The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

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This meta-analysis seeks to evaluate the therapeutic efficacy and safety profile of SGLT-2 inhibitors specifically in the diabetes KTR population. Methods We conducted a systemic review and meta-analysis following a registered protocol in the PROSPERO (CRD42023404886). A comprehensive literature search was performed using PubMed, Cochrane, and Scopus databases up to October 23th, 2024. We included observational and clinical trials which compared SGLT-2 inhibitors with control groups in KTRs. Risk of bias was evaluated by funnel plot. We reported differences in treatment effects as risk ratios (RRs) or weighted mean difference (WMD) with 95% confidence intervals (CIs). Results A total of seven studies comprising 2,713 patients were included in this analysis. SGLT-2 inhibitors were associated with a significant reduction in HbA1c levels (WMD -0.37%; 95% CI -0.73 to -0.01; p = 0.04) and BMI (WMD -0.89 kg/m2; 95% CI -1.27 to -0.50; p < 0.001). Additionally, SGLT-2 inhibitors demonstrated a beneficial effect in reducing mortality (RR 0.25; 95% CI 0.06 to 0.98; p = 0.05) and cardiovascular disease (CVD) (RR 0.41; 95% CI 0.17 to 0.98; p = 0.04). However, SGLT-2 inhibitors did not demonstrate benefit in kidney-related outcomes. Importantly, there was no significant increase in adverse events, including urinary tract infections, genital mycotic infections, urosepsis, or allograft rejection. Conclusions SGLT-2 inhibitors effectively reduced mortality, cardiovascular disease, HbA1c levels and BMI in KTRs without increasing the risk of infections or allograft rejection. However, they did not demonstrate a significant benefit in kidney-related outcomes. 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F1000Research 2025, 14 :329 ( https://doi.org/10.12688/f1000research.162502.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] Kanachai Boonpiraks 1 , Pajaree Krisanapan 2 , Suthiya Anumas https://orcid.org/0000-0002-2028-5037 1 , Charat Thongprayoon 3 , Wisit Cheungpasitporn https://orcid.org/0000-0001-9954-9711 3 , Pattharawin Pattharanitima https://orcid.org/0000-0002-6010-0033 1 Kanachai Boonpiraks 1 , Pajaree Krisanapan 2 , [...] Suthiya Anumas https://orcid.org/0000-0002-2028-5037 1 , Charat Thongprayoon 3 , Wisit Cheungpasitporn https://orcid.org/0000-0001-9954-9711 3 , Pattharawin Pattharanitima https://orcid.org/0000-0002-6010-0033 1 PUBLISHED 25 Mar 2025 Author details Author details 1 Chulabhorn International College of Medicine, Klong Luang, Pathum Thani, 12120, Thailand 2 Internal Medicine, Thammasat University, Klong Luang, Pathum Thani, 12120, Thailand 3 Department of Medicine, Mayo Clinic Minnesota, Rochester, Minnesota, 55905, USA Kanachai Boonpiraks Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Pajaree Krisanapan Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Suthiya Anumas Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Charat Thongprayoon Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Wisit Cheungpasitporn Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Pattharawin Pattharanitima Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have shown cardiorenal benefits in the general population; however, evidence regarding their efficacy and safety in kidney transplant recipients (KTRs) remains sparse. This meta-analysis seeks to evaluate the therapeutic efficacy and safety profile of SGLT-2 inhibitors specifically in the diabetes KTR population. Methods We conducted a systemic review and meta-analysis following a registered protocol in the PROSPERO (CRD42023404886). A comprehensive literature search was performed using PubMed, Cochrane, and Scopus databases up to October 23 th , 2024. We included observational and clinical trials which compared SGLT-2 inhibitors with control groups in KTRs. Risk of bias was evaluated by funnel plot. We reported differences in treatment effects as risk ratios (RRs) or weighted mean difference (WMD) with 95% confidence intervals (CIs). Results A total of seven studies comprising 2,713 patients were included in this analysis. SGLT-2 inhibitors were associated with a significant reduction in HbA1c levels (WMD -0.37%; 95% CI -0.73 to -0.01; p = 0.04) and BMI (WMD -0.89 kg/m 2 ; 95% CI -1.27 to -0.50; p < 0.001). Additionally, SGLT-2 inhibitors demonstrated a beneficial effect in reducing mortality (RR 0.25; 95% CI 0.06 to 0.98; p = 0.05) and cardiovascular disease (CVD) (RR 0.41; 95% CI 0.17 to 0.98; p = 0.04). However, SGLT-2 inhibitors did not demonstrate benefit in kidney-related outcomes. Importantly, there was no significant increase in adverse events, including urinary tract infections, genital mycotic infections, urosepsis, or allograft rejection. Conclusions SGLT-2 inhibitors effectively reduced mortality, cardiovascular disease, HbA1c levels and BMI in KTRs without increasing the risk of infections or allograft rejection. However, they did not demonstrate a significant benefit in kidney-related outcomes. READ ALL READ LESS Keywords SGLT-2 inhibitors, diabetes mellitus, kidney transplant Corresponding Author(s) Suthiya Anumas ( [email protected] ) Pattharawin Pattharanitima ( [email protected] ) Close Corresponding authors: Suthiya Anumas, Pattharawin Pattharanitima Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Boonpiraks K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Boonpiraks K, Krisanapan P, Anumas S et al. The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.12688/f1000research.162502.1 ) First published: 25 Mar 2025, 14 :329 ( https://doi.org/10.12688/f1000research.162502.1 ) Latest published: 25 Mar 2025, 14 :329 ( https://doi.org/10.12688/f1000research.162502.1 ) Introduction Diabetes mellitus (DM) and post-transplantation DM (PTDM) is a well-recognized transplant comorbidity. Despite the distinct pathophysiological mechanisms, both conditions contribute to poorer prognosis and decreased survival rates in kidney transplantation recipients (KTRs). 1 , 2 A recent meta-analysis indicated a significant increase in all-cause mortality and graft failure in PTDM patients with hazard ratios (HR) of 1.67 and 1.35, respectively. 3 Moreover, transplant recipients carry a significantly higher cardiovascular (CV) risks compared to the general population. 4 , 5 This risk is further heightened with comorbid pretransplant DM or PTDM. 6 , 7 For instance, a long-term study in KTRs reported that PTDM and pretransplant DM were associated with a 1.2-fold and 5.1-fold increased risk of all-cause mortality, respectively, with CV events being the leading cause of death. 7 Therefore, in order to improve outcomes among kidney transplant patients, it is crucial to prioritize proper glycemic control and reduce CV risks. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors demonstrate substantial potential in mitigating cardiovascular risks and improving long-term renal outcomes. 8 , 9 The EMPA-REG OUTCOME trial first reported the CV benefits of Empagliflozin in type 2 diabetic mellitus (T2DM) patients, demonstrating a notable decrease in CV death. 10 Subsequently, there has been a surge of interest in SGLT-2 inhibitors. Several meta-analyses have consistently demonstrated a reduction in the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction (MI), non-fatal stroke and CV deaths as well as a reduction in hospitalized heart failure. 