Efficacy and Safety of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes: An Umbrella Review

Objective: While sodium-glucose co-transporter 2 (SGLT2) inhibitors offer a novel, insulin-independent approach to managing type 2 diabetes (T2DM), their overall benefit-risk profile, encompassing cardio-renal outcomes and long-term safety, requires a comprehensive synthesis of the evidence. This umbrella review aims to definitively evaluate the efficacy and safety of SGLT2 inhibitors in patients with T2DM. Methods:This umbrella review systematically searched major databases for relevant systematic reviews and meta-analyses up to September 2025. The methodological quality and certainty of evidence were assessed using AMSTAR 2 and GRADE tools. Results:SGLT2 inhibitors demonstrated significant benefits in glycemic control (HbA1c WMD: -0.52% to -0.56%), body weight (MD: -1.76 to -2.63 kg), and systolic blood pressure (WMD: -4.08 mmHg). They also showed marked cardio-renal protection, reducing risks of major adverse cardiovascular events (RR=0.85), hospitalization for heart failure (RR=0.67), cardiovascular death (RR=0.75), all-cause mortality (RR=0.79), and composite renal outcomes (RR=0.59–0.64). Additionally, they positively modulated inflammatory markers and adipokines. However, these benefits were counterbalanced by increased risks of genital infections (OR=3.57), urinary tract infections (OR=1.34), and diabetic ketoacidosis (OR=2.19). The overall quality of evidence was generally low to very low. Conclusion:SGLT2 inhibitors offer a multi-faceted therapeutic option for T2DM, providing glycemic, cardiovascular, and renal benefits, which make them particularly valuable for high-risk patients. Clinicians should be aware of the associated adverse events. Future high-quality, long-term studies are warranted to strengthen these findings. Keywords:Sodium-glucose cotransporter 2 inhibitors; type 2 diabetes; umbrella review; cardiovascular outcomes; renal protection; safety . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. The management of hyperglycemia in type 2 diabetes mellitus (T2DM) remains challenging due to the limited efficacy and adverse side effects of traditional therapies. As a result, the development of novel glucose-lowering drugs has attracted increasing attention, among which sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) have emerged as a highly promising class of agents 1–6.By inhibiting glucose reabsorption in the proximal renal tubules, SGLT2 inhibitors promote urinary glucose excretion and improve glycemic control, independent of insulin secretion or sensitivity 7–11. In addition to their glucose-lowering effects, SGLT2 inhibitors offer multiple benefits, including weight reduction and blood pressure lowering, which has led to their increasing use in combination with metformin as part of dual therapy 10,12–14. Furthermore, growing evidence suggests that these agents provide cardiovascular and renal protection in high-risk T2DM patients. However, the precise extent of these benefits—particularly their impact on hard renal endpoints such as kidney failure, dialysis, transplantation, or death due to kidney disease—remains to be fully elucidated, as previous studies have not adequately assessed outcome differences across various stages of estimated glomerular filtration rate (eGFR) and proteinuria 14–17. Recent observations also suggest that SGLT2 inhibitors may enhance insulin sensitivity and modulate inflammatory biomarkers, mechanisms that are closely related to the pathophysiological processes of diabetes and its cardio-renal complications 13,18–20. In addition, although these drugs are generally well tolerated, the risk of adverse reactions still needs to be further explored in real-world studies 8,14,21,22. The currently approved SGLT2 inhibitors differ in pharmacological potency—some inhibit only renal glucose transporters, while others act on both renal and intestinal transporters—thus, comparative studies are needed to assess their efficacy and safety 11,18,19,23. Therefore, a comprehensive synthesis of existing evidence through systematic reviews and meta-analyses is essential to clarify the multiple effects of SGLT2 inhibitors on glycemic control, cardiovascular and renal outcomes, inflammatory markers, and safety, thereby providing guidance for clinical practice in type 2 diabetes17,19,24,25. As a higher-level method of evidence synthesis, umbrella review integrates existing systematic reviews and meta-analyses to evaluate the strength of evidence for different associations using unified standards, identify potential biases, and comprehensively determine the effectiveness of SGLT2 inhibitors on various health outcomes26–29. Based on this, the present study adopts the umbrella review approach, strictly following the PRISMA-P guidelines, to systematically integrate published evidence from relevant systematic reviews and meta-analyses 30,31. The aim is to comprehensively assess the effects of SGLT2 inhibitors on multiple health indicators, including blood glucose control, cardiovascular outcomes, renal function, weight changes, and safety, to clarify the evidence levels for different clinical populations and endpoint outcomes, provide a scientific basis for the clinical application and individualized treatment strategies of SGLT2 inhibitors, and offer a reference for future research directions11,14,16,32. 1 Methods 1. Umbrella Review Method . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint We systematically collected and integrated data from multiple systematic reviews (SRs) and meta-analyses (MAs) on the impact of Sodium-Glucose Transporter 2 Inhibitors interventions on health outcomes. By comprehensively evaluating all relevant clinical outcome information, we aimed to outline the full scope of evidence in this field and provide integrated insights for the application of SGLT2 interventions in healthcare. The protocol for this umbrella review was pre-registered on PROSPERO (ID: CRD420251145145), and the study results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 1.2 Literature Search To comprehensively obtain relevant literature, we searched multiple authoritative databases, covering the period from their inception to August 2025, including but not limited to Embase, Medline, the Cochrane Database of Systematic Reviews, and Web of Science. A pre-designed search strategy was used: (Sodium-Glucose Transporter 2 Inhibitors) AND (systematic review or meta-analysis), strictly following the SIGN guidelines to ensure accuracy and comprehensiveness. In addition, we carefully reviewed the reference lists of all peer-reviewed articles that met the preliminary screening criteria to avoid missing any potentially relevant studies. Discrepancies in the literature screening process were resolved by a third professional researcher to reach a final consensus. 