SGLT2 Inhibitors in Diabetic Nephropathy: A Systematic Review of SGLT2 Inhibitors Benefits in Diabetic Nephropathy

SGLT2 Inhibitors in Diabetic Nephropathy: A Systematic Review of SGLT2 Inhibitors Benefits in Diabetic Nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article SGLT2 Inhibitors in Diabetic Nephropathy: A Systematic Review of SGLT2 Inhibitors Benefits in Diabetic Nephropathy Syed Tayyab Shah, Gulmadin Hikmat, Ahsanullah Niazai, Bakht Muhammad, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7082203/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Diabetic nephropathy (DN), which affects 25–40% of those with type 2 diabetes (T2DM), is the main cause of end-stage kidney disease (ESKD) and a significant microvascular effect of diabetes mellitus. The need for better treatments is highlighted by the fact that disease progression frequently continues even after improvements in glycemic management and renin-angiotensin system (RAS) inhibition. Since they provide advantages beyond glucose management, such as kidney protection, sodium-glucose cotransporter-2 (SGLT2) inhibitors have become an attractive therapy option. Objective: This systematic review aims to evaluate the therapeutic potential, safety, and efficacy of SGLT2 inhibitors in the treatment of DN, with a focus on the renoprotective effects they have on individuals with type 2 diabetes. Method: A thorough literature search was carried out up until April 10, 2025, using PubMed, Google Scholar, PubMed Central, and ScienceDirect in accordance with PRISMA 2020 standards. Cohort studies published in English within the previous five years, meta-analyses, and randomized controlled trials (RCTs) were all considered eligible studies. The Quality Assessment Tool for Observational Cohort Studies, the Cochrane Risk of Bias Tool for RCTs, and AMSTAR 2 for meta-analyses were used to evaluate the risk of bias. Result: The inclusion of 243,682 patients from eight high-quality studies (two meta-analyses, three RCTs, and three cohort studies) was noted. SGLT2 inhibitors showed considerable renoprotective benefits, such as a 20–40% decrease in UACR, a 0.7–1.81 mL/min/year reduction in the rate of eGFR decline, and a 34–36% relative risk reduction in composite renal outcomes. Empagliflozin and dapagliflozin were especially effective due to their mechanisms, which included enhanced renal oxygenation, decreased glomerular hyperfiltration, and anti-inflammatory effects. The safety profiles were encouraging, with manageable adverse effects like genital infections and uncommon occurrences of diabetic ketoacidosis (DKA). Conclusion: Given their strong renal protective effects in diabetic nephropathy, SGLT2 inhibitors should be started early in Type 2 diabetes patients, with or without chronic kidney disease. They are a cornerstone in the management of DN since their advantages span all phases of renal illness. Additional study is needed to examine long-term results and comparative effectiveness among various SGLT2 medications. Diabetic nephropathy Diabetic Kidney Disease SGLT2 inhibitors renal protection albuminuria eGFR decline systematic review Figures Figure 1 Introduction Diabetic nephropathy (DN) is a progressive kidney disease brought on by persistent high blood sugar in people with diabetes mellitus. It features structural and functional alterations in the glomeruli, such as thickening of the glomerular basement membrane, expansion of the mesangium, and progressive glomerulosclerosis [ 1 ]. These changes result in proteinuria, a reduction in glomerular filtration rate (GFR), and, if unmanaged, can lead to end-stage renal disease (ESRD). The illness advances in phases, beginning with microalbuminuria and progressing to macroalbuminuria and kidney failure [ 2 ]. DN a significant microvascular complication of diabetes mellitus, has attained concerning prevalence globally, impacting around 25–40% of individuals with type 2 diabetes [ 3 ]. The worldwide effect is considerable, with diabetes rates noted at 9.3% (463 million people) in 2019, anticipated to rise to 10.9% (700 million) by 2045 (3). DN has emerged as the primary cause of end-stage kidney disease (ESKD), contributing to as much as 44% of cases in certain populations [ 4 ]. The pathophysiology includes ongoing hyperglycemia resulting in glomerular hyperfiltration, elevated intraglomerular pressure, and buildup of advanced glycation end products (AGEs) [ 3 ]. These processes lead to structural alterations such as thickening of the glomerular basement membrane, expansion of mesangial areas, and damage to podocytes, which ultimately causes proteinuria and advancing renal impairment [ 5 ]. Even with effective management through glycemic control and renin-angiotensin system (RAS) inhibition, disease progression frequently persists, underscoring the necessity for improved treatments [ 6 ]. Recent research involving Asian groups indicates a notably high prevalence, with chronic kidney disease found in 46.5% of Indian individuals with T2DM [ 7 ], and diabetic kidney disease responsible for 34% of kidney failure fatalities in Singapore [ 8 ]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors signify a significant advancement in DN treatment, providing advantages that extend beyond just glucose regulation [ 3 ]. These agents block glucose reabsorption in the proximal tubule, enhancing urinary glucose elimination [ 3 ]. Their protective effects on the kidneys involve restoring tubuloglomerular feedback to lower intraglomerular pressure, inducing a fasting-like metabolic state, and decreasing oxidative stress and inflammation [ 3 ]. Extensive clinical studies (EMPA-REG, CREDENCE, DAPA-CKD) have shown substantial kidney advantages, such as decreased albuminuria, slowed eGFR decline, and reduced likelihood of ESKD [ 9 ]. These effects remained consistent across stages of chronic kidney disease, with new real-world evidence indicating benefits even when treatment began in advanced chronic kidney disease (eGFR 15–44 mL/min/1.73 m2) [ 10 ]. SGLT2 inhibitors demonstrate additional advantages such as weight reduction, lowering blood pressure, and safeguarding cardiovascular health [ 3 ]. Their capacity to safeguard kidneys even in progressed chronic kidney disease has resulted in guideline suggestions as essential therapy for DN [ 9 ], with revised treatment protocols now including these agents for renal protection [ 7 ]. Current studies investigate their mechanisms and possible interactions with other nephroprotective agents [ 11 ], including their impacts on renal oxygenation assessed through BOLD-MRI in the early stages of DN [ 10 ]. Diabetic kidney disease is a severe complication of diabetes that contributes substantially to the prevalence of end-stage renal disease globally. Although there have been improvements in diabetes treatment, there is still a pressing need for effective therapies to slow the progression of DKD. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become promising agents for protecting kidney function, providing advantages that extend beyond just controlling blood sugar levels. This systematic review examines their effectiveness, safety, and therapeutic relevance for patients with type 2 diabetes and DKD. By compiling high-quality evidence from randomized trials, meta-analyses, and cohort studies, we highlight their importance in maintaining kidney function and enhancing patient outcomes. Method The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria (12) were closely followed during the systematic review, guaranteeing the highest levels of openness, rigor, and methodological accuracy in the synthesis and reporting of data. Eligibility Criteria: Only full-text, open access articles, English-language papers published in the last five years were included to provide a thorough and current study. The study included a variety of study methods, including meta-analyses for a compiled body of evidence, cohort studies for detailed patient data, and randomized control trials. All patients treated with SGLT2 inhibitors for type 2 diabetes who developed diabetic nephropathy were eligible to be included in this systematic review. Literature Search: A comprehensive and systematic search was conducted to evaluate the effects of "SGLT2 inhibitors" on "Diabetic Nephropathy" across four prominent databases—PubMed, Google Scholar, PubMed Central, and ScienceDirect—to guarantee a complete and all-encompassing collection of pertinent literature. This search concluded on April 10, 2025, which served as the cutoff date for article eligibility. To enhance the search approach, a mix of Medical Subject Headings (MeSH) and thoughtfully chosen keywords from previous studies was utilized, customized for the specific needs of each database. Table No.1 offers a thorough summary of the search procedure, detailing the selection of search criteria, MeSH terminology, and keywords, demonstrating the methodological rigor and clarity of the search approach adopted in the study. Below Table No. 01 show summary of the all literature search. Table No. 01: Literature Search Strategy Data Base table Databases Keywords Search strategy Filters Search results PubMed Diabetic Nephropathy AND SGLT2 inhibitors Concept 1 = Diabetic Nephropathy OR ( “Diabetic Nephropathies/blood”[Majr] OR “Diabetic Nephropathies/chemically induced”[Majr] OR “Diabetic Nephropathies/classification”[Majr] OR “Diabetic Nephropathies/complications”[Majr] OR “Diabetic Nephropathies/diagnosis”[Majr] OR “Diabetic Nephropathies/diagnostic imaging”[Majr] OR “Diabetic Nephropathies/diet therapy”[Majr] OR “Diabetic Nephropathies/drug therapy”[Majr] OR “Diabetic Nephropathies/enzymology”[Majr] OR “Diabetic Nephropathies/epidemiology”[Majr] OR “Diabetic Nephropathies/ethnology”[Majr] OR “Diabetic Nephropathies/etiology”[Majr] OR “Diabetic Nephropathies/genetics”[Majr] OR “Diabetic Nephropathies/metabolism”[Majr] OR “Diabetic Nephropathies/mortality”[Majr] OR “Diabetic Nephropathies/pathology”[Majr] OR “Diabetic Nephropathies/physiopathology”[Majr] OR “Diabetic Nephropathies/prevention and control”[Majr] OR “Diabetic Nephropathies/therapy”[Majr] OR “Diabetic Nephropathies/urine”[Majr] ) Concept 2 = SGLT2 Inhibitors OR ( “Sodium-Glucose Transporter 2 Inhibitors/administration and dosage”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/adverse effects”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/classification”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/metabolism”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/pharmacology”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/therapeutic use”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/toxicity”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/urine”[Majr] ) Concept 1 and Concept 2 Combine = Diabetic Nephropathy OR ( “Diabetic Nephropathies/blood”[Majr] OR “Diabetic Nephropathies/chemically induced”[Majr] OR “Diabetic Nephropathies/classification”[Majr] OR “Diabetic Nephropathies/complications”[Majr] OR “Diabetic Nephropathies/diagnosis”[Majr] OR “Diabetic Nephropathies/diagnostic imaging”[Majr] OR “Diabetic Nephropathies/diet therapy”[Majr] OR “Diabetic Nephropathies/drug therapy”[Majr] OR “Diabetic Nephropathies/enzymology”[Majr] OR “Diabetic Nephropathies/epidemiology”[Majr] OR “Diabetic Nephropathies/ethnology”[Majr] OR “Diabetic Nephropathies/etiology”[Majr] OR “Diabetic Nephropathies/genetics”[Majr] OR “Diabetic Nephropathies/metabolism”[Majr] OR “Diabetic Nephropathies/mortality”[Majr] OR “Diabetic Nephropathies/pathology”[Majr] OR “Diabetic Nephropathies/physiopathology”[Majr] OR “Diabetic Nephropathies/prevention and control”[Majr] OR “Diabetic Nephropathies/therapy”[Majr] OR “Diabetic Nephropathies/urine”[Majr] ) AND SGLT2 Inhibitors OR ( “Sodium-Glucose Transporter 2 Inhibitors/administration and dosage”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/adverse effects”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/classification”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/metabolism”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/pharmacology”[Majr] OR OR “Sodium-Glucose Transporter 2 Inhibitors/therapeutic use”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/toxicity”[Majr] OR “Sodium-Glucose Transporter 2 Inhibitors/urine”[Majr] ) Last 5 years English Full free text Human Meta-analysis Systematic Review April 10, 2025 278 Google Scholar Diabetic Nephropathy OR Diabetic Kidney Disease AND SGLT2 inhibitors Diabetic Nephropathy OR Diabetic Kidney Disease AND SGLT2 Inhibitors Last five years English In the title of the article April 10, 2025 30 PMC Diabetic Nephropathy AND SGLT2 Inhibitors “Diabetic Nephropathy” OR “Diabetic Kidney Disease” AND “SGLT2 Inhibitors” AND “Disease Progression” AND Observational Studies Last five years Open Access Observational Studies April 10, 2025 539 Science Direct Diabetic Nephropathy AND SGLT2 inhibitors Diabetic Nephropathy AND SGLT2 Inhibitors Open Access and Open Archive Last five years English April 10, 2025 461 Risk of Bias Assessment in Individual Studies: To attain the utmost levels of methodological quality, a tailored approach was implemented to assess the quality of the selected studies. Two meta-analyses were carefully evaluated using the AMSTAR 2 checklist, which is designed for reviewing systematic reviews and meta-analyses, ensuring adherence to rigorous criteria for synthesizing systematic evidence. The Cochrane Risk of Bias Tool was utilized to evaluate the quality of