11 , 12 In patients with chronic kidney disease (CKD), strong evidence from large randomized controlled trials (RCTs) has consistently shown that SGLT-2 inhibitors can significantly reduce kidney disease progression and cardiac death by 28-39%. 20 – 22 These reno-protective effects are particularly notable in patients, irrespective of coexisting type 2 diabetes (T2DM). 9 Nevertheless, there remains a paucity of large-scale randomized controlled trials (RCTs) and comprehensive meta-analyses to conclusively validate the efficacy and safety profile of SGLT-2 inhibitors in KTRs. As a result, clinical guidelines for the administration of SGLT-2 inhibitors in this specific population are currently constrained. A recent meta-analysis 13 performed in 2020, comprising 8 studies involving a total of 132 participants, has provided evidence of the effectiveness of SGLT-2 inhibitors in treating DM among KTRs. The analysis demonstrated that SGLT-2 inhibitors effectively lower HbA1c levels, reduce body weight, and preserve kidney function, without reporting any serious adverse events. Previous research has primarily concentrated on evaluating differences between baseline and study endpoint measures, rather than employing a comparative analysis with a control group. Thus, we conducted this meta-analysis to compare the outcomes of SGLT-2 inhibitors with control groups. The aim of this study is to investigate the efficacy of SGLT-2 inhibitors in terms of renal benefits, glycemic control, metabolic profile improvement, mortality, and CVD outcome, as well as the safety profiles of SGLT-2 inhibitors among KTRs. Methods Search strategy and selection criteria The meta-analysis was conducted following a registered protocol in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023404886). A systematic literature search of PubMed, Cochrane and Scopus databases from the inception until October 23, 2024 was conducted independently by three investigators (K.B., P.K. and P.P.). The search terms, including “Kidney” AND “Transplant” AND “Sodium glucose co-transporter 2 inhibitor” were used to assess the efficacy and safety of SGLT-2 inhibitors among kidney transplant recipients. Supplement material ( Supplement; Table S1 ) provides a comprehensive description of the search strategy employed. The search was limited to human studies, and no language restrictions were applied. Additionally, a manual search of the references of the included studies was conducted for additional relevant studies. The implementation and reporting of this meta-analysis adhered to the standards of the PRISMA Statement. 14 Studies were included in this meta-analysis if they were observational (case-control or cohort) or clinical trials that evaluated cardiovascular and kidney outcomes of SGLT-2 inhibitors compared to a control group in adults aged 18 years or older who had undergone kidney transplantation. Eligible studies had to report alterations in at least one of the following outcomes: estimated glomerular filtration rate (eGFR), urine protein creatinine ratio (UPCR), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and adverse outcomes. Studies that primarily reported other outcomes or that included other glucose lowering medications without a subgroup report for SGLT-2 inhibitors alone were excluded. Retrieved studies were independently reviewed for eligibility by three investigators (K.B., S.A. and P.P.). Discrepancies were resolved through discussion among all authors. Data extraction and quality assessment Data collection was done independently by three investigators (K.B., S.A. and P.P). A standardized data collection form was used to collect the following variables from each included study: study title, author names, publication year, study type, the country where the study was conducted, study drugs, number of participants, age, gender, type of DM (T2DM vs PTDM), transplant duration, immunosuppressive drugs, follow-up time, eGFR, UPCR, HbA1c, BMI, SBP, DBP, and adverse events. The quality of each study was independently assessed by each investigator (P.P. and P.K.). Randomized controlled trials (RCTs) were evaluated using the Cochrane Risk of Bias (RoB 2) tool 15 (Supplement; Table S2), while non-randomized control studies were evaluated by the Risk of Bias In Non-randomized Studies – of Interventions (ROBIN-I) tool 16 (Supplement; Table S3). Publication bias was examined by a funnel plot. Statistical analysis This meta-analysis was conducted using Review Manager (RevMan) [Computer program] Version 5.4. The Cochrane Collaboration, 2020. The differences in effects were reported as risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and the weighted mean difference (WMD) with 95% CIs for continuous outcomes. In cases where the required data was not originally provided in the articles, we procured it through direct communication with the investigators. Participants in RCTs were analyzed in intention-to-treat groups. Heterogeneity was evaluated using χ 2 and/or the I 2 statistic, where an I 2 value above 50% or a p-value below 0.1 indicated significant heterogeneity. In cases of significant heterogeneity, a random-effect model was employed for the meta-analysis. Publication bias was assessed by funnel plot. 17 . Planned subgroup analysis for the primary outcomes stratified by the types of publication (observational studies vs. controlled trials) was not performed due to insufficient data. For all analyses, statistical significance was defined as a p-value less than 0.05. Results Study characteristics Our search strategy identified a total of 611 potential articles as shown in Figure 1 , with 92 duplicates identified and subsequently removed. The remaining 519 articles underwent an initial screening based on their titles and abstracts, leading to the exclusion of 351 articles due to their lack of relevance. Consequently, 168 articles underwent a full comprehensive review. 161 studies were excluded based on factors such as publication type, lack of outcomes of interest, inappropriate population of interest, ongoing trials, and full-text unavailable. As a result, a total of 7 studies were included in this meta-analysis, consisting of 5 retrospective cohort studies, 17 – 21 1 RCT, 22 and 1 prospective interventional trial, 23 with baseline characteristics summarized as shown in Table 1 . Figure 1. PRISMA flow of search methodology and selection process. Table 1. Characteristics of the Included Studies. Author (Year) Halden et al. (2019) Schwaiger et al. (2019) Hisadome et al. (2021) Lim et al. (2022) Demir et al. (2023) Mahmoud et al. (2023) Lim et al. (2024) Study type Double-blinded, randomized controlled trial Prospective, interventional trial (with 2 phases of insulin and a switch to SGLT2i) Retrospective cohort with IPTW analysis Retrospective cohort with propensity score matching Retrospective cohort Retrospective cohort with case-matching Retrospective cohort with propensity score matching Country Norway Austria Japan Korea Türkiye Kuwait Korea Total participants, n 44 14 a 85 2083 57 168 f 254 SGLT2i 22 8 28 226 36 98 127 Control 22 14 57 1857 21 70 127 Study drug(s) Empagliflozin Empagliflozin Various SGLT2i b Empagliflozin or dapagliflozin Empagliflozin or dapagliflozin Canagliflozin Empagliflozin or dapagliflozin Control(s) Placebo Insulin Other oral hypoglycemic agents c Metformin or DDP-4 inhibitors or insulin Other antiglycemic therapies, including insulin Metformin, sulfonylurea, DPP4 inhibitors or insulin Metformin, Sulfonylurea, DPP4 inhibitors or insulin Total follow-up