduction in proteinuria than losartan, independent of blood pressure differences. The superior renoprotective effect of telmisartan may be attributed to its extended pharmacokinetic properties and distinct molecular actions (Boehringer Ingelheim., 2023).

Randomized controlled trials involving patients with advanced Chronic Kidney Disease (CKD), the addition of telmisartan to standard antihypertensive regimens resulted in a marked decrease in the progression to renal replacement therapy, with a reported relative risk reduction of 45%. Furthermore, telmisartan significantly lowered proteinuria levels. These therapeutic effects were observed without a corresponding rise in serious adverse events, demonstrating the safety and efficacy of telmisartan in this patient population with advanced renal impairment (Tokunagaet al., 2010).

Observational clinical trials and meta-analyses have consistently shown that telmisartan administration effectively reduces proteinuria levels and may retard the decline of renal function in both diabetic and non-diabetic patients with chronic kidney disease. These renoprotective benefits are particularly apparent in patients who have significant proteinuria at baseline (Agrawalet al., 2016).

Telmisartan significantly reduces proteinuria, an important marker and mediator of DKD. Studies show up to a 50% reduction in albuminuria with telmisartan therapy, especially when used at higher doses (Yuyunet al., 2004). Its potent antihypertensive action contributes to lowering glomerular hypertension, a key pathogenic factor in DKD progression. Moreover, telmisartan stabilizes or slows the decline of estimated Glomerular Filtration Rate (eGFR), indicating renal preservation (Bakris et al., 2008).

Telmisartan is generally well tolerated, with a safety profile comparable to or better than other ARBs. Adverse effects are infrequent and include mild hypotension, hyperkalemia, and dizziness (Michelet al., 2013). Unlike ACE inhibitors, telmisartan does not cause cough or angioedema, making it suitable for long-term use. Importantly, it is safe in patients with mild to moderate renal impairment, though serum potassium and creatinine should be monitored regularly in advanced Chronic Kidney Disease (CKD) stages (Bakris et al., 2008).

Dapagliflozin is a selective Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitor that reduces glucose reabsorption in the proximal renal tubules, leading to increased urinary glucose excretion and improved glycemic control (DeFronzo et al., 2013). By lowering blood glucose levels independently of insulin secretion, it avoids the risk of hypoglycemia associated with traditional antidiabetic medications (Baileyet al., 2010). Moreover, its glucuronic effect contributes to mild weight loss and blood pressure reduction, indirectly benefiting renal health.

Dapagliflozin improves renal hemodynamic through restoration of Tubuloglomerular Feedback (TGF). In diabetes, increased proximal glucose and sodium reabsorption reduces sodium delivery to the macula densa, blunting TGF and causing afferent arteriolar vasodilation and glomerular hyperfiltration (Cherney and Perkins, 2014). By inhibiting SGLT2, dapagliflozin increases sodium delivery to the distal nephron, restoring TGF, causing afferent vasoconstriction, and reducing glomerular pressure-a key pathogenic mechanism in diabetic kidney disease (Heerspinket al., 2021).

One of dapagliflozin’s hallmark renal benefits is its ability to reduce intraglomerular pressure and albuminuria, independent of its glycemic effects. Clinical studies have demonstrated significant reductions in Urinary Albumin-To-Creatinine Ratio (UACR) and preservation of estimated Glomerular Filtration Rate (eGFR) in diabetic and non-diabetic populations (Wanneret al., 2016). These effects are attributed to improvements in glomerular hemodynamics, reduced inflammation, and better oxygenation of renal tissues (Vallon and Thomson, 2017).

Beyond hemodynamic changes, dapagliflozin exerts anti-inflammatory and anti-fibrotic actions. It reduces renal inflammation by downregulating pro-inflammatory cytokines like IL-6, TNF-α, and MCP-1, and inhibits NLRP3 inflammasome activation (Birnbaumet al., 2021). Dapagliflozin also decreases fibrotic markers such as TGF-β1 and collagen IV, thereby slowing tubulointerstitial fibrosis and chronic kidney damage (Kanget al., 2020). These pleiotropic effects contribute to long-term nephroprotection.

Dapagliflozin significantly reduces the progression of chronic kidney disease and lowers the risk of kidney failure and cardiovascular death. This benefit was observed in patients both with and without type 2 diabetes. Patients receiving dapagliflozin showed slower decline in kidney function and fewer hospitalizations for heart failure compared to placebo. The drug was well tolerated, with a safety profile similar to placebo. These results highlight dapagliflozin as a key treatment option for improving renal and cardiovascular outcomes in CKD.