three randomized controlled trials, judging their robustness. For the trio of cohort studies, the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies assessed their dependability. Only those studies that surpassed a high-quality threshold of more than 70% in their evaluations were incorporated into the final analysis. This approach guaranteed that the outcomes were grounded in credible, high-quality, and reliable evidence, as shown in Table No. 02, Table No. 03, and Table No. 04 for the Meta Analysis, Randomized Controlled Trials, and Cohort Studies respectively. Table No.02: Meta-Analysis AMSTAR 2 for the Quality Assessment of the individual study Name of First Author Year of the Study Fang L 2021 et al. Bose D 2023 et al. 1. Did the research questions and inclusion criteria for the review include the components of PICO? Low Risk Low Risk 2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? Unclear Unclear 3. Did the review authors explain their selection of the study designs for inclusion in the review? Low Risk Unclear 4. Did the review authors use a comprehensive literature search strategy? Low Risk Low Risk 5. Did the review authors perform study selection in duplicate? Unclear Unclear 6. Did the review authors perform data extraction in duplicate? Unclear Unclear 7. Did the review authors provide a list of excluded studies and justify the exclusions? Low Risk Low Risk 8. Did the review authors describe the included studies in adequate detail? Low Risk Low Risk 9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? Low Risk Low Risk 10. Did the review authors report on the sources of funding for the studies included in the review? Unclear Unclear 11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? Low Risk Low Risk 12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? Low Risk Low Risk 13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? Low Risk Low Risk 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? Low Risk Low Risk 15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? Unclear Unclear 16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? Low Risk Low Risk Quality Assessment 13.5/16 = 84.375% 13/16 = 81.25% Table No.03: Randomized Control Trial Cochrane Risk of Bias for the Quality Assessment of the individual study Name of First Author Year of the study Cherney D Z.I 2022 et al. Laursen J C, MD 2021 et al. Zhou S 2021 et al. Mosenzn O 2022 et al. Selection bias Random sequence generation. Described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups Unclear Unclear Unclear Low Risk Selection bias Allocation concealment. Described the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen before or during enrollment Unclear Unclear Unclear Unclear Reporting bias Selective reporting. Stated how the possibility of selective outcome reporting was examined by the authors and what was found Low Risk Unclear Unclear Low Risk Other bias Other sources of bias. Any important concerns about bias not addressed above (If particular questions/entries were pre-specified in the study's protocol, responses should be provided for each question/entry) Unclear Unclear Unclear Unclear Performance bias Blinding (participants and personnel). Described all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provided any information relating to whether the intended blinding was effective. Low Risk Low Risk Unclear Low Risk Detection bias Blinding (outcome assessment). Described all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provided any information relating to whether the intended blinding was effective. Low Risk Low Risk Unclear Low Risk Attrition bias Incomplete outcome data. Described the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. Stated whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported Low Risk Low Risk Unclear Low Risk Quality Assessment 5.5/7 = 78.571% 5/7 = 71.428% 3.5/7 = 50% 6/7 = 85.714% Table No.04: Cohort Studies Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies for the Quality Assessment of the individual study Name of First Author Year of the Study Capelli I 2023 et al. Fadini G P 2024 et al. Lin F 2021 et al. Liu A Y L 2022 et al. Takeuchi M 2022 et al. 1. Was the research question or objective in this paper clearly stated? Low Risk Low Risk Low Risk Low Risk Low Risk 2. Was the study population clearly specified and defined? Low Risk Low Risk Low Risk Low Risk Low Risk 3. Was the participation rate of eligible persons at least 50%? Unclear Low Risk Unclear Unclear Unclear 4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? Low Risk Low Risk Low Risk Low Risk Low Risk 5. Was a sample size justification, power description, or variance and effect estimates provided? Unclear Low Risk Unclear High Risk High Risk 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? Low Risk Low Risk Low Risk Low Risk Low Risk 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? Low Risk Low Risk Unclear Low Risk Low Risk 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? High Risk Low Risk Low Risk Unclear Low Risk 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? Unclear Low Risk Low Risk High Risk Low Risk 10. Was the exposure(s) assessed more than once over time? High Risk Low Risk High Risk High Risk High Risk 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? Low Risk Unclear Low Risk Low Risk Low Risk 12. Were the outcome assessors blinded to the exposure status of participants? Unclear Unclear High Risk High Risk High Risk 13. Was loss to follow-up after baseline 20% or less? Unclear Unclear Unclear Unclear Unclear 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Low Risk Low Risk Low Risk Low Risk Low Risk Quality Assessment 9.5/14 = 67.857% 12.5/14 = 89.285% 10/14 = 89.285% 8.5/14 = 60.71% 10/14 = 71.248% RESULTS Study Selection Process: After conducting an extensive search through various databases, duplicates were carefully eliminated to enhance efficiency. There were 1308 results in the initial search. After 276 duplicates were removed, 888 entries were disqualified for title reasons. After carefully reviewing the abstracts of the articles, 119 were determined to be irrelevant and were therefore dismissed. Seventeen more articles were excluded for the following reasons: eleven were narrative reviews, three were mechanistic and animal studies, and three had quality assessment scores lower than 70%. Ultimately, eight articles were chosen for inclusion after scoring over 70% on the quality assessment tool. To maintain objectivity and accuracy, two separate authors diligently reviewed and assessed the articles at each phase, ensuring that the highest standards of academic rigor and precision were upheld. Study Characteristics: The studies encompassed a diverse population of 243,682 patients overall, with sample sizes ranging from small mechanistic investigations with 19 participants to big meta-analyses with over 70,000 subjects. The evidence base was multidimensional because the research designs included rigorous randomized controlled trials, extensive meta-analyses, and real-world cohort studies. The follow-up periods in the studies varied greatly, ranging from 8.5 months of relatively short-term assessments to 5.5 years of lengthy observations, making it possible to examine both immediate and long-lasting impacts. The studies' participants spanned a broad age spectrum, with average ages ranging from 30 years in a study on type 1 diabetes to over 60 years in studies focusing on older groups. Most of the studies also revealed a male majority in their gender distribution, with males accounting for 57.5–69.1% of the total. Generally, the inclusion criteria required a confirmed diagnosis of type 2 diabetes and stable kidney function, which was typically defined by baseline eGFR thresholds of 20–30 mL/min/1.73 m² or higher. However, some studies were specifically targeted at individuals with cardiovascular comorbidities. Typical exclusion criteria eliminated potential confounding by excluding individuals who were pregnant, had end-stage renal disease or were receiving dialysis, those with type 1 diabetes, and those with inadequate follow-up time. The primary intervention comparison involved SGLT2 inhibitors against placebo or other glucose-lowering medications, with renal protection endpoints including eGFR decline, albuminuria progression, and composite kidney outcomes. While big observational cohort studies offered valuable real-world evidence on long-term renal safety profiles, randomized trials provided controlled efficacy data. The variation in baseline characteristics among studies, such as differing degrees of kidney function impairment and unique cardiovascular risk profiles, underscores the importance of individualized clinical decision-making when using these results in patient care. When combined, this large body of evidence improves our understanding of renal outcomes in diabetic patients treated with SGLT2 inhibitors. Table No. 05 below shows characteristics from all studies, such as two meta-analyses, three randomized controlled trials, and three cohort studies. Below Table No. O5 show summary of characteristics of the all the studies. Table No.5: Characteristics of all the studies GFR (Glomerular Filtration Rate), RCT (Randomized Controlled Trial), T2DM (Type 2 Diabetes Mellitus), T1DM (Type 1 Diabetes Mellitus), M (Male), F (Female), NDKD (Non-Diabetic Kidney Disease), UACR (Urine Albumin-to-Creatinine Ratio), BP (Blood Pressure), MRI (Magnetic Resonance Imaging), SGLT2i (Sodium-Glucose Cotransporter-2 Inhibitors), oGLD (other Glucose-Lowering Drugs), eGFR (estimated Glomerular Filtration Rate), CrCl (Creatinine Clearance), DKA (Diabetic Ketoacidosis), ASCVD (Atherosclerotic Cardiovascular Disease), CKD (Chronic Kidney Disease), ESRD (End-Stage Renal Disease), CV (Cardiovascular), HbA1c (Hemoglobin A1c), NM (Not Mentioned), HF (Heart Failure). Studies Characteristics First Author, Year of Study Study Type Number of Patients Gender Distribution Total Follow-up Period Mean Age of Patients Baseline Kidney Function (GFR) Exclusion Criteria Inclusion Criteria Fang L 2021 et al. Meta-Analysis 51,925 M: 61.5% F: 38.5% 24 weeks to 4.2 years 52 to 68.7 years 39.1 to 92.7 mL/min/1.73 m² Non-RCTs, follow-up < 12 weeks, non-T2DM patients, no renal outcomes, or duplicate/subgroup analyses. RCTs comparing SGLT2 inhibitors with placebo in T2DM patients, duration ≥ 12 weeks. Reporting at least one renal-related outcome. Laursen J C 2021 et al. Randomized Control Trial 19 M: 66% F: 34% 8.5 months 30 to 86 years ≥ 15 mL/min/1.73 m² NDKD, severe renal failure, dialysis, arrhythmia, pregnancy, BP issues, MRI limits, surgery, or restlessness. Adults with type 1 diabetes (T1DM) and albuminuria (UACR ≥ 30 mg/g). Lin F 2021 et al. Cohort Study 27,332 M: 57.5% F: 42.5% 20 months ≥ 20 years Low: ~48.6, Mid: ~75.5, High: ~113 SGLT2i/oGLD use, age < 20, no pre-index data, T1/gestational diabetes, or < 2 eGFR tests 180 days apart. Patients (20+) with T2DM, starting SGLT-2is or oGLDs, ≥ 2 pre-index eGFRs, no study drug use for ≥ 1 year, and baseline eGFR measured within 180 days before treatment start. Mosenzn O 2022 et al. Randomized Control Trial 17,160 M: 62.6% F: 37.4% 4.2 years ≥ 40 years ≥ 30 mL/min CrCl < 60 mL/min, dialysis, type 1 diabetes, recent DKA, SGLT2i use, pregnancy, or significant liver disease. Adults (≥ 40 years with ASCVD or ≥ 55/60 years [men/women] with CV risk factors) with type 2 diabetes, HbA1c 6.5–12%, and CrCl ≥ 60 mL/min. Cherney D Z.I 2022 et al. Randomized Control Trial 8,030 M: 69.1% F: 30.9% 5.5 years NM ≥ 30 mL/min/1.73 m² Post hoc design, no adjustment, false positives, low power for subgroups, limited generalizability to ASCVD. Adults with type 2 diabetes (T2DM) and established atherosclerotic cardiovascular disease (ASCVD), with baseline eGFR ≥ 30 mL/min/1.73 m² and available UACR data. Takeuchi M 2022 et al. Cohort Study 36,237 NM 77 months ≥ 20 years ≥ 30 mL/min/1.73 m² Baseline eGFR < 30 mL/min/1.73 m², missing lab data, type 1 diabetes, and unspecified non-T2DM cases. Adults (≥ 20) with T2DM, eGFR ≥ 30 mL/min/1.73 m², HbA1c data available, using glucose-lowering meds (excluding SGLT2 inhibitors) at baseline. Bose D 2023 et al. Meta-Analysis 71,553 NM 9 months to 4.2 years ≥ 60 years ≥ 20 mL/min/1.73 m² T1DM, ESRD (eGFR 5 mL/min/year decline). Adults with T2DM (with/without CKD/CVD) from RCTs, eGFR ≥ 30 (≥ 25 in some CKD trials, ≥ 20 in HF trials). Fadini G P 2024 et al. Cohort Study 12,394 M: 61% F: 39% 54 months 18–80 years ≥ 25 mL/min/1.73 m² Age 80 years, non-T2DM, prior SGLT2i use, CKD stage V/dialysis, or missing renal outcome data. Individuals aged 18 to 80 with T2DM for at least one year, beginning dapagliflozin or non-SGLT2i medications (excluding insulin), without SGLT2i usage in the past year, not in CKD V or requiring dialysis, and having at least one eGFR measurement after the baseline. Study Outcome: SGLT2 inhibitors exhibit various protective effects on the kidneys in diabetic nephropathy. A meta-analysis indicated that these agents substantially lower UACR, with empagliflozin showing notable effectiveness [ 1 ]. Randomized controlled trials indicated that prolonged use results in decreased albuminuria and stabilization of long-term eGFR [ 2 ]. Cohort studies showed a reduced eGFR decline (HR 0.53 − 0.42) in patients with early-stage CKD [ 13 ]. Clinical trials recorded reductions in UACR of 20–40% alongside an initial decrease in eGFR, followed by a gradual long-term decline [ 14 ]. Studies showed a 34% relative decrease in renal progression risk (HR 0.66) among various patient subgroups [ 15 ]. Observational findings indicated that these drugs lower the yearly eGFR decrease by 0.80 mL/min/year [ 16 ]. Extensive meta-analyses indicated a 36% decrease in composite renal outcomes [ 17 ]. Recent studies demonstrated notable reductions in UACR (-44.3 mg/g) and maintenance of kidney function (+ 1.81 mL/min/year) [ 18 ]. The safety profile continues to be positive with controllable side effects. These reliable results from various study designs endorse SGLT2 inhibitors as a crucial treatment option. Their advantages span all phases of diabetic kidney disease. Below Table No. 06 show outcome summary of all the studies. Table No.6: Outcomes of all the studies : UACR (Urinary Albumin-to-Creatinine Ratio), eGFR (Estimated Glomerular Filtration Rate), ESRD (End-Stage Renal Disease), RR (Relative Risk), SUCRA (Surface Under the Cumulative Ranking Curve), KDIGO (Kidney Disease Improving Global Outcomes), HbA1c (Hemoglobin A1c), CKD (Chronic Kidney Disease), NM (Not Mentioned), HR (Hazard Ratio), RRT (Renal Replacement Therapy). First Author, Year of Study UACR Reduction eGFR Decline Kidney Protection Inflammation Biomarkers Safety Composite Renal Outcome New-Onset CKD ESKD Risk Fang L 2021 et al. Significant reduction with empagliflozin (-83.01 MD). This reflects a robust lowering of protein excretion, reducing nephropathy progression. NM Significant reduction in composite kidney outcomes (e.g., RR: 0.74–0.82). High SUCRA suggests superiority. NM No concerns Reduction in ESRD, doubling of serum creatinine, and kidney death risks. NM 15% ESRD risk reduction indicates substantial clinical benefit. Laursen J C 2021 et al. NM NM Improved renal oxygenation, indicative of protective effects on kidney metabolism. No change observed. Tolerated. NM NM NM Lin F 2021 et al. NM Slowed eGFR decline. Initial acute dip followed by stabilization suggests tubular function improvement. Reduced hazard ratio for eGFR reductions by 30%, 40%, 50%. NM Not assessed. Focused on defined eGFR thresholds, composite outcomes not evaluated. NM NM Mosenzn O 2022 et al. Not quantified but observed in albuminuric subgroups, implying specific benefits for proteinuric patients. Slower chronic eGFR decline highlights the consistent renal protection of dapagliflozin. lowering of risk in all KDIGO categories, especially in high-risk subgroups. NM Well tolerated. Kidney-specific composite outcomes (e.g., HR 0.53), showing efficacy. NM Low dialysis requirement supports efficacy in advanced cases. Cherney D Z.I 2022 et al. Reduction in albuminuria progression, most pronounced in high-risk groups. Slower eGFR decline; acute dip aligns with expected pharmacological effects. Consistent albuminuria reduction, showing subgroup robustness. NM No new safety signals detected. Composite outcomes improved by 34%, affirming therapeutic benefit. Lower macroalbuminuria progression implies new-onset CKD reduction. ESKD risk reduction probable but not directly quantified. Takeuchi M 2022 et al. NM Annual decline slower with HbA1c thresholds ≤ 6.5%. Early intervention benefits highlighted. Reduction in endpoints tied to early treatment initiation, emphasizing timing. NM Not assessed. Improved outcomes with early treatment (HbA1c reduction within 3 months). Implicit in early reductions observed. Improved outcomes suggest ESKD delay. Bose D 2023 et al. Combined reduction in renal death, RRT, and eGFR > 40% underscores broad effectiveness. Significant eGFR decline reduction, supporting long-term kidney health. Lower sustained eGFR < 15 mL/min/1.73 m² incidence supports advanced protection. NM Not significant. Risk ratio across endpoints (e.g., RR: 0.64), showing efficacy. Subgroup analyses suggest benefits. Reduction in dialysis rates affirms kidney protection. Fadini G P 2024 et al. Adjusted reduction (-44 mg/g) highlights effectiveness in albuminuria patients. The mean eGFR difference (+ 1.81) shows that renal function has stabilized. Reduction in CKD and ESRD risks in low-risk populations highlights prevention focus. NM Not significant. Improved outcomes in eGFR decline, ESRD, and dialysis (HR: 0.70). HR: 0.76 in low-risk cohorts suggests broad applicability. Consistency in reducing advanced kidney disease events. Discussion SGLT2 inhibitors have demonstrated protective effects on the kidneys in diabetic kidney disease (DKD), significantly enhancing renal cortical oxygenation, reducing albuminuria, and slowing the progression of kidney disease. Dapagliflozin does not influence renal blood flow or oxygen delivery but decreases renal cortical oxygen tension primarily by reducing energy demand in proximal tubules. This supports the notion that SGLT2 inhibition lessens renal hypoxia, a key factor in the development of DKD. Empagliflozin reliably decreases the urine albumin-to-creatinine ratio (UACR) and improves composite renal outcomes among SGLT2 inhibitors, with differences between agents potentially attributed to study design, patient demographics, and drug pharmacology. SGLT2 inhibitors are utilized not only for glycemic control but also for direct kidney protection, with clinical trials and meta-analyses showing that they reduce the advancement of chronic kidney disease regardless of initial eGFR. The processes involve alteration of kidney blood flow, reduced inflammation, lowered glomerular hyperfiltration, and improved tubuloglomerular feedback. Most of the evidence originates from individuals with type 2 diabetes, but findings in those with type 1 diabetes indicate certain benefits that warrant further investigation. Some examples of limitations include variability in trial designs, indirect comparisons within meta-analyses, and small sample sizes in mechanistic studies. The evidence, nonetheless, strongly supports SGLT2 inhibitors as primary therapies for DKD, emphasizing the need for further head-to-head studies and long-term investigations to enhance treatment methods and understand prolonged effects. Pathophysiology, Prevalence and Current Treatment Review of Diabetic Nephropathy: DN is defined by the gradual decline in kidney function resulting from metabolic and hemodynamic changes associated with diabetes. The pathophysiology of DN entails several mechanisms, such as oxidative stress from hyperglycemia, inflammation, and changes in hemodynamics. Persistent high blood sugar triggers pathways like the polyol and hexosamine pathways, resulting in advanced glycation end-products (AGEs) that harm kidney tissues [ 13 ]. Moreover, the renin-angiotensin-aldosterone system (RAAS) is excessively activated, leading to intraglomerular hypertension and hyperfiltration, which worsen kidney injury [ 14 ]. Tubulointerstitial fibrosis and podocyte damage are also key characteristics of DN, leading to permanent loss of kidney function [ 15 ]. DN is a primary contributor to chronic kidney disease and end-stage renal disease globally, impacting around 30–40% of individuals with type 2 diabetes mellitus (T2DM) [ 16 ]. The occurrence is greater in groups with inadequate glycemic management, high blood pressure, and hereditary factors. Timely identification via screening for albuminuria and decline in eGFR is essential to reduce progression [ 17 ]. The traditional approach to managing diabetic neuropathy (DNP) involves stringent glycemic control, blood pressure regulation (frequently using RAAS inhibitors such as ACEIs or ARBs), and changes to one's lifestyle [ 18 ]. Nevertheless, many patients cannot have their disease progression stopped by these treatments alone. Due to their renoprotective effects, recent findings have highlighted the significance of sodium-glucose cotransporter-2 inhibitors (SGLT2is) as a novel therapy for DNP [ 1 ]. The SGLT2 Inhibitors' Mode of Action: SGLT2 inhibitors lower blood glucose levels independently of insulin by selectively blocking the SGLT2 transporter in the proximal tubule, which decreases sodium and glucose reabsorption and encourages glycosuria [ 2 ]. SGLT2 inhibitors also improve renal hemodynamics by restoring tubuloglomerular feedback, decreasing intraglomerular pressure, and alleviating hyperfiltration [ 13 ]. Metabolic impacts through decreased tubular oxygen requirement and enhanced cortical oxygen supply [ 2 ]. Anti-fibrotic/Anti-inflammatory effects achieved by decreasing HIF-1α and sodium-hydrogen exchanger activity to lessen fibrosis [ 15 , 17 ].Acute eGFR declines (for instance, -2.99 mL/min/6 months with dapagliflozin) signify the initial hemodynamic variations, succeeded by a phase of extended stabilization [ 14 , 16 ]. SGLT2 Inhibitors Protection Against Diabetic Nephropathy: SGLT2 inhibitors provide renoprotective benefits via several mechanisms. They lessen glomerular hyperfiltration and intraglomerular pressure by constricting the afferent arteriole [ 14 ]. They also enhance renal oxygenation by lowering oxidative stress and tubular workload [ 15 ]. While traditional treatments (like RAAS inhibitors) are crucial, SGLT2 inhibitors offer extra benefits. Meta-analyses indicate a 30–40% reduction in overall renal outcomes (including ESRD and eGFR decline) in different trials [ 17 , 18 ]. Regarding UACR reduction, empagliflozin is superior (SUCRA: 0.993), while canagliflozin and dapagliflozin have shown robust renal protection in advanced CKD [ 1 , 13 ]. Clinical trials have shown that SGLT2is significantly reduce albuminuria and slow the decline of eGFR, with empagliflozin demonstrating especially strong activity in lowering the UACR in comparison to placebo, empagliflozin lowers UACR by 83.01 mg/g [ 1 ]. Real-world research, including DARWIN-Renal, corroborates the trial results, showing that dapagliflozin reduces albuminuria by 44 mg/g and decreases the eGFR decline rate by 0.67 ml/min/year [ 18 ]. By reducing inflammation and fibrosis, these medications also help to maintain kidney function even more [ 16 ]. Consistent chronic slope improvements (+ 0.55 to + 1.23 mL/min/year) are observed across eGFR subgroups [ 13 , 15 ].Decreases in risk are observed for ESRD (HR 0.70) and ≥ 40% reduction in eGFR (HR 0.53) [ 14 , 17 ]. The effectiveness of SGLT2is in improving renal outcomes is consistently shown in both real-world studies and clinical trials. For example, dapagliflozin decreased the risk of composite renal outcomes by 36% and slowed the eGFR decline by 0.7 mL/min/year [ 18 ]. Empagliflozin and canagliflozin also demonstrated considerable advantages, with hazard ratios (HRs) for ESRD or renal death ranging from 0.62 to 0.70 [ 1 ]. Renal protection is further improved by the early initiation of SGLT2is at lower HbA1c cutoff points (e.g., 6.5%) [ 16 ]. Diabetic nephropathy advances from microalbuminuria to macroalbuminuria and a decrease in eGFR, exhibiting variability in clinical manifestation. Significantly, 10.8% of patients show diabetic kidney disease without albuminuria, marked by a slower decline in eGFR while still gaining advantages from SGLT2 inhibitors [ 15 ]. Data from real-world studies indicate that early intervention (HbA1c ≥ 6.5%) markedly improves renal outcomes, highlighting the importance of prompt treatment [ 16 ]. Subgroup analyses from DECLARE-TIMI 58 indicate that low-risk patients (eGFR ≥ 90 mL/min/1.73 m²) also show delayed CKD progression when treated with dapagliflozin [ 14 , 18 ]. SGLT2 Inhibitors' Side Effects: SGLT2 inhibitors are effective, but their adverse effects deserve attention. The most frequent complications are genitourinary infections, which occur in 5–10% of patients [ 17 ]. Volume depletion and hypotension can occur, particularly in elderly patients or those using diuretics. In insulin-deficient patients, rare cases of DKA call for close attention [ 18 ]. Acute drops in eGFR are temporary and benign [ 16 ]. Real-world evidence supports their application in CKD (eGFR ≥ 30 mL/min) as they do not elevate the risk of AKI [ 18 ]. Euglycemic diabetic ketoacidosis (DKA) and acute kidney injury (AKI) are rare but serious dangers, even if recent meta-analyses have not found that SGLT2is increase the risk of AKI [ 18 ]. For the majority of patients, the advantages of SGLT2is in preserving renal function exceed the potential hazards, despite these risks. Limitations: This systematic review, despite its careful methodology, has several shortcomings. First, only English-language publications from the last five years were taken into account, which could have resulted in selection bias by ignoring earlier studies or better non-English research. Second, by only relying on publicly available full-text papers, important research in favor of paywalls may have been left out, thereby reducing the evidence's comprehensiveness. Finally, the search strategy might have missed new or relevant terms in the quickly evolving field of SGLT2 inhibitor therapy, even though it was thorough. In order to overcome these limitations, these disparities highlight the need for careful interpretation of results and further research. Conclusion Alongside offering significant renoprotective benefits beyond glycemic regulation, SGLT2 inhibitors have emerged as an essential element in managing diabetic nephropathy (DN). Meta-analyses and landmark studies like EMPA-REG, CREDENCE, and DAPA-CKD have demonstrated robust evidence of their ability to reduce albuminuria, slow the progression of eGFR decline, and improve renal outcomes at various stages of CKD. An innovative approach to managing DN, these findings are attributed to mechanisms such as reducing oxidative stress, enhancing renal oxygen levels, and decreasing glomerular hyperfiltration. Despite their solid safety history, issues like genitourinary infections and rare occurrences of euglycemic DKA require careful patient selection and vigilant monitoring. To reduce the global impact of DN, healthcare providers can enhance kidney and heart health by including SGLT2 inhibitors in treatment plans. To enhance their clinical effectiveness, upcoming research should focus on personalizing care and broadening its application to diverse patient populations. Declarations 1. Ethics (IRB) Approval: Not required 2. Funding: No funding was received for writing this systematic review 3. Clinical trial registration: Not applicable 4. Consent: Not applicable 5. Conflict of interest: There was no conflict of interest between authors Author Contribution Syed Tayyab Shah: Data collection, article writing, designing and supervision.Gulmadin Hikmat: data collection, proof readingAhsan Niazai: assisted in data collectionBakht Muhammad: contributed to the literature reviewMah Rukh Nisar: Reviewed and approved the final version of manuscript References Fang L, Duan J, Geng J, Liu Z, Dong J. Sodium-glucose cotransporter 2 (SGLT2) inhibitors for the prevention and treatment of diabetic kidney disease: A network meta-analysis of randomized controlled trials. Diabetic Nephropathy. 