duration, months 6 12 12 9 e 12 12 56.3 Type of DM, n (%) PTDM 44 (100) 14 (100) 0 475 (22.8) 31 (54.4) 75 (44.6) 43 (16.9) T2DM 0 0 85 (100) 1608 (77.2) 26 (45.6) 93 (55.4) 211 (83.1) Duration of DM, years N/A 5.7 ± 4.8 N/A N/A 14.8 ± 11.0 N/A N/A Male, n (%) 34 (77.3) 7 (50) 65 (76.5) 1399 (67.2) 36 (63.2) 107 (63.7) 179 (70.5) Age, years SGLT-2i : 63 [31, 72] Control : 59 [21,75] 56.5 ± 7.9 55.4 ± 8.7 52.4 ± 10.7 51.3 ± 11.0 SGLT-2i : 56 [N/A] Control : 57 [N/A] SGLT-2i : 54 [46, 60] Control : 55 [47, 60] Weight, kg SGLT-2i : 92 [81.8, 104.5] Control : 84 [79.3, 94.0] 74.8 ± 17.2 71.0 ± 10.4 N/A N/A N/A N/A BMI, kg/m 2 SGLT-2i : 28.8 [24.7, 39.3] Control : 27.5 [22.4, 45.8] 27.3 ± 5.2 25.7 ± 3.6 23.9 ± 3.6 28.5 ± 4.5 SGLT-2i : 31.4 [N/A] Control : 29.7 [N/A] SGLT-2i : 25.3 [22.0, 27.4] Control : 25.2 [23.1, 27.7] History of CAD, n (%) N/A 10 (71) 43 (50.6) 253 (12.1) 27 (47.4) N/A 33 (13.0) Systolic BP, mmHg SGLT-2i : 143 [111, 176] Control : 140 [100, 163] 150 ± 26 128 ± 15 N/A N/A N/A N/A Diastolic BP, mmHg SGLT-2i : 79 [63, 94] Control : 82 [55, 94] 86 ± 14 73 ± 10 N/A N/A N/A N/A eGFR, ml/min/1.73m 2 SGLT-2i : 66 [41, 83] Control : 59 [44, 82] 55.6 ± 20.3 48.5 ± 13.4 68.2 ± 19.9 72.4 ± 18.7 SGLT-2i : 67.2 [N/A] Control : 63.8 [N/A] N/A Creatinine, mg/dL N/A 1.3 ± 0.4 N/A 1.2 ± 0.5 1.1 ± 0.3 N/A N/A UPCR (mg/g) SGLT-2i : 100 [60, 150] Control : 90 [50, 120] 289 [190-808] 400 ± 600 N/A SGLT-2i : 321 [45, 2565] Control : 229 [63, 909] N/A N/A Fasting blood sugar (mg/dL) SGLT-2i : 144 [90, 236] Control : 132 [81, 225] N/A N/A 143 ± 67 N/A N/A N/A HbA1c (%) SGLT-2i : 6.9 [6.5, 8.2] Control : 6.8 [6.1, 7.2] 6.5 ± 0.8 7.6 ± 1.2 7.3 ± 1.4 8.1 ± 1.9 SGLT-2i : 8.0 [N/A] Control : 7.2 [N/A] SGLT-2i : 7.1 [6.3, 8.1] Control : 6.9 [6.1, 7.8] Hemoglobin (g/dL) SGLT-2i : 13.9 [13.1, 14.4] Control : 13.2 [12.1, 14.6] 12.7 ± 1.9 N/A N/A N/A N/A N/A Hematocrit (%) SGLT-2i : 43 [39, 45] Control : 43 [39, 44] 38.8 ± 5.4 N/A N/A N/A N/A N/A Other glucose-lowering therapy, n (%) Insulin 8 (18.2) 14 (100) 61 (71.8) 1155 (55.4) 29 (50.9) d 102 (60.7) N/A Metformin 2 (4.5) N/A 4 (4.7) d 1224 (58.8) N/A 136 (81) N/A Sulfonylurea 7 (15.9) N/A 4 (4.7) d 725 (34.8) N/A 16 (9.5) N/A DPP4 inhibitors N/A N/A 42 (49.4) d 1144 (54.9) N/A 66 (39.3) N/A Time Since Transplant, years SGLT-2i : 3 [1, 16] Control : 3 [1, 15] 5.8 ± 4.8 N/A 0.25 SGLT-2i : 5 [0, 13] Control : 1.5 [0, 9] 7.4 ± N/A 1.12 [0.2, 2.51] Living donor, n (%) 16 (36) N/A N/A 1483 (71.2) 54 (94.7) 127 (75.6) 200 (78.7) Immunosuppressive drugs, n (%) Tacrolimus 35 (79.5) 11 (79) 83 (97.6) 1705 (81.9) 57 (100) 127 (75.6) 221 (87.0) Cyclosporin 6 (13.6) 3 (21) 3 (3.5) 406 (19.5) N/A 31 (18.5) 36 (14.2) Everolimus 2 (4.5) 0 25 (29.4) N/A N/A N/A N/A Mycophenolate 40 (90.9) 14 (100) 61 (71.8) N/A 57 (100) N/A N/A Steroid 43 (97.7) 14 (100) 85 (100) 2038 (97.9) 57 (100) N/A N/A Trough level, ng/mL Tacrolimus SGLT-2i : 5.4 [4.6, 6.9] Control : 6.2 [5.0, 6.8] 8.4 ± 3.1 2.0 ± 1.1 6.0 ± 1.5 N/A N/A N/A Cyclosporin SGLT-2i : 94 [80, 105] Control : 100 [94, 100] 64.0 ± 11.5 N/A N/A N/A N/A N/A Everolimus SGLT-2i : 6.2 [6.2, 6.2] Control : 10 [10, 10] N/A N/A N/A N/A N/A N/A Source of funding South-Eastern Norway Regional Health Authority, the Norwegian Diabetes Association, and Oslo Diabetes Research Centre. None None Ministry of Health & Welfare, Republic of Korea and the Korean Society of Nephrology None None Ministry of Health & Welfare, Republic of Korea and the Ministry of Education a Started with 14 patients but completed study with only 8 b Canagliflozin or Ipragliflozin or Luseogliflozin or Empagliflozin or Dapagliflozin or Tofogliflozin c DDP-4 inhibitors or Glinides or Metformin or Sulfonylureas or Alpha-glucosidase inhibitors-1 d Exclusively in the control group e Total follow-up time was 62.9 ± 42.2 months but the efficacy outcomes were reported after 9 months from the baseline f Counted only patients received SGLT2i and the control group Overall, a total of 2,713 patients were included in this systematic review, with 545 patients in the SGLT-2 inhibitors group. These agents were primarily indicated for T2DM (74%) more than PTDM (26%). Specific SGLT-2 inhibitors prescription was reported in 383 participants from 5 studies, 17 – 19 , 22 , 23 empagliflozin was the most frequently administered, accounting for 48%, followed by canagliflozin (28%), dapagliflozin (20.6%), ipragliflozin (1.8%), luseogliflozin (1.3%), and tofogliflozin (0.3%). In the control group, only one RCT 22 used a placebo, while the remaining studies 17 – 21 , 23 utilized other hypoglycemic agents, including insulin, metformin, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sulfonylurea. Insulin was prescribed for 13.4% of 2,451 patients, whereas metformin was the most common oral hypoglycemic agent (OHA), accounting for 57% of 2,380 patients evaluated, 18 – 20 , 22 followed by DPP-4 inhibitors, which accounted for 54% of 1,252 patients evaluated. 18 – 20 The median total follow-up duration was 9 [9, 12] months. Most patients were male (67%) with a mean age of 53.1 ± 11.7 years and a BMI of 24.7 ± 4.3 kg/m 2 . The baseline HbA1c was 7.3 ± 1.4, and the duration of DM was reported in only 2 studies 17 , 23 with a mean of 13.0 ± 10.1 years among 99 patients evaluated. Notably, only 15% of the 2,501 patients evaluated 17 – 19 , 21 , 23 had a history of coronary artery disease (CAD). In terms of baseline allograft function, the mean serum creatinine (Cr) was 1.2 ± 0.5 mg/dL among 2,154 evaluated patients, 17 , 19 , 23 and the mean eGFR was 67 ± 21 ml/min/1.73 m 2 among 2,451 evaluated patients. Of the 200 available patients, the mean UPCR was 293 ± 919 mg/g of Cr. 17 , 18 , 22 , 23 The time since transplant ranged from 3 months to 7.4 years with a median duration of 1.8 [0.3, 5.6] years. Nearly two-thirds (77%) of 2,454 reported patients received kidneys from living-donors. 17 , 19 – 22 The most predominant immunosuppressive medication was tacrolimus. Among 2,226 patients, the tacrolimus trough level was 5.9 ± 1.7 ng/mL. 18 , 19 , 22 , 23 Efficacy of SGLT-2 inhibitors on kidney-related outcomes Kidney related outcomes were evaluated based on changes in eGFR and reductions in UPCR from baseline. Among 6 studies, 17 – 20 , 22 , 23 the use of SGLT-2 inhibitors did not result in a significantly higher eGFR compared to the control, with a weighted median difference (WMD) of 0.69 mL/min/1.73 m 2 (95%CI -0.96, 2.34; p = 0.41; I 2 = 55%) as shown in Figure 2A . In terms of UPCR reduction, only 3 studies 17 , 18 , 22 involving 186 patients reported no statistically significant decrease in UPCR during the follow-up period (WMD = 9.42 mg/g; 95%CI -18.93, 37.76; p =0.51, I 2 = 0%) as shown in Figure 2B . Figure 2. Forest plots of the efficacy of SGLT-2 inhibitors on kidney-related outcomes. Efficacy of SGLT-2 inhibitors on metabolic profiles Across 6 studies, 17 – 20 , 22 , 23 SGLT-2 inhibitors resulted in a significant reduction in HbA1c levels by -0.37% (95% CI -0.73, -0.01; p = 0.04) compared with the control, with significant heterogeneity (I 2 = 93%) as shown in Figure 3A . Additionally, SGLT-2 inhibitors significantly reduced BMI from baseline compared with the control, with a WMD of -0.89 kg/m 2 (95% CI -1.27, -0.50, p <0.001, I 2 = 55%) as shown in Figure 3B . Figure 3. Forest plots of the efficacy of SGLT-2 inhibitors on metabolic profiles. However, regarding the effect on blood pressure, data on systolic blood pressure (SBP) were reported in only 3 studies 18 , 20 , 22 involving a total of 297 patients. The analysis revealed no significant reduction in SBP with SGLT-2 inhibitors compared to the control, with a WMD of -0.18 mmHg (95%CI -8.57, 8.21; p = 0.97), with significant heterogeneity (I 2 = 89%) as shown in Figure 3C . Efficacy of SGLT-2 inhibitors on all-cause mortality and cardiovascular diseases Among the 7 studies involving 2,168 patients, there were only 40 deaths reported, primarily in 3 studies. 