The DAPA-CKD trial provided robust evidence of dapagliflozin’s renoprotective and cardioprotective benefits. In patients with CKD-with or without type 2 diabetes-dapagliflozin significantly reduced the risk of sustained eGFR decline, ESRD, and renal or cardiovascular death by 39% compared to placebo. The drug was well tolerated, with a safety profile similar to placebo. These results highlight dapagliflozin as a key treatment option for improving renal and cardiovascular outcomes in CKD (Heerspinket al., 2020). Similarly, the DECLARE-TIMI 58 trial showed that dapagliflozin reduced the risk of heart failure hospitalization and preserved renal function in high-risk diabetic patients (Wiviottet al., 2019). These landmark trials underscore dapagliflozin’s therapeutic role in cardiorenal protection.

Dapagliflozin is generally well tolerated, with a low risk of hypoglycemia and a favorable safety profile. Common adverse effects include genital mycotic infections and mild volume depletion, especially in older adults or those on diuretics (Zinmanet al., 2015). Rare complications such as euglycemic Diabetic Ketoacidosis (DKA) and urinary tract infections have been reported but are manageable with proper patient selection and monitoring. Importantly, dapagliflozin has been shown to be safe and effective even in patients with moderate to advanced CKD (eGFR >25 mL/min/1.73 m²), expanding its utility in renal care (Heerspinket al., 2021).

The combination of dapagliflozin (SGLT2 inhibitor) and telmisartan (ARB and partial PPAR-γ agonist) offers a multifaceted therapeutic approach for managing Diabetic Kidney Disease (DKD). While telmisartan acts primarily on the renin-angiotensin-aldosterone system (RAAS) to reduce glomerular pressure and fibrotic signalling, dapagliflozin enhances Tubuloglomerular Feedback (TGF) and modulates glucose and sodium reabsorption (DeFronzo et al., 2013; Schuppet al., 2004). Their complementary mechanisms address distinct yet converging pathways in the pathophysiology of DKD-hemodynamic, metabolic, and inflammatory.

Telmisartan reduces efferent arteriolar resistance, while dapagliflozin lowers afferent arteriolar pressure via restoration of TGF (Heerspinket al., 2021; Vallon and Thomson, 2017). This dual modulation optimally reduces intraglomerular hypertension, a major contributor to glomerular injury and proteinuria in DKD (Andersonet al., 1993). By targeting both vascular poles of the glomerulus, the combination can normalize glomerular hemodynamic more effectively than monotherapy.

Both agents independently reduce albuminuria and blood pressure, but their combination yields additive or even synergistic effects. Telmisartan reduces proteinuria by attenuating RAAS-mediated glomerular injury, while dapagliflozin lowers albuminuria through pressure-independent mechanisms, including reduced tubular workload and metabolic stress (Barnettet al., 2007; Wiviottet al., 2019). Furthermore, dapagliflozin improves glycemic control, body weight, and insulin sensitivity, and telmisartan enhances PPAR-γ-mediated metabolic regulation, offering broad systemic benefits (Bensonet al., 2004).

Chronic inflammation and fibrosis are key drivers of progressive DKD. Telmisartan suppresses pro-inflammatory cytokines like TNF-α and IL-6 via RAAS inhibition and PPAR-γ activation (Schuppet al., 2004). Dapagliflozin complements this action by reducing NLRP3 inflammasome activity, oxidative stress, and macrophage infiltration in renal tissues (Birnbaumet al., 2021). Their co-administration may exert synergistic antifibrotic effects by downregulating TGF-β1 and inhibiting mesangial matrix expansion, slowing DKD progression (Kanget al., 2020).

Preclinical models of diabetic nephropathy have shown enhanced renal protection when combining SGLT2 inhibitors with RAAS blockers. For instance, mice treated with telmisartan and dapagliflozin had reduced glomerulosclerosis, albuminuria, and renal inflammation compared to monotherapy groups (Uminoet al., 2018). Clinically, subgroup analyses from the DAPA-CKD trial indicated consistent renal and cardiovascular benefits of dapagliflozin in patients already receiving ARBs, including telmisartan (Heerspinket al., 2020). While direct head-to-head trials are limited, real-world data support the safety and enhanced efficacy of this dual approach in high-risk diabetic populations (Alicicet al., 2017).