2021 Dec 1;1(3):114–24. Laursen JC, Søndergaard-Heinrich N, de Melo JML, Haddock B, Rasmussen IKB, Safavimanesh F, et al. Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial. EClinicalMedicine. 2021 Jul 1;37. Gao YM, Feng ST, Wen Y, Tang TT, Wang B, Liu BC. Cardiorenal protection of SGLT2 inhibitors-Perspectives from metabolic reprogramming-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). EBioMedicine [Internet]. 2022;83:104215. Available from: https://doi.org/10.1016/j. Capelli I, Ribichini D, Provenzano M, Vetrano D, Aiello V, Cianciolo G, et al. Impact of Baseline Clinical Variables on SGLT2i’s Antiproteinuric Effect in Diabetic Kidney Disease. Life. 2023 Apr 1;13(4). Guo W, Li H, Li Y, Kong W. Renal intrinsic cells remodeling in diabetic kidney disease and the regulatory effects of SGLT2 Inhibitors. Vol. 165, Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2023. Klen J, Dolžan V. SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation. Vol. 15, Pharmaceutics. Multidisciplinary Digital Publishing Institute (MDPI); 2023. Wheeler June James Dipesh Patel Adie Viljoen Amar Ali Marc Evans Kevin Fernando Debbie Hicks Nicola Milne Philip Newland-Jones John Wilding DC, Wheeler Á D Patel DC, James J, Viljoen Lister Hospital A, Ali UA, Fernando K, et al. SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes. Available from: https://doi.org/10.6084/m9.figshare.12937334. Zhou S, Zhang YL, Wang TD, Huang S, Gong S, Wang J, et al. Canagliflozin could improve the levels of renal oxygenation in newly diagnosed type 2 diabetes patients with normal renal function. Diabetes Metab. 2021 Sep 1;47(5). Thomas MC, Neuen BL, Twigg SM, Cooper ME, Badve S V. SGLT2 inhibitors for patients with type 2 diabetes and CKD: a narrative review. Endocr Connect. 2023 Aug 1;12(8). Liu AYL, Low S, Yeoh E, Lim EK, Renaud CJ, Teoh STY, et al. A real-world study on SGLT2 inhibitors and diabetic kidney disease progression. Clin Kidney J. 2022 Jul 1;15(7):1403–14. Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, et al. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med [Internet]. 2025 Feb 13;14(4):1241. Available from: https://www.mdpi.com/2077-0383/14/4/1241 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Vol. 372, The BMJ. BMJ Publishing Group; 2021. Lin FJ, Wang CC, Hsu CN, Yang CY, Wang CY, Ou HT. Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study. Cardiovasc Diabetol. 2021 Dec 1;20(1). Mosenzon O, Raz I, Wiviott SD, Schechter M, Goodrich EL, Yanuv I, et al. Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial. Diabetes Care. 2022 Oct 1;45(10):2350–9. Cherney DZI, Dagogo-Jack S, Cosentino F, Pratley RE, Frederich R, Maldonado M, et al. Heart and Kidney Outcomes With Ertugliflozin in People with Non-albuminuric Diabetic Kidney Disease: A post hoc Analysis from the Randomized VERTIS CV Trial. Kidney Int Rep. 2022 Aug 1;7(8):1782–92. Takeuchi M, Ogura M, Inagaki N, Kawakami K. Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling. BMJ Open Diabetes Res Care. 2022 Jun 8;10(3). Bose D, Maurya M, Konwar M. Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials. Vol. 55, Indian Journal of Pharmacology. Wolters Kluwer Medknow Publications; 2023. p. 119–27. Fadini GP, Longato E, Morieri ML, Del Prato S, Avogaro A, Solini A, et al. Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk. The Lancet Regional Health - Europe. 2024 Mar 1;38. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":171018,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow Diagram for Study and Selection Process\u003c/strong\u003e [12].\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7082203/v1/478f71b32a1df27b681a8b54.jpg"},{"id":95797958,"identity":"f75c9ef4-743d-45a7-8807-da54bb6d8fbc","added_by":"auto","created_at":"2025-11-13 08:13:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1609150,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7082203/v1/24a73d87-c52a-4763-8fa8-97181d27de1b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"SGLT2 Inhibitors in Diabetic Nephropathy: A Systematic Review of SGLT2 Inhibitors Benefits in Diabetic Nephropathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetic nephropathy (DN) is a progressive kidney disease brought on by persistent high blood sugar in people with diabetes mellitus. It features structural and functional alterations in the glomeruli, such as thickening of the glomerular basement membrane, expansion of the mesangium, and progressive glomerulosclerosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These changes result in proteinuria, a reduction in glomerular filtration rate (GFR), and, if unmanaged, can lead to end-stage renal disease (ESRD). The illness advances in phases, beginning with microalbuminuria and progressing to macroalbuminuria and kidney failure [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. DN a significant microvascular complication of diabetes mellitus, has attained concerning prevalence globally, impacting around 25\u0026ndash;40% of individuals with type 2 diabetes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The worldwide effect is considerable, with diabetes rates noted at 9.3% (463\u0026nbsp;million people) in 2019, anticipated to rise to 10.9% (700\u0026nbsp;million) by 2045 (3). DN has emerged as the primary cause of end-stage kidney disease (ESKD), contributing to as much as 44% of cases in certain populations [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The pathophysiology includes ongoing hyperglycemia resulting in glomerular hyperfiltration, elevated intraglomerular pressure, and buildup of advanced glycation end products (AGEs) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These processes lead to structural alterations such as thickening of the glomerular basement membrane, expansion of mesangial areas, and damage to podocytes, which ultimately causes proteinuria and advancing renal impairment [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Even with effective management through glycemic control and renin-angiotensin system (RAS) inhibition, disease progression frequently persists, underscoring the necessity for improved treatments [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recent research involving Asian groups indicates a notably high prevalence, with chronic kidney disease found in 46.5% of Indian individuals with T2DM [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and diabetic kidney disease responsible for 34% of kidney failure fatalities in Singapore [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSodium-glucose cotransporter-2 (SGLT2) inhibitors signify a significant advancement in DN treatment, providing advantages that extend beyond just glucose regulation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These agents block glucose reabsorption in the proximal tubule, enhancing urinary glucose elimination [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Their protective effects on the kidneys involve restoring tubuloglomerular feedback to lower intraglomerular pressure, inducing a fasting-like metabolic state, and decreasing oxidative stress and inflammation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Extensive clinical studies (EMPA-REG, CREDENCE, DAPA-CKD) have shown substantial kidney advantages, such as decreased albuminuria, slowed eGFR decline, and reduced likelihood of ESKD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These effects remained consistent across stages of chronic kidney disease, with new real-world evidence indicating benefits even when treatment began in advanced chronic kidney disease (eGFR 15\u0026ndash;44 mL/min/1.73 m2) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. SGLT2 inhibitors demonstrate additional advantages such as weight reduction, lowering blood pressure, and safeguarding cardiovascular health [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Their capacity to safeguard kidneys even in progressed chronic kidney disease has resulted in guideline suggestions as essential therapy for DN [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with revised treatment protocols now including these agents for renal protection [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Current studies investigate their mechanisms and possible interactions with other nephroprotective agents [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], including their impacts on renal oxygenation assessed through BOLD-MRI in the early stages of DN [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDiabetic kidney disease is a severe complication of diabetes that contributes substantially to the prevalence of end-stage renal disease globally. Although there have been improvements in diabetes treatment, there is still a pressing need for effective therapies to slow the progression of DKD. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become promising agents for protecting kidney function, providing advantages that extend beyond just controlling blood sugar levels. This systematic review examines their effectiveness, safety, and therapeutic relevance for patients with type 2 diabetes and DKD. By compiling high-quality evidence from randomized trials, meta-analyses, and cohort studies, we highlight their importance in maintaining kidney function and enhancing patient outcomes.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria (12) were closely followed during the systematic review, guaranteeing the highest levels of openness, rigor, and methodological accuracy in the synthesis and reporting of data.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eEligibility Criteria:\u003c/h2\u003e\u003cp\u003eOnly full-text, open access articles, English-language papers published in the last five years were included to provide a thorough and current study. The study included a variety of study methods, including meta-analyses for a compiled body of evidence, cohort studies for detailed patient data, and randomized control trials. All patients treated with SGLT2 inhibitors for type 2 diabetes who developed diabetic nephropathy were eligible to be included in this systematic review.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLiterature Search:\u003c/h3\u003e\n\u003cp\u003eA comprehensive and systematic search was conducted to evaluate the effects of \"SGLT2 inhibitors\" on \"Diabetic Nephropathy\" across four prominent databases\u0026mdash;PubMed, Google Scholar, PubMed Central, and ScienceDirect\u0026mdash;to guarantee a complete and all-encompassing collection of pertinent literature. This search concluded on April 10, 2025, which served as the cutoff date for article eligibility. To enhance the search approach, a mix of Medical Subject Headings (MeSH) and thoughtfully chosen keywords from previous studies was utilized, customized for the specific needs of each database. Table No.1 offers a thorough summary of the search procedure, detailing the selection of search criteria, MeSH terminology, and keywords, demonstrating the methodological rigor and clarity of the search approach adopted in the study. Below Table No. 01 show summary of the all literature search.