17 , 19 , 21 Over a 9-month follow-up period, SGLT-2 inhibitors showed significantly reduced all-cause mortality compared to placebo, with a risk ratio (RR) of 0.25 (95%CI 0.06, 0.98; p = 0.05; I 2 = 33%) as shown in Figure 4A . Figure 4. Forest plots of the efficacy of SGLT-2 inhibitors on mortality and CVD. Regarding CV outcomes only 3 studies 18 , 20 , 21 involving 253 patients assessed the impact of SGLT-2 inhibitors on cardiovascular disease (CVD). Over a follow-up period of 9 months, SGLT-2 inhibitors showed significantly reduced CVD compared to the control, with a risk ratio (RR) of 0.41 (95%CI 0.17, 0.98; p = 0.04; I 2 = 0%) as shown in Figure 4B . Adverse events of SGLT-2 inhibitors There were no significant differences in adverse events incidence between the SGLT-2 inhibitors and the control group. In terms of infection, SGLT-2 inhibitors did not significantly increase the risk of overall urinary tract infection (UTI), compared to the control group, with a RR of 0.51 (95% CI 0.25, 1.01; p = 0.05) with a significant heterogeneity (I 2 = 79%) across 7 studies 17 – 23 as shown in Figure 5A . When specifically examining genital mycotic infections, only 4 studies with 2,438 patients reported outcomes. 17 , 19 , 21 , 22 SGLT-2 inhibitors also did not significantly increase the risk of genital mycotic infection compared to the control, with a RR of 0.88 (95% CI 0.19, 4.08; p = 0.87; I 2 = 18%) as shown in Figure 5B . Of 2 studies 20 , 22 involving 212 patients that evaluated the outcome of urosepsis, SGLT-2 inhibitors also did not significantly increase the risk of urosepsis, with a RR of 1.33 (95% CI 0.17, 10.58; p = 0.79; I 2 = 0%) as shown in Figure 5C . Figure 5. Forest plots of the adverse events of SGLT-2 inhibitors. Regarding other adverse events, SGLT-2 inhibitors did not significantly increase the risk of allograft rejection compared to the control, with a RR of 0.53 (95% CI 0.11, 2.44; p = 0.23; I 2 = 31%) across 3 studies, 17 , 18 , 22 involving 186 patients as shown in Figure 5D . There were no any diabetic ketoacidosis (DKA) cases reported among included studies. Evaluation of publication bias The funnel plots depicting standard error by mean differences and risk ratios were evaluated, as illustrated in Supplemental Figure S5-S7 (Refer Extended data). These assessments revealed no significant evidence of publication bias, as the plots exhibit symmetry. Discussion Our systematic review and meta-analysis focused on the safety and efficacy of SGLT-2 inhibitors among KTRs. Our findings indicate that SGLT-2 inhibitors significantly reduced HbA1c and BMI compared to the control, without increasing adverse events, including infection and allograft rejection. Notably, while SGLT-2 inhibitors showed no measurable impact on kidney-related outcomes, they conferred a substantial benefit by markedly reducing mortality and cardiovascular disease risk among KTRs. In non-transplant population, a recent meta-analysis of large placebo-controlled trials demonstrated a significant 37% reduction in the kidney disease progression among T2 DM patients using SGLT-2 inhibitors. 24 This kidney benefit was consistent across subgroups, regardless of diabetic status, primary kidney diseases, or kidney function. 24 The renal benefits of SGLT-2 inhibitors can be attributed to increased urinary glucose excretion, leading to osmotic diuresis and enhanced excretion of sodium and fluid. 25 This helps mitigate glomerular hyperfiltration, reduce renal inflammation and fibrosis, and preserve renal function. 25 Based on these findings, similar renal benefits may be anticipated in the context of kidney transplant recipients (KTRs). However, the mechanism of SGLT-2 inhibitors, which promotes glucose excretion via urine, could potentially increase infection risk—an important concern in this population. In contrast to findings in the non-transplant population, our meta-analysis revealed a neutral impact of SGLT-2 inhibitors on kidney function, as assessed by eGFR and UPCR. This finding was consistent with a previous meta-analysis by Chewcharat et al, 13 which demonstrated no significant decline in eGFR and UPCR by the end of the study with SGLT-2 inhibitors. This neutral effect may be attributed to the comparatively shorter follow-up periods, with a median duration of 12 months. In contrast, non-transplant studies typical have 2-3 years follow-ups, during which the renal benefits of SGLT-2 inhibitors, especially in eGFR, become more pronounced compared to the placebo group after 12 months. 26 – 28 Given that KTRs have a significant elevated risk of CV death, 10 to 20 times higher than the general population, 5 , 29 SGLT-2 inhibitors have been proposed as a new hope in this group. Previous meta-analysis in non-transplant CKD patients have shown promising results for SGLT-2 inhibitors in reducing composite CV death or hospitalization for heart failure, with a remarkable 23% decrease compared to placebo. These finding were observed in patients with an average baseline eGFR of 65 mL/min/1.73 m 2. 24 The recent EMPA-KIDNEY trial, 26 and DAPA-CKD trial, 27 which included CKD patients with eGFR as low as 20 and 25 mL/min/1.73 m 2 , respectively, demonstrated a significant reduction in CV death: 16% with empagliflozin and 31% with dapagliflozin over a 2-year follow-up period. This benefit was consistent across a range of eGFR levels, though KTRs were not included in these trials. Despite the absence of large-scale studies specifically involving KTRs, our meta-analysis reveals that SGLT-2 inhibitors significantly reduce mortality and cardiovascular disease in this unique population, offering a compelling new therapeutic avenue to address their elevated cardiovascular risk. Regarding the efficacy of SGLT-2 inhibitors on metabolic profiles, the reduction of 0.37% in HbA1c levels compared to the control group aligns with previous meta-analyses conducted by Okinomaki et al. 30 and Chewcharat et al., 13 which reported reductions of 0.45% and 0.57% in HbA1c levels from baseline, respectively. Our findings demonstrated that SGLT-2 inhibitors are also effective when compared to standard therapies, including insulin and other oral hypoglycemic agents. Given that tacrolimus can elevate blood glucose levels by inducing insulin resistance and increasing glucose absorption in the gastrointestinal tract, 31 it should be noted that 82.5% of our patients received tacrolimus as part of their immunosuppressive regimen. Moreover, our meta-analysis showed that SGLT-2 inhibitors also benefit BMI, with a significant reduction of 0.89 kg/m 2 compared to the control. This is consistent with the previous 2 meta-analyses conducted in non-diabetic adults with overweight, which reported a reduction of 0.47 kg/m 2 compared to placebo. 32 , 33 Within current clinical practice, concerns persist regarding the potential adverse events associated with SGLT-2 inhibitors, particularly UTIs 13 and DKA, 34 which may pose a greater risk for KTRs due to their concurrent administration of immunosuppressive agents. 