The prospective observational study investigated the efficacy of combination therapy with dapagliflozin and telmisartan in patients with diabetic nephropathy over 12 weeks. Compared to telmisartan monotherapy, the combination significantly reduced albuminuria as measured by Urinary Albumin-To-Creatinine Ratio (UACR), along with improvements in glycaemic control (fasting blood glucose and HbA1c), lipid profile, and waist-to-hip ratio. Notably, inflammatory markers such as CCL21 mRNA and MCP-1 were also substantially decreased in the combination therapy group, indicating reduced systemic inflammation. These findings suggest that dapagliflozin plus telmisartan not only confers superior renal protection by lowering albuminuria but also attenuates inflammation, thereby enhancing overall renal function recovery in diabetic nephropathy patients. The combination therapy was well tolerated and demonstrated notable clinical benefits over monotherapy, highlighting its potential as an effective treatment strategy for diabetic kidney disease (Chauhanet al., 2025).

Although direct Randomized Controlled Trials (RCTs) specifically evaluating the combination of dapagliflozin and telmisartan in DKD are limited, evidence from individual studies and subgroup analyses strongly supports their concurrent use. Most major trials, such as DAPA-CKD, permitted background RAAS blockade (including telmisartan), providing indirect but robust support for the dual therapy strategy (Heerspinket al., 2020). Additionally, real-world observational data and small-scale cohort studies have explored the additive effects of this combination in slowing kidney function decline in patients with Type 2 Diabetes Mellitus (T2DM) and early-stage DKD (Bakriset al., 2021).

In comparative analyses, the combination therapy consistently outperforms monotherapies in improving renal outcomes. A study by Umino et al., (2018) using a mouse model of diabetic nephropathy found that dapagliflozin + telmisartan significantly reduced mesangial expansion, glomerular hypertrophy, and albuminuria compared to either drug alone. Clinical data from the DAPA-CKD trial showed that dapagliflozin added to existing RAAS blockade led to a further 39% risk reduction in the composite renal endpoint compared to placebo (Heerspinket al., 2020). This suggests a synergistic benefit when both drugs are used together.

Key renal outcome measures-estimated Glomerular Filtration Rate (eGFR) decline, albuminuria, and progression to End-Stage Renal Disease (ESRD)-are favorably affected by the dual therapy. Dapagliflozin slows eGFR decline through hemodynamic and anti-inflammatory mechanisms, while telmisartan’s RAAS inhibition reduces glomerular pressure and proteinuria (Barnettet al., 2007). In the DAPA-CKD trial, patients receiving dapagliflozin on top of an ARB (telmisartan in many cases) experienced a significant delay in ESRD progression, and more patients achieved ≥50% reduction in UACR compared to monotherapy (Heerspinket al., 2020; Wanneret al., 2016).

Cardiorenal protection is a major advantage of this combination. Telmisartan reduces cardiovascular events through RAAS modulation and potential lipid/lipoprotein effects (Bensonet al., 2004), while dapagliflozin improves heart failure outcomes and reduces Major Adverse Cardiovascular Events (MACE), as shown in the DECLARE-TIMI 58 trial (Wiviottet al., 2019). In high-risk patients, the combination therapy enhances systolic blood pressure control, reduces left ventricular hypertrophy, and improves vascular function, resulting in better cardiovascular outcomes (Cherney and Zinman, 2016).

Although there is no dedicated meta-analysis solely focused on dapagliflozin + telmisartan, a few meta-analyses have evaluated SGLT2 inhibitors plus RAAS blockers in general. A meta-analysis by Neuen et al., (2019) concluded that SGLT2 inhibitors added to background RAAS blockade significantly reduce risks of renal failure, albuminuria, and cardiovascular death across patient populations with CKD and diabetes. These results strongly support the additive nephroprotective and cardioprotective roles of dual therapy.

Comparative meta-analyses reveal no significant differences between dapagliflozin and empagliflozin regarding reductions in major cardiovascular events such as myocardial infarction, heart failure, stroke, or cardiovascular mortality, highlighting a consistent class effect (Tanawan et al., 2023). Dapagliflozin’s impact on eGFR in CKD closely aligns with the effects seen with other SGLT2 inhibitors, characterized by an early dip followed by slower progression of kidney function decline and strong renal protection (Heerspinket al., 2020). Notably, dapagliflozin’s lower selectivity ratio for SGLT2 versus SGLT1 receptors may provide additional cardioprotective benefits by modulating myocardial SGLT1 pathways that are less influenced by other agents. Furthermore, dapagliflozin does not elevate levels of plasma noradrenaline or aldosterone, which could contribute to its favourable cardiovascular profile. These pharmacodynamic characteristics, combined with well-substantiated clinical safety and efficacy data, support dapagliflozin’s role as an optimal adjunct to telmisartan in managing diabetic kidney disease to enhance cardiorenal protection. Overall, the comprehensive evidence underscores dapagliflozin as a reliable and effective option within the SGLT2 inhibitor class.