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No. 01: Literature Search Strategy Data Base table\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDatabases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKeywords\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSearch strategy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFilters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSearch results\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePubMed\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiabetic Nephropathy AND SGLT2 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eConcept 1\u0026thinsp;=\u0026thinsp;Diabetic Nephropathy OR ( \u0026ldquo;Diabetic Nephropathies/blood\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/chemically induced\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/classification\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/complications\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diagnosis\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diagnostic imaging\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diet therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/drug therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/enzymology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/epidemiology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/ethnology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/etiology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/genetics\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/metabolism\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/mortality\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/pathology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/physiopathology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/prevention and control\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/urine\u0026rdquo;[Majr] ) Concept 2\u0026thinsp;=\u0026thinsp;SGLT2 Inhibitors OR ( \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/administration and dosage\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/adverse effects\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/classification\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/metabolism\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/pharmacology\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/therapeutic use\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/toxicity\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/urine\u0026rdquo;[Majr] ) Concept 1 and Concept 2 Combine\u0026thinsp;=\u0026thinsp;Diabetic Nephropathy OR ( \u0026ldquo;Diabetic Nephropathies/blood\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/chemically induced\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/classification\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/complications\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diagnosis\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diagnostic imaging\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/diet therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/drug therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/enzymology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/epidemiology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/ethnology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/etiology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/genetics\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/metabolism\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/mortality\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/pathology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/physiopathology\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/prevention and control\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/therapy\u0026rdquo;[Majr] OR \u0026ldquo;Diabetic Nephropathies/urine\u0026rdquo;[Majr] ) AND SGLT2 Inhibitors OR ( \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/administration and dosage\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/adverse effects\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/classification\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/metabolism\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/pharmacology\u0026rdquo;[Majr] OR OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/therapeutic use\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/toxicity\u0026rdquo;[Majr] OR \u0026ldquo;Sodium-Glucose Transporter 2 Inhibitors/urine\u0026rdquo;[Majr] )\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLast 5 years\u003c/p\u003e\u003cp\u003eEnglish\u003c/p\u003e\u003cp\u003eFull free text\u003c/p\u003e\u003cp\u003eHuman\u003c/p\u003e\u003cp\u003eMeta-analysis\u003c/p\u003e\u003cp\u003eSystematic Review\u003c/p\u003e\u003cp\u003eApril 10, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e278\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGoogle Scholar\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiabetic Nephropathy OR Diabetic Kidney Disease AND SGLT2 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDiabetic Nephropathy OR Diabetic Kidney Disease AND SGLT2 Inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLast five years\u003c/p\u003e\u003cp\u003eEnglish\u003c/p\u003e\u003cp\u003eIn the title of the article\u003c/p\u003e\u003cp\u003eApril 10, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePMC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiabetic Nephropathy AND SGLT2 Inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ldquo;Diabetic Nephropathy\u0026rdquo; OR \u0026ldquo;Diabetic Kidney Disease\u0026rdquo; AND \u0026ldquo;SGLT2 Inhibitors\u0026rdquo; AND \u0026ldquo;Disease Progression\u0026rdquo; AND Observational Studies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLast five years\u003c/p\u003e\u003cp\u003eOpen Access\u003c/p\u003e\u003cp\u003eObservational Studies\u003c/p\u003e\u003cp\u003eApril 10, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e539\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eScience Direct\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiabetic Nephropathy AND SGLT2 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDiabetic Nephropathy AND SGLT2 Inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOpen Access and Open Archive\u003c/p\u003e\u003cp\u003eLast five years\u003c/p\u003e\u003cp\u003eEnglish\u003c/p\u003e\u003cp\u003eApril 10, 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e461\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment in Individual Studies:\u003c/h3\u003e\n\u003cp\u003eTo attain the utmost levels of methodological quality, a tailored approach was implemented to assess the quality of the selected studies. Two meta-analyses were carefully evaluated using the AMSTAR 2 checklist, which is designed for reviewing systematic reviews and meta-analyses, ensuring adherence to rigorous criteria for synthesizing systematic evidence. The Cochrane Risk of Bias Tool was utilized to evaluate the quality of three randomized controlled trials, judging their robustness. For the trio of cohort studies, the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies assessed their dependability. Only those studies that surpassed a high-quality threshold of more than 70% in their evaluations were incorporated into the final analysis. This approach guaranteed that the outcomes were grounded in credible, high-quality, and reliable evidence, as shown in Table No. 02, Table No. 03, and Table No. 04 for the Meta Analysis, Randomized Controlled Trials, and Cohort Studies respectively.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No.02: Meta-Analysis AMSTAR 2 for the Quality Assessment of the individual study\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eName of First Author\u003c/p\u003e\u003cp\u003eYear of the Study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFang L 2021 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBose D 2023 et al.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. Did the research questions and inclusion criteria for the review include the components of PICO?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. Did the review authors explain their selection of the study designs for inclusion in the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. Did the review authors use a comprehensive literature search strategy?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5. Did the review authors perform study selection in duplicate?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. Did the review authors perform data extraction in duplicate?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. Did the review authors provide a list of excluded studies and justify the exclusions?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. Did the review authors describe the included studies in adequate detail?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10. Did the review authors report on the sources of funding for the studies included in the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQuality Assessment\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.5/16\u0026thinsp;=\u0026thinsp;84.375%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13/16\u0026thinsp;=\u0026thinsp;81.25%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No.03: Randomized Control Trial Cochrane Risk of Bias for the Quality Assessment of the individual study\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eName of First Author\u003c/p\u003e\u003cp\u003eYear of the study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCherney D Z.I\u003c/p\u003e\u003cp\u003e2022 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLaursen J C, MD\u003c/p\u003e\u003cp\u003e2021 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZhou S 2021 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMosenzn O 2022 et al.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSelection bias Random sequence generation. Described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSelection bias Allocation concealment. Described the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen before or during enrollment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporting bias Selective reporting. Stated how the possibility of selective outcome reporting was examined by the authors and what was found\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther bias Other sources of bias. Any important concerns about bias not addressed above (If particular questions/entries were pre-specified in the study's protocol, responses should be provided for each question/entry)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePerformance bias Blinding (participants and personnel). Described all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provided any information relating to whether the intended blinding was effective.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDetection bias Blinding (outcome assessment). Described all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provided any information relating to whether the intended blinding was effective.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAttrition bias Incomplete outcome data. Described the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. Stated whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQuality Assessment\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.5/7\u0026thinsp;=\u0026thinsp;78.571%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/7\u0026thinsp;=\u0026thinsp;71.428%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.5/7\u0026thinsp;=\u0026thinsp;50%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6/7\u0026thinsp;=\u0026thinsp;85.714%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No.04: Cohort Studies Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies for the Quality Assessment of the individual study\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eName of First Author\u003c/p\u003e\u003cp\u003eYear of the Study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCapelli I 2023 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFadini G P 2024 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLin F\u003c/p\u003e\u003cp\u003e2021 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLiu A Y L 2022 et al.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTakeuchi M\u003c/p\u003e\u003cp\u003e2022 et al.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e1. Was the research question or objective in this paper clearly stated?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e2. Was the study population clearly specified and defined?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e3. Was the participation rate of eligible persons at least 50%?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e5. Was a sample size justification, power description, or variance and effect estimates provided?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e10. Was the exposure(s) assessed more than once over time?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e12. Were the outcome assessors blinded to the exposure status of participants?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e13. Was loss to follow-up after baseline 20% or less?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow Risk\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQuality Assessment\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e9.5/14\u0026thinsp;=\u0026thinsp;67.857%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.5/14\u0026thinsp;=\u0026thinsp;89.285%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10/14\u0026thinsp;=\u0026thinsp;89.285%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8.5/14\u0026thinsp;=\u0026thinsp;60.71%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10/14\u0026thinsp;=\u0026thinsp;71.248%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStudy Selection Process:\u003c/h2\u003e\u003cp\u003eAfter conducting an extensive search through various databases, duplicates were carefully eliminated to enhance efficiency. There were 1308 results in the initial search. After 276 duplicates were removed, 888 entries were disqualified for title reasons. After carefully reviewing the abstracts of the articles, 119 were determined to be irrelevant and were therefore dismissed. Seventeen more articles were excluded for the following reasons: eleven were narrative reviews, three were mechanistic and animal studies, and three had quality assessment scores lower than 70%. Ultimately, eight articles were chosen for inclusion after scoring over 70% on the quality assessment tool. To maintain objectivity and accuracy, two separate authors diligently reviewed and assessed the articles at each phase, ensuring that the highest standards of academic rigor and precision were upheld.