35 However, our meta-analysis observed that SGLT-2 inhibitors did not increase risk of serious infection, including UTIs, genital mycotic infection, and urosepsis, compared to the control group. Notably, a meta-analysis conducted by Li et al., 36 evaluating UTIs and genital infections in non-transplant T2DM patients, revealed that only dapagliflozin 10 mg exhibited a significantly higher incidence of UTIs than placebo. In our analysis, only 20.6% of cases was prescribed with dapagliflozin. The overall infection rate of SGLT-2 inhibitors was comparable to that of the control group. Importantly, our study did not find an increase rate of genital infection with SGLT-2 inhibitors, unlike in non-transplant population. 36 This may be attributed to the effective routine post-transplant screening, care, and patient education in transplant clinics. Additionally, our meta-analysis demonstrated that SGLT-2 inhibitors did not increase the risk of DKA and graft rejection. Therefore, our findings shed new light on the safety profile of SGLT-2 inhibitors in kidney transplant recipients. To the best of our knowledge, our meta-analysis included the most recent studies investigating the efficacy and safety outcomes of SGLT-2 inhibitors in KTRs. This encompasses both preexisting T2DM and PTDM status and is the first to assess mortality and cardiovascular outcomes, which was absent from previous meta-analysis. 13 However, certain limitations must be acknowledged. Firstly, there are limited studies in our systematic review due to the lack of current studies in KTRs populations, which most existing studies are case series or observational designs without control groups. Secondly, there was significant heterogeneity among included studies, particularly in HbA1c, SBP, and UTI outcomes. This may result from the limited number of studies and the different types of studies for each outcome. Thirdly, the subgroup analysis based on study types (clinical trial vs cohort) and DM type (T2DM vs PTDM) could not be performed due to the limited available data in the included studies. Fourthly, the funnel plots for publication bias need to be interpreted with caution due to the limited number of included studies. Lastly, the follow-up duration in included studies might not have been sufficiently long to fully elucidate the potential renal benefits with SGLT-2 inhibitors. Conclusion SGLT-2 inhibitors have demonstrated significant benefits in reducing mortality and cardiovascular disease in diabetes KTRs. Furthermore, they effectively reduced HbA1c and BMI compared to controls, without increasing adverse events, including infections and allograft rejection. However, these agents did not show a significant benefit in kidney-related outcomes. Ethical considerations This study was approved by the Human Research Ethics Committee of Thammasat University (Medicine), which provided an exemption for this study (COE 243/2567). Reporting guidelines Zenodo: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis-supplemental materials and PRISMA checklist, DOI: https://doi.org/10.5281/zenodo.14928362 . 37 The project contains the following reporting guidelines: • PRISMA checklist • Flow chart Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Data availability No data are associated with this article. Extended data Zenodo: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis-supplemental materials and PRISMA checklist, DOI: https://doi.org/10.5281/zenodo.14988603 . 37 This project contains the following extended data: • Table S1 Search Terms • Table S2 Risk of bias summary for included RCT • Table S3 Graph and summary of Risk of Bias in Non-randomized Studies of Interventions (ROBIN-I) for included non-randomized controlled studies • Figure S4 Funnel Plots of Standard Error on Kidney-Related Outcomes • Figure S5 Funnel Plots of Standard Error on Metabolic Profiles • Figure S6 Funnel Plots of Standard Error on Mortality and Cardiovascular Diseases • Figure S7 Funnel Plots of Standard Error on Adverse Events Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgement This study was supported by the Research Group in Nephrology and Renal Replacement Therapy from the Faculty of Medicine, Thammasat University. We also want to express our sincere gratitude to Dr. Prapasri Kulalert and Dr. Phichayut Phinyo for their invaluable advice and guidance and suggestions regarding the different stages of the meta-analysis presented in this manuscript. References 1. Cosio FG, Hickson LJ, Griffin MD, et al. : Patient survival and cardiovascular risk after kidney transplantation: the challenge of diabetes. Am. J. Transplant. 2008; 8 (3): 593–599. PubMed Abstract | Publisher Full Text 2. Cosio FG, Pesavento TE, Kim S, et al. : Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int. 2002; 62 (4): 1440–1446. PubMed Abstract | Publisher Full Text 3. 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Lim JH, Kwon S, Jeon Y, et al. : The Efficacy and Safety of SGLT2 Inhibitor in Diabetic Kidney Transplant Recipients. Transplantation. 2022; 106 (9): e404–e412. PubMed Abstract | Publisher Full Text 20. Mahmoud T, Yagan J, Hasan A, et al. : Sodium-glucose co-transporter 2 inhibitors & glucagon-like peptide-1 receptor agonists, efficacy & safety in diabetic kidney transplant recipients. Clin. Transpl. 2023; 37 (12): e15144. Publisher Full Text 21. Lim JH, Kwon S, Seo YJ, et al. : Cardioprotective Effect of SGLT2 Inhibitor in Diabetic Kidney Transplant Recipients: A Multicenter Propensity Score Matched Study. Kidney Int Rep. 2024; 9 (8): 2474–2483. PubMed Abstract | Publisher Full Text | Free Full Text 22. Halden TAS, Kvitne KE, Midtvedt K, et al. : Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care. 2019; 42 (6): 1067–1074. PubMed Abstract | Publisher Full Text 23. Schwaiger E, Burghart L, Signorini L, et al. : Empagliflozin in posttransplantation diabetes mellitus: A prospective, interventional pilot study on glucose metabolism, fluid volume, and patient safety. Am. J. Transplant. 2019; 19 (3): 907–919. PubMed Abstract | Publisher Full Text | Free Full Text 24. Nuffield Department of Population Health Renal Studies GConsortium SiM-AC-RT: Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022; 400 (10365): 1788–1801. PubMed Abstract | Publisher Full Text | Free Full Text 25. Fonseca-Correa JI, Correa-Rotter R: Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Front Med (Lausanne). 2021; 8 : 777861. PubMed Abstract | Publisher Full Text | Free Full Text 26. EMPA-Kidney Collaborative Group: Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 2023; 388 (2): 117–127. PubMed Abstract | Publisher Full Text | Free Full Text 27. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. : Dapagliflozin in Patients with Chronic Kidney Disease. N. Engl. J. Med. 2020; 383 (15): 1436–1446. Publisher Full Text 28. Perkovic V, Jardine MJ, Neal B, et al. : Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019; 380 (24): 2295–2306. Publisher Full Text 29. Bottomley MJ, Harden PN: Update on the long-term complications of renal transplantation. Br. Med. Bull. 2013; 106 : 117–134. Publisher Full Text 30. Oikonomaki D, Dounousi E, Duni A, et al. : Incretin based therapies and SGLT-2 inhibitors in kidney transplant recipients with diabetes: A systematic review and meta-analysis. Diabetes Res. Clin. Pract. 