The dual use of dapagliflozin and telmisartan is generally well tolerated but requires attention to specific adverse effects. Telmisartan, an ARB, can cause hyperkalemia, particularly in patients with advanced Chronic Kidney Disease (CKD) or those taking potassium-sparing diuretics (Weir, 2011). Concurrent use of dapagliflozin, which causes natriuresis and osmotic diuresis, may potentiate volume depletion and lead to hypotension, especially in elderly or volume-depleted individuals (Zinmanet al., 2015).

Although SGLT2 inhibitors were initially associated with concerns over Acute Kidney Injury (AKI), large-scale trials have shown that dapagliflozin reduces AKI incidence in the long term by stabilizing intraglomerular hemodynamic and mitigating inflammatory damage (Heerspinket al., 2020; Neuenet al., 2019). Nonetheless, transient eGFR reduction may occur early in treatment due to hemodynamic changes and should not be mistaken for renal injury.

Both drugs have low potential for serious pharmacokinetic interactions, but certain combinations require caution. Telmisartan, being a substrate of CYP2C9 and inhibitor of P-glycoprotein, may affect drugs with similar metabolic pathways (Bensonet al., 2004). Co-administration with NSAIDs, potassium supplements, or aldosterone antagonists can increase the risk of renal dysfunction and hyperkalaemia (Bakriset al., 2000).

Dapagliflozin is primarily excreted via glucuronidation and poses minimal cytochrome-related interactions. However, its combination with loop diuretics may augment diuresis and increase dehydration risk (Vallon and Thomson, 2017).

Regular monitoring of renal function (eGFR, serum creatinine), electrolytes (especially potassium), and blood pressure is essential, especially during initiation and dose escalation. A baseline and periodic assessment of urinary albumin-to-creatinine ratio (UACR) is recommended to track nephroprotective effects (KDIGO, 2020).

In cases of acute illness, surgery, or volume depletion (e.g., vomiting, diarrhoea), temporary discontinuation of dapagliflozin is advisable to avoid euglycemic Diabetic Ketoacidosis (DKA) and further kidney stress (ADA, 2023). Similarly, telmisartan may be withheld if hyperkalaemia or rising creatinine is observed.

Elderly patients are more prone to adverse effects such as hypotension and volume depletion, necessitating careful dose titration and monitoring (Cherney and Zinman, 2016). Both drugs are effective in patients with CKD stages 2-4, but caution is needed when eGFR falls below 25 mL/min/1.73 m², where SGLT2 inhibitor efficacy may diminish (Heerspinket al., 2020).

In patients with heart failure, especially those with reduced ejection fraction (HFrEF), dapagliflozin has shown significant mortality and hospitalization benefits, making it a preferred agent (McMurrayet al., 2019). Telmisartan is also safe and beneficial in heart failure patient’s intolerant to ACE inhibitors, but careful potassium and renal function monitoring remains essential (Yusuf et al., 2003).

As evidence continues to accumulate on the efficacy of dapagliflozin and telmisartan individually, there is growing interest in combination therapies targeting multiple pathogenic pathways in Diabetic Kidney Disease (DKD). Preclinical studies have shown additive renal benefits when SGLT2 inhibitors are combined with agents like RAAS blockers, endothelin receptor antagonists, and Mineralocorticoid Receptor Antagonists (MRAs) (Uminoet al., 2018). Ongoing clinical trials, such as EMPA-KIDNEY and FLOW, are expanding the scope by including broader CKD populations and evaluating dual or triple therapy strategies (Herringtonet al., 2023).

A promising area of research involves direct comparison and combination of SGLT2 inhibitors (e.g., dapagliflozin) with PPAR-γ active ARBs like telmisartan, focusing on long-term renal and cardiovascular endpoints. These trials are expected to define optimized treatment protocols and evaluate whether early dual therapy initiation provides superior renal preservation.

Identifying predictive biomarkers remains a key area of future research to optimize patient selection and enhance treatment efficacy. Biomarkers such as urinary NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury molecule-1), TGF-β, and IL-18 are being studied to assess early kidney injury and therapeutic response in DKD (Parikhet al., 2011). Moreover, plasma copeptin and SUPAR (soluble urokinase-type plasminogen activator receptor) are emerging as potential markers for glomerular stress and inflammation (Hayeket al., 2015).