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStudy Characteristics:\u003c/h2\u003e\u003cp\u003e The studies encompassed a diverse population of 243,682 patients overall, with sample sizes ranging from small mechanistic investigations with 19 participants to big meta-analyses with over 70,000 subjects. The evidence base was multidimensional because the research designs included rigorous randomized controlled trials, extensive meta-analyses, and real-world cohort studies. The follow-up periods in the studies varied greatly, ranging from 8.5 months of relatively short-term assessments to 5.5 years of lengthy observations, making it possible to examine both immediate and long-lasting impacts. The studies' participants spanned a broad age spectrum, with average ages ranging from 30 years in a study on type 1 diabetes to over 60 years in studies focusing on older groups. Most of the studies also revealed a male majority in their gender distribution, with males accounting for 57.5\u0026ndash;69.1% of the total. Generally, the inclusion criteria required a confirmed diagnosis of type 2 diabetes and stable kidney function, which was typically defined by baseline eGFR thresholds of 20\u0026ndash;30 mL/min/1.73 m\u0026sup2; or higher. However, some studies were specifically targeted at individuals with cardiovascular comorbidities. Typical exclusion criteria eliminated potential confounding by excluding individuals who were pregnant, had end-stage renal disease or were receiving dialysis, those with type 1 diabetes, and those with inadequate follow-up time. The primary intervention comparison involved SGLT2 inhibitors against placebo or other glucose-lowering medications, with renal protection endpoints including eGFR decline, albuminuria progression, and composite kidney outcomes. While big observational cohort studies offered valuable real-world evidence on long-term renal safety profiles, randomized trials provided controlled efficacy data. The variation in baseline characteristics among studies, such as differing degrees of kidney function impairment and unique cardiovascular risk profiles, underscores the importance of individualized clinical decision-making when using these results in patient care. When combined, this large body of evidence improves our understanding of renal outcomes in diabetic patients treated with SGLT2 inhibitors. Table No. 05 below shows characteristics from all studies, such as two meta-analyses, three randomized controlled trials, and three cohort studies. Below Table No. O5 show summary of characteristics of the all the studies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No.5: Characteristics of all the studies\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGFR (Glomerular Filtration Rate), RCT (Randomized Controlled Trial), T2DM (Type 2 Diabetes Mellitus), T1DM (Type 1 Diabetes Mellitus), M (Male), F (Female), NDKD (Non-Diabetic Kidney Disease), UACR (Urine Albumin-to-Creatinine Ratio), BP (Blood Pressure), MRI (Magnetic Resonance Imaging), SGLT2i (Sodium-Glucose Cotransporter-2 Inhibitors), oGLD (other Glucose-Lowering Drugs), eGFR (estimated Glomerular Filtration Rate), CrCl (Creatinine Clearance), DKA (Diabetic Ketoacidosis), ASCVD (Atherosclerotic Cardiovascular Disease), CKD (Chronic Kidney Disease), ESRD (End-Stage Renal Disease), CV (Cardiovascular), HbA1c (Hemoglobin A1c), NM (Not Mentioned), HF (Heart Failure).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabe\" border=\"1\"\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudies\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"8\" nameend=\"c9\" namest=\"c2\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst Author, Year of Study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy Type\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNumber of Patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGender Distribution\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal Follow-up Period\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMean Age of Patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBaseline Kidney Function (GFR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExclusion Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eInclusion Criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFang L 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeta-Analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51,925\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 61.5% F: 38.5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24 weeks to 4.2 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e52 to 68.7 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e39.1 to 92.7 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNon-RCTs, follow-up \u0026lt;\u0026thinsp;12 weeks, non-T2DM patients, no renal outcomes, or duplicate/subgroup analyses.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRCTs comparing SGLT2 inhibitors with placebo in T2DM patients, duration\u0026thinsp;\u0026ge;\u0026thinsp;12 weeks. Reporting at least one renal-related outcome.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLaursen J C 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRandomized Control Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 66% F: 34%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8.5 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30 to 86 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;15 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNDKD, severe renal failure, dialysis, arrhythmia, pregnancy, BP issues, MRI limits, surgery, or restlessness.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdults with type 1 diabetes (T1DM) and albuminuria (UACR\u0026thinsp;\u0026ge;\u0026thinsp;30 mg/g).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLin F 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort Study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27,332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 57.5% F: 42.5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;20 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow: ~48.6, Mid: ~75.5, High: ~113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSGLT2i/oGLD use, age\u0026thinsp;\u0026lt;\u0026thinsp;20, no pre-index data, T1/gestational diabetes, or \u0026lt;\u0026thinsp;2 eGFR tests 180 days apart.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePatients (20+) with T2DM, starting SGLT-2is or oGLDs, \u0026ge;\u0026thinsp;2 pre-index eGFRs, no study drug use for \u0026ge;\u0026thinsp;1 year, and baseline eGFR measured within 180 days before treatment start.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMosenzn O 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRandomized Control Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17,160\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 62.6% F: 37.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.2 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;40 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;30 mL/min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min, dialysis, type 1 diabetes, recent DKA, SGLT2i use, pregnancy, or significant liver disease.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdults (\u0026ge;\u0026thinsp;40 years with ASCVD or \u0026ge;\u0026thinsp;55/60 years [men/women] with CV risk factors) with type 2 diabetes, HbA1c 6.5\u0026ndash;12%, and CrCl\u0026thinsp;\u0026ge;\u0026thinsp;60 mL/min.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCherney D Z.I 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRandomized Control Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8,030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 69.1% F: 30.9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.5 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePost hoc design, no adjustment, false positives, low power for subgroups, limited generalizability to ASCVD.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdults with type 2 diabetes (T2DM) and established atherosclerotic cardiovascular disease (ASCVD), with baseline eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u0026sup2; and available UACR data.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTakeuchi M 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort Study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36,237\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e77 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;20 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBaseline eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;, missing lab data, type 1 diabetes, and unspecified non-T2DM cases.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdults (\u0026ge;\u0026thinsp;20) with T2DM, eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u0026sup2;, HbA1c data available, using glucose-lowering meds (excluding SGLT2 inhibitors) at baseline.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBose D 2023 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeta-Analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71,553\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9 months to 4.2 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;60 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;20 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eT1DM, ESRD (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15/dialysis), rapidly progressing CKD (\u0026gt;\u0026thinsp;5 mL/min/year decline).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdults with T2DM (with/without CKD/CVD) from RCTs, eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30 (\u0026ge;\u0026thinsp;25 in some CKD trials, \u0026ge;\u0026thinsp;20 in HF trials).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFadini G P 2024 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort Study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12,394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM: 61% F: 39%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e54 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18\u0026ndash;80 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;25 mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;18 or \u0026gt;\u0026thinsp;80 years, non-T2DM, prior SGLT2i use, CKD stage V/dialysis, or missing renal outcome data.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIndividuals aged 18 to 80 with T2DM for at least one year, beginning dapagliflozin or non-SGLT2i medications (excluding insulin), without SGLT2i usage in the past year, not in CKD V or requiring dialysis, and having at least one eGFR measurement after the baseline.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Outcome:\u003c/h3\u003e\n\u003cp\u003eSGLT2 inhibitors exhibit various protective effects on the kidneys in diabetic nephropathy. A meta-analysis indicated that these agents substantially lower UACR, with empagliflozin showing notable effectiveness [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Randomized controlled trials indicated that prolonged use results in decreased albuminuria and stabilization of long-term eGFR [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cohort studies showed a reduced eGFR decline (HR 0.53\u0026thinsp;\u0026minus;\u0026thinsp;0.42) in patients with early-stage CKD [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Clinical trials recorded reductions in UACR of 20\u0026ndash;40% alongside an initial decrease in eGFR, followed by a gradual long-term decline [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Studies showed a 34% relative decrease in renal progression risk (HR 0.66) among various patient subgroups [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Observational findings indicated that these drugs lower the yearly eGFR decrease by 0.80 mL/min/year [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Extensive meta-analyses indicated a 36% decrease in composite renal outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Recent studies demonstrated notable reductions in UACR (-44.3 mg/g) and maintenance of kidney function (+\u0026thinsp;1.81 mL/min/year) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The safety profile continues to be positive with controllable side effects. These reliable results from various study designs endorse SGLT2 inhibitors as a crucial treatment option. Their advantages span all phases of diabetic kidney disease. Below Table No. 06 show outcome summary of all the studies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTable No.6: Outcomes of all the studies\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eUACR (Urinary Albumin-to-Creatinine Ratio), eGFR (Estimated Glomerular Filtration Rate), ESRD (End-Stage Renal Disease), RR (Relative Risk), SUCRA (Surface Under the Cumulative Ranking Curve), KDIGO (Kidney Disease Improving Global Outcomes), HbA1c (Hemoglobin A1c), CKD (Chronic Kidney Disease), NM (Not Mentioned), HR (Hazard Ratio), RRT (Renal Replacement Therapy).