2021; 172 : 108604. PubMed Abstract | Publisher Full Text 31. Li Z, Sun F, Zhang Y, et al. : Tacrolimus Induces Insulin Resistance and Increases the Glucose Absorption in the Jejunum: A Potential Mechanism of the Diabetogenic Effects. PLoS One. 2015; 10 (11): e0143405. PubMed Abstract | Publisher Full Text | Free Full Text 32. Zheng H, Liu M, Li S, et al. : Sodium-Glucose Co-Transporter-2 Inhibitors in Non-Diabetic Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021; 12 : 706914. PubMed Abstract | Publisher Full Text | Free Full Text 33. Cho YK, Kim YJ, Jung CH: Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Weight Reduction in Overweight and Obese Populations without Diabetes: A Systematic Review and a Meta-Analysis. J Obes Metab Syndr. 2021; 30 (4): 336–344. PubMed Abstract | Publisher Full Text | Free Full Text 34. Peters AL, Buschur EO, Buse JB, et al. : Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015; 38 (9): 1687–1693. PubMed Abstract | Publisher Full Text | Free Full Text 35. Karuthu S, Blumberg EA: Common infections in kidney transplant recipients. Clin. J. Am. Soc. Nephrol. 2012; 7 (12): 2058–2070. Publisher Full Text 36. Li D, Wang T, Shen S, et al. : Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017; 19 (3): 348–355. PubMed Abstract | Publisher Full Text 37. Pattharanitima P, Anumas S: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis-supplemental materials and PRISMA checklist. Zenodo. 2025. Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 25 Mar 2025 ADD YOUR COMMENT Comment Author details Author details 1 Chulabhorn International College of Medicine, Klong Luang, Pathum Thani, 12120, Thailand 2 Internal Medicine, Thammasat University, Klong Luang, Pathum Thani, 12120, Thailand 3 Department of Medicine, Mayo Clinic Minnesota, Rochester, Minnesota, 55905, USA Kanachai Boonpiraks Roles: Conceptualization, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing Pajaree Krisanapan Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Suthiya Anumas Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Charat Thongprayoon Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Wisit Cheungpasitporn Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Pattharawin Pattharanitima Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 25 Mar 2025, 14:329 https://doi.org/10.12688/f1000research.162502.1 Copyright © 2025 Boonpiraks K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Boonpiraks K, Krisanapan P, Anumas S et al. The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.12688/f1000research.162502.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 25 Mar 2025 Views 0 Cite How to cite this report: Xiao Y. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432370 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432370 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 24 Dec 2025 Yang Xiao , Central South University, Changsha, China Approved VIEWS 0 https://doi.org/10.5256/f1000research.178712.r432370 The rationale is explicitly presented.The study provides comprehensive methodological details.The statistical approach aligns with standard meta-analysis practices. The conclusions directly reflect the study results.But,the title and abstract do not mention “living” terminology，The search was conducted up to a fixed date.The ... Continue reading READ ALL The rationale is explicitly presented.The study provides comprehensive methodological details.The statistical approach aligns with standard meta-analysis practices. The conclusions directly reflect the study results.But,the title and abstract do not mention “living” terminology，The search was conducted up to a fixed date.The study’s major significance lies in addressing an unmet clinical need: evaluating SGLT-2 inhibitors in diabetic KTRs.But,when an abbreviation is first used, its full form must be provided ."IPTW" is not explained in Table 1And in the discussion, a reasonable explanation should be provided for the "kidney results". Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests: No competing interests were disclosed. Reviewer Expertise: metabolic diseases，immunometabolism，diabetes I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Xiao Y. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432370 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432370 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mukherjee S. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432374 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432374 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Dec 2025 Shatavisa Mukherjee , Calcutta School of Tropical Medicine, Kolkata, West Bengal, India Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.178712.r432374 This manuscript does not meet the scientific, statistical, or interpretive standards required for publication as a meta-analysis and should be rejected in its current form. Although the topic is clinically relevant, the analysis is fundamentally flawed and the conclusions ... Continue reading READ ALL This manuscript does not meet the scientific, statistical, or interpretive standards required for publication as a meta-analysis and should be rejected in its current form. Although the topic is clinically relevant, the analysis is fundamentally flawed and the conclusions are misleading. The authors rely predominantly on small retrospective observational cohorts with heterogeneous comparator groups and inadequate adjustment for confounding, yet present pooled mortality and cardiovascular outcomes as though derived from robust randomized evidence. The mortality signal, based on only 40 events from three studies with short follow-up, is statistically fragile and unsuitable for causal inference, particularly in a transplant population where competing risks and selection bias are profound. Likewise, cardiovascular benefit is asserted from fewer than 300 patients across three cohorts, representing an insufficient evidential base for clinical recommendations. A major methodological error is the inappropriate use of a random-effects model as a default analytic strategy. While random-effects modeling is theoretically justified when studies estimate different underlying effects, it is not a solution for combining fundamentally incomparable designs and exposures. In this manuscript, randomized trials, uncontrolled interventional studies, and retrospective cohorts are improperly pooled; more critically, control arms ranging from placebo to insulin, metformin, sulfonylureas, and DPP-4 inhibitors are treated as if they were equivalent. Under these conditions, random-effects modeling merely averages bias rather than accounts for heterogeneity. This issue is magnified in outcomes with sparse events, where random-effects weighting disproportionately favors small, unstable cohorts and can artificially amplify significance. The authors neither justify model choice nor conduct influence analysis, leave-one-out testing, or meta-regression to explore extreme observed heterogeneity (e.g., HbA1c I² > 90%), instead defaulting to random-effects without methodological rationale. The result is spurious numerical precision with little biological or clinical meaning. The renal analysis—the central justification for transplant relevance—is underpowered and inconclusive. Proteinuria outcomes are based on fewer than 200 patients, and eGFR analyses show substantial heterogeneity with no detectable effect. Despite this, mechanistic speculation on kidney protection is presented in the discussion without supporting evidence. Safety conclusions are equally unreliable: infection, rejection, and ketoacidosis outcomes are