Omics-based approaches such as proteomics and metabolomics are expected to help identify signatures that differentiate responders from non-responders to dual therapy (Gadegbekuet al., 2020). Integration of such biomarkers into clinical practice could facilitate personalized nephroprotection strategies.

The paradigm is gradually shifting from generalized treatment to personalized nephroprotection, which considers individual genetic, metabolic, and environmental factors in therapy design. Advances in pharmacogenomics may enable clinicians to predict patient-specific efficacy and adverse reactions to telmisartan or dapagliflozin (Patelet al., 2016). Machine learning models are also being developed to stratify DKD patients based on progression risk, response prediction, and optimal drug selection (Nadkarniet al., 2022).

In this context, dual therapy with dapagliflozin and telmisartan may be particularly beneficial in patients with high baseline albuminuria, insulin resistance, and metabolic syndrome, but prospective validation in stratified cohorts is essential.

Pharmacotherapy alone cannot fully address the complexity of DKD. Emerging research underscores the value of integrating dietary modifications (e.g., reduced sodium/protein intake, DASH and Mediterranean diets) and lifestyle interventions such as regular physical activity, smoking cessation, and weight loss with pharmacologic regimens (Ikizleret al., 2020). These non-pharmacologic strategies enhance the effectiveness of telmisartan and dapagliflozin by mitigating inflammation, oxidative stress, and hemodynamic load.

Future studies are expected to focus on holistic DKD management models that blend precision medicine, dual-agent pharmacotherapy, and behavior change interventions to delay renal decline and improve quality of life.

Many of the available studies investigating the individual or combined effects of dapagliflozin and telmisartan have relatively short follow-up periods-often ranging from 12 to 36 months-which may not fully capture the long-term progression of Diabetic Kidney Disease (DKD) or sustained renal function decline (Barnettet al., 2007). Given that DKD is a slowly progressive condition, extended follow-up is essential to evaluate the durability of nephroprotection, particularly the ability of dual therapy to delay End-Stage Renal Disease (ESRD) or reduce long-term cardiovascular mortality (Neuenet al., 2019).

Several trials and preclinical studies exploring the synergistic effects of dapagliflozin and telmisartan are limited by small sample sizes. For example, the study by Umino et al., (2018), although promising, was conducted in a murine model and lacked human data. Even in clinical settings, subgroup analyses of patients on combination therapy often include limited participants, reducing the statistical power and generalizability of findings. Small sample sizes hinder the detection of rare adverse effects and limit stratification by age, sex, and comorbid conditions (Alicicet al., 2017).

A critical limitation in the current literature is the absence of randomized head-to-head trials comparing dual therapy (dapagliflozin + telmisartan) against either monotherapy alone in patients with DKD. Most available data are derived from studies allowing background RAAS blockade while evaluating SGLT2 inhibitors, or vice versa, rather than directly evaluating comparative efficacy and safety (Heerspinket al., 2020). Without such trials, it remains challenging to quantify the incremental benefit or potential risks of the combination over established monotherapies.

Randomized controlled trials often involve carefully selected participants under controlled conditions, which may not reflect the complexity of real-world populations. There is a pressing need for large-scale real-world observational studies or registry data that assess the long-term safety, adherence, cost-effectiveness, and efficacy of dual therapy across diverse patient demographics, including those with multiple comorbidities, polypharmacy, or socioeconomic challenges (Jhaet al., 2013). Real-world evidence would help determine the practical applicability of dual nephroprotective strategies in routine clinical care.

Diabetic Kidney Disease (DKD) remains a major global health challenge, with limited success from monotherapy in halting disease progression. The combination of dapagliflozin, a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor, and telmisartan, an angiotensin II receptor blocker with partial PPAR-γ agonist activity, offers a complementary and synergistic approach to nephroprotection. Telmisartan lowers intraglomerular pressure and reduces inflammation and fibrosis, while dapagliflozin improves renal hemodynamics, lowers albuminuria, and provides anti-inflammatory and antifibrotic effects independent of glycemic control. Together, these agents can slow the decline in estimated Glomerular Filtration Rate (eGFR), reduce cardiovascular risk, and improve renal outcomes, particularly in patients with persistent albuminuria and declining kidney function despite standard therapy. Their cardioprotective properties further support their use in patients with coexisting cardiovascular disease, and their oral administration and good tolerability make integration into clinical practice feasible with appropriate monitoring of renal function, electrolytes, and blood pressure.

The authors gratefully acknowledge Sigma University for providing academic guidance and institutional support during the preparation of this review. The constructive insights and encouragement received were instrumental in the successful completion of this work.