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabf\" border=\"1\"\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst Author, Year of Study\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUACR Reduction\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eeGFR Decline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eKidney Protection\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eInflammation Biomarkers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSafety\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eComposite Renal Outcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNew-Onset CKD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eESKD Risk\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFang L 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSignificant reduction with empagliflozin (-83.01 MD). This reflects a robust lowering of protein excretion, reducing nephropathy progression.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSignificant reduction in composite kidney outcomes (e.g., RR: 0.74\u0026ndash;0.82). High SUCRA suggests superiority.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReduction in ESRD, doubling of serum creatinine, and kidney death risks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e15% ESRD risk reduction indicates substantial clinical benefit.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLaursen J C 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eImproved renal oxygenation, indicative of protective effects on kidney metabolism.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo change observed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTolerated.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLin F 2021 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSlowed eGFR decline. Initial acute dip followed by stabilization suggests tubular function improvement.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReduced hazard ratio for eGFR reductions by 30%, 40%, 50%.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot assessed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFocused on defined eGFR thresholds, composite outcomes not evaluated.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMosenzn O 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot quantified but observed in albuminuric subgroups, implying specific benefits for proteinuric patients.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSlower chronic eGFR decline highlights the consistent renal protection of dapagliflozin.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003elowering of risk in all KDIGO categories, especially in high-risk subgroups.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWell tolerated.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKidney-specific composite outcomes (e.g., HR 0.53), showing efficacy.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLow dialysis requirement supports efficacy in advanced cases.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCherney D Z.I 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduction in albuminuria progression, most pronounced in high-risk groups.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSlower eGFR decline; acute dip aligns with expected pharmacological effects.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConsistent albuminuria reduction, showing subgroup robustness.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo new safety signals detected.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eComposite outcomes improved by 34%, affirming therapeutic benefit.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLower macroalbuminuria progression implies new-onset CKD reduction.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eESKD risk reduction probable but not directly quantified.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTakeuchi M 2022 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAnnual decline slower with HbA1c thresholds\u0026thinsp;\u0026le;\u0026thinsp;6.5%. Early intervention benefits highlighted.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReduction in endpoints tied to early treatment initiation, emphasizing timing.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot assessed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eImproved outcomes with early treatment (HbA1c reduction within 3 months).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eImplicit in early reductions observed.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eImproved outcomes suggest ESKD delay.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBose D 2023 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCombined reduction in renal death, RRT, and eGFR\u0026thinsp;\u0026gt;\u0026thinsp;40% underscores broad effectiveness.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSignificant eGFR decline reduction, supporting long-term kidney health.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLower sustained eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 mL/min/1.73 m\u0026sup2; incidence supports advanced protection.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot significant.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRisk ratio across endpoints (e.g., RR: 0.64), showing efficacy.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSubgroup analyses suggest benefits.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReduction in dialysis rates affirms kidney protection.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFadini G P 2024 et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdjusted reduction (-44 mg/g) highlights effectiveness in albuminuria patients.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThe mean eGFR difference (+\u0026thinsp;1.81) shows that renal function has stabilized.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReduction in CKD and ESRD risks in low-risk populations highlights prevention focus.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot significant.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eImproved outcomes in eGFR decline, ESRD, and dialysis (HR: 0.70).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHR: 0.76 in low-risk cohorts suggests broad applicability.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConsistency in reducing advanced kidney disease events.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSGLT2 inhibitors have demonstrated protective effects on the kidneys in diabetic kidney disease (DKD), significantly enhancing renal cortical oxygenation, reducing albuminuria, and slowing the progression of kidney disease. Dapagliflozin does not influence renal blood flow or oxygen delivery but decreases renal cortical oxygen tension primarily by reducing energy demand in proximal tubules. This supports the notion that SGLT2 inhibition lessens renal hypoxia, a key factor in the development of DKD. Empagliflozin reliably decreases the urine albumin-to-creatinine ratio (UACR) and improves composite renal outcomes among SGLT2 inhibitors, with differences between agents potentially attributed to study design, patient demographics, and drug pharmacology. SGLT2 inhibitors are utilized not only for glycemic control but also for direct kidney protection, with clinical trials and meta-analyses showing that they reduce the advancement of chronic kidney disease regardless of initial eGFR. The processes involve alteration of kidney blood flow, reduced inflammation, lowered glomerular hyperfiltration, and improved tubuloglomerular feedback. Most of the evidence originates from individuals with type 2 diabetes, but findings in those with type 1 diabetes indicate certain benefits that warrant further investigation. Some examples of limitations include variability in trial designs, indirect comparisons within meta-analyses, and small sample sizes in mechanistic studies. The evidence, nonetheless, strongly supports SGLT2 inhibitors as primary therapies for DKD, emphasizing the need for further head-to-head studies and long-term investigations to enhance treatment methods and understand prolonged effects.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePathophysiology, Prevalence and Current Treatment Review of Diabetic Nephropathy:\u003c/h2\u003e\u003cp\u003eDN is defined by the gradual decline in kidney function resulting from metabolic and hemodynamic changes associated with diabetes. The pathophysiology of DN entails several mechanisms, such as oxidative stress from hyperglycemia, inflammation, and changes in hemodynamics. Persistent high blood sugar triggers pathways like the polyol and hexosamine pathways, resulting in advanced glycation end-products (AGEs) that harm kidney tissues [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, the renin-angiotensin-aldosterone system (RAAS) is excessively activated, leading to intraglomerular hypertension and hyperfiltration, which worsen kidney injury [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Tubulointerstitial fibrosis and podocyte damage are also key characteristics of DN, leading to permanent loss of kidney function [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. DN is a primary contributor to chronic kidney disease and end-stage renal disease globally, impacting around 30\u0026ndash;40% of individuals with type 2 diabetes mellitus (T2DM) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The occurrence is greater in groups with inadequate glycemic management, high blood pressure, and hereditary factors. Timely identification via screening for albuminuria and decline in eGFR is essential to reduce progression [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The traditional approach to managing diabetic neuropathy (DNP) involves stringent glycemic control, blood pressure regulation (frequently using RAAS inhibitors such as ACEIs or ARBs), and changes to one's lifestyle [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nevertheless, many patients cannot have their disease progression stopped by these treatments alone. Due to their renoprotective effects, recent findings have highlighted the significance of sodium-glucose cotransporter-2 inhibitors (SGLT2is) as a novel therapy for DNP [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eThe SGLT2 Inhibitors' Mode of Action:\u003c/h2\u003e\u003cp\u003eSGLT2 inhibitors lower blood glucose levels independently of insulin by selectively blocking the SGLT2 transporter in the proximal tubule, which decreases sodium and glucose reabsorption and encourages glycosuria [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. SGLT2 inhibitors also improve renal hemodynamics by restoring tubuloglomerular feedback, decreasing intraglomerular pressure, and alleviating hyperfiltration [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Metabolic impacts through decreased tubular oxygen requirement and enhanced cortical oxygen supply [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Anti-fibrotic/Anti-inflammatory effects achieved by decreasing HIF-1α and sodium-hydrogen exchanger activity to lessen fibrosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].Acute eGFR declines (for instance, -2.99 mL/min/6 months with dapagliflozin) signify the initial hemodynamic variations, succeeded by a phase of extended stabilization [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSGLT2 Inhibitors Protection Against Diabetic Nephropathy:\u003c/h2\u003e\u003cp\u003eSGLT2 inhibitors provide renoprotective benefits via several mechanisms. They lessen glomerular hyperfiltration and intraglomerular pressure by constricting the afferent arteriole [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. They also enhance renal oxygenation by lowering oxidative stress and tubular workload [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. While traditional treatments (like RAAS inhibitors) are crucial, SGLT2 inhibitors offer extra benefits. Meta-analyses indicate a 30\u0026ndash;40% reduction in overall renal outcomes (including ESRD and eGFR decline) in different trials [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Regarding UACR reduction, empagliflozin is superior (SUCRA: 0.993), while canagliflozin and dapagliflozin have shown robust renal protection in advanced CKD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Clinical trials have shown that SGLT2is significantly reduce albuminuria and slow the decline of eGFR, with empagliflozin demonstrating especially strong activity in lowering the UACR in comparison to placebo, empagliflozin lowers UACR by 83.01 mg/g [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Real-world research, including DARWIN-Renal, corroborates the trial results, showing that dapagliflozin reduces albuminuria by 44 mg/g and decreases the eGFR decline rate by 0.67 ml/min/year [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. By reducing inflammation and fibrosis, these medications also help to maintain kidney function even more [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Consistent chronic slope improvements (+\u0026thinsp;0.55 to +\u0026thinsp;1.23 mL/min/year) are observed across eGFR subgroups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].Decreases in risk are observed for ESRD (HR 0.70) and \u0026ge;\u0026thinsp;40% reduction in eGFR (HR 0.53) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The effectiveness of SGLT2is in improving renal outcomes