derived from short-term datasets with very wide confidence intervals in an immunosuppressed population, yet the authors assert clinical safety based on non-significant findings—a classic misinterpretation of statistical non-difference as proof of absence of harm. Statistical rigor is notably lacking. Multiplicity across many secondary endpoints is ignored. Funnel plots are used inappropriately in a dataset with too few studies to meaningfully assess publication bias. Heterogeneity is reported but not interrogated. Planned subgroup analyses were abandoned without analytical restructuring. The manuscript repeatedly imports mechanistic and outcome evidence from non-transplant populations to support conclusions in kidney transplant recipients, ignoring the unique pharmacology, immunosuppressive interactions, and metabolic profiles of this cohort. The Discussion and Conclusions substantially overstate the evidence, with language implying disease-modifying, cardioprotective, and mortality-reducing effects that are not supported by the data. The recurring framing of SGLT-2 inhibitors as a “therapeutic breakthrough” in kidney transplantation is unsupported and risks misleading readers into inappropriate extrapolation. At best, the current evidence supports cautious short-term glycemic and weight effects; it does not justify claims of cardiovascular protection, safety assurance, or survival benefit in this population. This is not a failure of reporting but of design, methodology, and interpretation. Without study-level stratification, comparator-specific analyses, conservative inference, and elimination of causal language, this work does not meaningfully advance knowledge and carries a significant risk of clinical misinterpretation. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Pharmacoepidemiology, Pharmacology, Biostatistics, Research Ethics I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mukherjee S. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432374 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432374 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mahmoud T. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r378428 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-378428 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 12 May 2025 Tarek Mahmoud , Jaber Al Ahmed Armed Forces Hospital, Subhan, Kuwait Approved VIEWS 0 https://doi.org/10.5256/f1000research.178712.r378428 Article Overview This study aimed to evaluate the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs) with diabetes. After comprehensive literature search including observational and clinical trials they collected seven studies. There results ... Continue reading READ ALL Article Overview This study aimed to evaluate the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs) with diabetes. After comprehensive literature search including observational and clinical trials they collected seven studies. There results indicated that SGLT2 inhibitors effectively reduced mortality, cardiovascular disease, HbA1c and BMI without increasing risk of infections and allograft rejection however it did not show clear benefit in kidney outcomes. Strengths The systematic review and meta-analysis helped to gather data randomly from the related studies reducing the bias and strengthening the findings. The improvement in diabetes related and cardiovascular end-points supported the effectiveness of SGLT2 inhibitors in managing diabetes in KTRs. The absence of serious adverse events, specifically the urinary tract and genital infections, supports the safety of SGLT2 inhibitors in this population. Limitations The majority of the included studies were case series and not randomized controlled ones, which is understandable from the available studies in the literature, but this may introduce bias and limit the generalizability of the results. The criteria for selection may be tight to allow some more studies, specially early ones, to be included. The selected studies have different designs and inclusion criteria which makes the comparison difficult. The median follow-up period was 9 (9,12) months, which may not be enough to assess renal outcomes and detect long-term complications or benefits.​ Clinical Implications The study results support the benefits of SGLT2 inhibitors in managing diabetic KTRs with reasonable safety. However, the limitations highlight the need of larger randomized controlled trials including also non-diabetic KTRs with longer follow up duration to confirm these findings and lay down the guidelines for their use. Conclusion This systematic review and meta-analysis will add to the knowledge on the use of SGLT2i for KTRs. It should also stimulate further research to validate these findings and establish a comprehensive treatment guidelines. N.B. in the title " ... Diabetes Kidney Transplant Recipients" It should be " ... Diabetic ..." Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Kidney transplantation, outcomes in special groups, diabetes, transplant infections, pregnancy, Ramadan Fast. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mahmoud T. Reviewer Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r378428 ) The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-378428 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 25 Mar 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 25 Mar 25 read read read Tarek Mahmoud , Jaber Al Ahmed Armed Forces Hospital, Subhan, Kuwait Shatavisa Mukherjee , Calcutta School of Tropical Medicine, Kolkata, India Yang Xiao , Central South University, Changsha, China Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Xiao Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Dec 2025 | for Version 1 Yang Xiao , Central South University, Changsha, China 0 Views copyright © 2025 Xiao Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The rationale is explicitly presented.The study provides comprehensive methodological details.The statistical approach aligns with standard meta-analysis practices. The conclusions directly reflect the study results.But,the title and abstract do not mention “living” terminology，The search was conducted up to a fixed date.The study’s major significance lies in addressing an unmet clinical need: evaluating SGLT-2 inhibitors in diabetic KTRs.But,when an abbreviation is first used, its full form must be provided ."IPTW" is not explained in Table 1And in the discussion, a reasonable explanation should be provided for the "kidney results". Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests No competing interests were disclosed. Reviewer Expertise metabolic diseases，immunometabolism，diabetes I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Xiao Y. Peer Review Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432370) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432370 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Mukherjee S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Dec 2025 | for Version 1 Shatavisa Mukherjee , Calcutta School of Tropical Medicine, Kolkata, West Bengal, India 0 Views copyright © 2025 Mukherjee S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript does not meet the scientific, statistical, or interpretive standards required for publication as a meta-analysis and should be rejected in its current form. Although the topic is clinically relevant, the analysis is fundamentally flawed and the conclusions are misleading. The authors rely predominantly on small retrospective observational cohorts with heterogeneous comparator groups and inadequate adjustment for confounding, yet present pooled mortality and cardiovascular outcomes as though derived from robust randomized evidence. The mortality signal, based on only 40 events from three studies with short follow-up, is statistically fragile and unsuitable for causal inference, particularly in a transplant population where competing risks and selection bias are profound. Likewise, cardiovascular benefit is asserted from fewer than 300 patients across three cohorts, representing an insufficient evidential base for clinical recommendations. A major methodological error is the inappropriate use of a random-effects model as a default analytic strategy. While random-effects modeling is theoretically justified when studies estimate different underlying effects, it is not a solution for combining fundamentally incomparable designs and exposures. In this manuscript, randomized trials, uncontrolled interventional studies, and retrospective cohorts are improperly pooled; more critically, control arms ranging from placebo to insulin, metformin, sulfonylureas, and DPP-4 inhibitors are treated as if they were equivalent. Under these conditions, random-effects modeling merely averages bias rather than accounts for heterogeneity. This issue is magnified in outcomes with sparse events, where random-effects weighting disproportionately favors small, unstable cohorts and can artificially amplify significance. The authors neither justify model choice nor conduct influence analysis, leave-one-out testing, or meta-regression to explore extreme observed heterogeneity (e.g., HbA1c I² > 90%), instead defaulting to random-effects without methodological rationale. The result is spurious numerical precision with little biological or clinical meaning. The renal analysis—the central justification for transplant relevance—is underpowered and inconclusive. Proteinuria outcomes are based on fewer than 200 patients, and eGFR analyses show substantial heterogeneity with no detectable effect. Despite this, mechanistic speculation on kidney protection is presented in the discussion without supporting evidence. Safety conclusions are equally unreliable: infection, rejection, and ketoacidosis outcomes are derived from short-term datasets with very wide confidence intervals in an immunosuppressed population, yet the authors assert clinical safety based on non-significant findings—a classic misinterpretation of statistical non-difference as proof of absence of harm. Statistical rigor is notably lacking. Multiplicity across many secondary endpoints is ignored. Funnel plots are used inappropriately in a dataset with too few studies to meaningfully assess publication bias. Heterogeneity is reported but not interrogated. Planned subgroup analyses were abandoned without analytical restructuring. The manuscript repeatedly imports mechanistic and outcome evidence from non-transplant populations to support conclusions in kidney transplant recipients, ignoring the unique pharmacology, immunosuppressive interactions, and metabolic profiles of this cohort. The Discussion and Conclusions substantially overstate the evidence, with language implying disease-modifying, cardioprotective, and mortality-reducing effects that are not supported by the data. The recurring framing of SGLT-2 inhibitors as a “therapeutic breakthrough” in kidney transplantation is unsupported and risks misleading readers into inappropriate extrapolation. At best, the current evidence supports cautious short-term glycemic and weight effects; it does not justify claims of cardiovascular protection, safety assurance, or survival benefit in this population. This is not a failure of reporting but of design, methodology, and interpretation. Without study-level stratification, comparator-specific analyses, conservative inference, and elimination of causal language, this work does not meaningfully advance knowledge and carries a significant risk of clinical misinterpretation. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Pharmacoepidemiology, Pharmacology, Biostatistics, Research Ethics I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Mukherjee S. Peer Review Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r432374) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-329/v1#referee-response-432374 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Mahmoud T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 12 May 2025 | for Version 1 Tarek Mahmoud , Jaber Al Ahmed Armed Forces Hospital, Subhan, Kuwait 0 Views copyright © 2025 Mahmoud T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Article Overview This study aimed to evaluate the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs) with diabetes. After comprehensive literature search including observational and clinical trials they collected seven studies. There results indicated that SGLT2 inhibitors effectively reduced mortality, cardiovascular disease, HbA1c and BMI without increasing risk of infections and allograft rejection however it did not show clear benefit in kidney outcomes. Strengths The systematic review and meta-analysis helped to gather data randomly from the related studies reducing the bias and strengthening the findings. The improvement in diabetes related and cardiovascular end-points supported the effectiveness of SGLT2 inhibitors in managing diabetes in KTRs. The absence of serious adverse events, specifically the urinary tract and genital infections, supports the safety of SGLT2 inhibitors in this population. Limitations The majority of the included studies were case series and not randomized controlled ones, which is understandable from the available studies in the literature, but this may introduce bias and limit the generalizability of the results. The criteria for selection may be tight to allow some more studies, specially early ones, to be included. The selected studies have different designs and inclusion criteria which makes the comparison difficult. The median follow-up period was 9 (9,12) months, which may not be enough to assess renal outcomes and detect long-term complications or benefits.​ Clinical Implications The study results support the benefits of SGLT2 inhibitors in managing diabetic KTRs with reasonable safety. However, the limitations highlight the need of larger randomized controlled trials including also non-diabetic KTRs with longer follow up duration to confirm these findings and lay down the guidelines for their use. Conclusion This systematic review and meta-analysis will add to the knowledge on the use of SGLT2i for KTRs. It should also stimulate further research to validate these findings and establish a comprehensive treatment guidelines. N.B. in the title " ... Diabetes Kidney Transplant Recipients" It should be " ... Diabetic ..." Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Kidney transplantation, outcomes in special groups, diabetes, transplant infections, pregnancy, Ramadan Fast. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Mahmoud T. Peer Review Report For: The Efficacy and Safety of SGLT2 Inhibitors in Diabetes Kidney Transplant Recipients: A Systematic Review and Meta-Analysis [version 1; peer review: 2 approved, 1 not approved] . F1000Research 2025, 14 :329 ( https://doi.org/10.5256/f1000research.178712.r378428) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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