is consistently shown in both real-world studies and clinical trials. For example, dapagliflozin decreased the risk of composite renal outcomes by 36% and slowed the eGFR decline by 0.7 mL/min/year [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Empagliflozin and canagliflozin also demonstrated considerable advantages, with hazard ratios (HRs) for ESRD or renal death ranging from 0.62 to 0.70 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Renal protection is further improved by the early initiation of SGLT2is at lower HbA1c cutoff points (e.g., 6.5%) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Diabetic nephropathy advances from microalbuminuria to macroalbuminuria and a decrease in eGFR, exhibiting variability in clinical manifestation. Significantly, 10.8% of patients show diabetic kidney disease without albuminuria, marked by a slower decline in eGFR while still gaining advantages from SGLT2 inhibitors [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Data from real-world studies indicate that early intervention (HbA1c\u0026thinsp;\u0026ge;\u0026thinsp;6.5%) markedly improves renal outcomes, highlighting the importance of prompt treatment [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Subgroup analyses from DECLARE-TIMI 58 indicate that low-risk patients (eGFR\u0026thinsp;\u0026ge;\u0026thinsp;90 mL/min/1.73 m\u0026sup2;) also show delayed CKD progression when treated with dapagliflozin [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSGLT2 Inhibitors' Side Effects:\u003c/h2\u003e\u003cp\u003eSGLT2 inhibitors are effective, but their adverse effects deserve attention. The most frequent complications are genitourinary infections, which occur in 5\u0026ndash;10% of patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Volume depletion and hypotension can occur, particularly in elderly patients or those using diuretics. In insulin-deficient patients, rare cases of DKA call for close attention [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Acute drops in eGFR are temporary and benign [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Real-world evidence supports their application in CKD (eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min) as they do not elevate the risk of AKI [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Euglycemic diabetic ketoacidosis (DKA) and acute kidney injury (AKI) are rare but serious dangers, even if recent meta-analyses have not found that SGLT2is increase the risk of AKI [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For the majority of patients, the advantages of SGLT2is in preserving renal function exceed the potential hazards, despite these risks.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eLimitations:\u003c/h2\u003e\u003cp\u003eThis systematic review, despite its careful methodology, has several shortcomings. First, only English-language publications from the last five years were taken into account, which could have resulted in selection bias by ignoring earlier studies or better non-English research. Second, by only relying on publicly available full-text papers, important research in favor of paywalls may have been left out, thereby reducing the evidence's comprehensiveness. Finally, the search strategy might have missed new or relevant terms in the quickly evolving field of SGLT2 inhibitor therapy, even though it was thorough. In order to overcome these limitations, these disparities highlight the need for careful interpretation of results and further research.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlongside offering significant renoprotective benefits beyond glycemic regulation, SGLT2 inhibitors have emerged as an essential element in managing diabetic nephropathy (DN). Meta-analyses and landmark studies like EMPA-REG, CREDENCE, and DAPA-CKD have demonstrated robust evidence of their ability to reduce albuminuria, slow the progression of eGFR decline, and improve renal outcomes at various stages of CKD. An innovative approach to managing DN, these findings are attributed to mechanisms such as reducing oxidative stress, enhancing renal oxygen levels, and decreasing glomerular hyperfiltration. Despite their solid safety history, issues like genitourinary infections and rare occurrences of euglycemic DKA require careful patient selection and vigilant monitoring. To reduce the global impact of DN, healthcare providers can enhance kidney and heart health by including SGLT2 inhibitors in treatment plans. To enhance their clinical effectiveness, upcoming research should focus on personalizing care and broadening its application to diverse patient populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e1. Ethics (IRB) Approval: Not required\u003c/p\u003e\n\u003cp\u003e2. Funding: No funding was received for writing this systematic review\u003c/p\u003e\n\u003cp\u003e3. Clinical trial registration: Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Consent: Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. Conflict of interest: There was no conflict of interest between authors\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSyed Tayyab Shah: Data collection, article writing, designing and supervision.Gulmadin Hikmat: data collection, proof readingAhsan Niazai: assisted in data collectionBakht Muhammad: contributed to the literature reviewMah Rukh Nisar: Reviewed and approved the final version of manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFang L, Duan J, Geng J, Liu Z, Dong J. Sodium-glucose cotransporter 2 (SGLT2) inhibitors for the prevention and treatment of diabetic kidney disease: A network meta-analysis of randomized controlled trials. Diabetic Nephropathy. 2021 Dec 1;1(3):114\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eLaursen JC, S\u0026oslash;ndergaard-Heinrich N, de Melo JML, Haddock B, Rasmussen IKB, Safavimanesh F, et al. Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial. EClinicalMedicine. 2021 Jul 1;37. \u003c/li\u003e\n\u003cli\u003eGao YM, Feng ST, Wen Y, Tang TT, Wang B, Liu BC. Cardiorenal protection of SGLT2 inhibitors-Perspectives from metabolic reprogramming-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). EBioMedicine [Internet]. 2022;83:104215. Available from: https://doi.org/10.1016/j.\u003c/li\u003e\n\u003cli\u003eCapelli I, Ribichini D, Provenzano M, Vetrano D, Aiello V, Cianciolo G, et al. Impact of Baseline Clinical Variables on SGLT2i\u0026rsquo;s Antiproteinuric Effect in Diabetic Kidney Disease. Life. 2023 Apr 1;13(4). \u003c/li\u003e\n\u003cli\u003eGuo W, Li H, Li Y, Kong W. Renal intrinsic cells remodeling in diabetic kidney disease and the regulatory effects of SGLT2 Inhibitors. Vol. 165, Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2023. \u003c/li\u003e\n\u003cli\u003eKlen J, Dolžan V. SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation. Vol. 15, Pharmaceutics. Multidisciplinary Digital Publishing Institute (MDPI); 2023. \u003c/li\u003e\n\u003cli\u003eWheeler June James Dipesh Patel Adie Viljoen Amar Ali Marc Evans Kevin Fernando Debbie Hicks Nicola Milne Philip Newland-Jones John Wilding DC, Wheeler \u0026Aacute; D Patel DC, James J, Viljoen Lister Hospital A, Ali UA, Fernando K, et al. SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes. Available from: https://doi.org/10.6084/m9.figshare.12937334.\u003c/li\u003e\n\u003cli\u003eZhou S, Zhang YL, Wang TD, Huang S, Gong S, Wang J, et al. Canagliflozin could improve the levels of renal oxygenation in newly diagnosed type 2 diabetes patients with normal renal function. Diabetes Metab. 2021 Sep 1;47(5). \u003c/li\u003e\n\u003cli\u003eThomas MC, Neuen BL, Twigg SM, Cooper ME, Badve S V. SGLT2 inhibitors for patients with type 2 diabetes and CKD: a narrative review. Endocr Connect. 2023 Aug 1;12(8). \u003c/li\u003e\n\u003cli\u003eLiu AYL, Low S, Yeoh E, Lim EK, Renaud CJ, Teoh STY, et al. A real-world study on SGLT2 inhibitors and diabetic kidney disease progression. Clin Kidney J. 2022 Jul 1;15(7):1403\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eViggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, et al. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med [Internet]. 2025 Feb 13;14(4):1241. Available from: https://www.mdpi.com/2077-0383/14/4/1241\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Vol. 372, The BMJ. BMJ Publishing Group; 2021. \u003c/li\u003e\n\u003cli\u003eLin FJ, Wang CC, Hsu CN, Yang CY, Wang CY, Ou HT. Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study. Cardiovasc Diabetol. 2021 Dec 1;20(1). \u003c/li\u003e\n\u003cli\u003eMosenzon O, Raz I, Wiviott SD, Schechter M, Goodrich EL, Yanuv I, et al. Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial. Diabetes Care. 2022 Oct 1;45(10):2350\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eCherney DZI, Dagogo-Jack S, Cosentino F, Pratley RE, Frederich R, Maldonado M, et al. Heart and Kidney Outcomes With Ertugliflozin in People with Non-albuminuric Diabetic Kidney Disease: A post hoc Analysis from the Randomized VERTIS CV Trial. Kidney Int Rep. 2022 Aug 1;7(8):1782\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eTakeuchi M, Ogura M, Inagaki N, Kawakami K. Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling. BMJ Open Diabetes Res Care. 2022 Jun 8;10(3). \u003c/li\u003e\n\u003cli\u003eBose D, Maurya M, Konwar M. Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials. Vol. 55, Indian Journal of Pharmacology. Wolters Kluwer Medknow Publications; 2023. p. 119\u0026ndash;27. \u003c/li\u003e\n\u003cli\u003eFadini GP, Longato E, Morieri ML, Del Prato S, Avogaro A, Solini A, et al. Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk. The Lancet Regional Health - Europe. 2024 Mar 1;38. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diabetic nephropathy, Diabetic Kidney Disease, SGLT2 inhibitors, renal protection, albuminuria, eGFR decline, systematic review","lastPublishedDoi":"10.21203/rs.3.rs-7082203/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7082203/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDiabetic nephropathy (DN), which affects 25\u0026ndash;40% of those with type 2 diabetes (T2DM), is the main cause of end-stage kidney disease (ESKD) and a significant microvascular effect of diabetes mellitus. The need for better treatments is highlighted by the fact that disease progression frequently continues even after improvements in glycemic management and renin-angiotensin system (RAS) inhibition. Since they provide advantages beyond glucose management, such as kidney protection, sodium-glucose cotransporter-2 (SGLT2) inhibitors have become an attractive therapy option.\u003c/p\u003e\u003cp\u003e\u003cb\u003eObjective:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis systematic review aims to evaluate the therapeutic potential, safety, and efficacy of SGLT2 inhibitors in the treatment of DN, with a focus on the renoprotective effects they have on individuals with type 2 diabetes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethod:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA thorough literature search was carried out up until April 10, 2025, using PubMed, Google Scholar, PubMed Central, and ScienceDirect in accordance with PRISMA 2020 standards. Cohort studies published in English within the previous five years, meta-analyses, and randomized controlled trials (RCTs) were all considered eligible studies. The Quality Assessment Tool for Observational Cohort Studies, the Cochrane Risk of Bias Tool for RCTs, and AMSTAR 2 for meta-analyses were used to evaluate the risk of bias.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResult:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe inclusion of 243,682 patients from eight high-quality studies (two meta-analyses, three RCTs, and three cohort studies) was noted. SGLT2 inhibitors showed considerable renoprotective benefits, such as a 20\u0026ndash;40% decrease in UACR, a 0.7\u0026ndash;1.81 mL/min/year reduction in the rate of eGFR decline, and a 34\u0026ndash;36% relative risk reduction in composite renal outcomes. Empagliflozin and dapagliflozin were especially effective due to their mechanisms, which included enhanced renal oxygenation, decreased glomerular hyperfiltration, and anti-inflammatory effects. The safety profiles were encouraging, with manageable adverse effects like genital infections and uncommon occurrences of diabetic ketoacidosis (DKA).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGiven their strong renal protective effects in diabetic nephropathy, SGLT2 inhibitors should be started early in Type 2 diabetes patients, with or without chronic kidney disease. They are a cornerstone in the management of DN since their advantages span all phases of renal illness. Additional study is needed to examine long-term results and comparative effectiveness among various SGLT2 medications.\u003c/p\u003e","manuscriptTitle":"SGLT2 Inhibitors in Diabetic Nephropathy: A Systematic Review of SGLT2 Inhibitors Benefits in Diabetic Nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 16:29:53","doi":"10.21203/rs.3.rs-7082203/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73788ac9-bf76-4371-baaa-3bc2818e7dba","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-11T14:24:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 16:29:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7082203","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7082203","identity":"rs-7082203","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}