1.3 Inclusion and Exclusion Criteria This study included systematic reviews and meta-analyses of observational and/or interventional studies evaluating the application of Sodium-Glucose Transporter 2 Inhibitors as an intervention in the field of human health. Participants included populations of any country or region, race, or gender. If a single article presented multiple health outcomes, each outcome was extracted and analyzed separately. When two or more meta-analyses addressed the same Sodium-Glucose Transporter 2 Inhibitors intervention topic, priority was given to the meta-analysis with a broader study population. In addition, data from meta-analyses with smaller sample sizes but without overlap with other studies were also extracted to maximize the use of all relevant information. We excluded literature not published in English, as well as literature based on animal experiments and/or in vitro study data. Furthermore, articles focusing solely on the principles of Sodium-Glucose Transporter 2 Inhibitors without assessing their impact on health outcomes were also excluded. If two or more meta-analyses existed on the same topic, priority was given to the meta-analysis with a broader study population. 1.4 Data Extraction Data were extracted from the included articles by two independent researchers. The extracted data included: 1) name of the first author and year of publication; 2) journal name; 3) characteristics of the study population; 4) health outcome indicators; 5) interventions; 6) number of cases in each meta-analysis; 7) number of original studies included in each meta-analysis; 8) study design type of the original studies; 9) effect size measures used in the meta-analysis and their corresponding estimates; 13) type of effect model (note: numbering follows the original text); 10) results of heterogeneity tests; 11) results of publication bias assessment. For quantitative synthesis, priority was given to fully adjusted, study-specific pooled effect size estimates (including odds ratio [OR], mean estimate [ME], relative risk [RR], weighted mean difference . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint [WMD], standardized mean difference [SMD], etc.) and their 95% confidence intervals (CIs). In case of discrepancies in data extraction, a third researcher reviewed the data and made the final decision. 1.5 Methodological Quality Assessment and Evidence Grading The methodological quality of the included studies was rigorously assessed using the 11 items of AMSTAR2 to ensure the scientific rigor and standardization of the research process 33. At the same time, the GRADE system was used to grade the quality of evidence and provide corresponding recommendations, thereby clarifying the reliability and credibility of different research results34. 1.6 Data Analysis For each meta-analysis, a random-effects model (or a fixed-effects model as actually applied) was used to present the extracted intervention exposure data, health outcome data, and fully adjusted study-specific pooled effect sizes with their 95% CIs. The I ² statistic and Cochran's Q test were used to assess the degree of heterogeneity between studies and to determine the consistency of the results. Egger’ s test was used to assess small-study effects (marked as NA if not reported in the literature). For small-study effects and heterogeneity tests, a P-value < 0.1 was considered statistically significant; for other tests, a P-value < 0.05 was considered statistically significant. 2 Outcome 2.1 Characteristics of MA Figure 1 shows the flowchart of the literature selection process. After a systematic search, a total of 5759 articles were identified. After applying the inclusion and exclusion criteria, 36 MAs were included, covering 8 different outcome measures (Figure 2). The characteristics of all the included studies are shown in Table 1. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Fig. 1. Flowchart of the selection process. Figure 2 Sankey diagram showing the associations between various studies and health-related outcome categories . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Table1 Evidence summary Outcome Intervention measures for the experimental group Intervention measures for the control group Study No. of total group No. of studies in MA RCT Cohort Case control Effects model I² Egger test P value Glycated Hemoglobin Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0.14 NA Fasting Plasma Glucose Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0.18 NA Body Mass Index Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Random 0.9 NA Waist Circumference Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Systolic Blood Pressure Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Diastolic Blood Pressure Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Serum Uric Acid Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Random 0.5 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Incident Hypoglycemia Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Urinary Tract Infection Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Genital Tract Infection Sodium glucose co-transport-2 inhibitors Placebo Giovanni Musso et al. 20127 4063 Type 2 Diabetes Mellitus 13 13 0 0 Fixed 0 NA Hemoglobin Level Sodium-glucose cotransporter 2 inhibitors Placebo Mehmet Kanbay et al. 20229 14748 Type 2 Diabetes Mellits 7 7 0 0 Random 0.94 NA Hematocrit Level Sodium-glucose cotransporter 2 inhibitors Placebo Mehmet Kanbay et al. 20229 14748 Type 2 Diabetes Mellitus 13 13 0 0 Random 0.99 NA Insulin Sensitivity/Insulin Resistance in T2DM Population Sodium-glucose cotransporter 2 inhibitors Placebo Mohammad Fakhrolmobasheri et al. 202319 1178 Type 2 Diabetes Mellitus 13 13 0 0 Random 0.848 0.19 Major Cardiovascular Events Sodium-glucose cotransporter 2 inhibitors Placebo/active control Karin Ra˚dholm et al. 201815 32893 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA Cardiovascular Death Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0.804 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Non-fatal Myocardial Infarction Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA Non-fatal Stroke Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0.614 NA Hospitalisation for Unstable Angina Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA Hospitalisation for Heart Failure Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA All-cause Death Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 30210 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0.546 NA Composite renal outcomes Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 18064 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA Albuminuria Progression Sodium-glucose cotransporter 2 inhibitors Placebo Karin Ra˚dholm et al. 201815 15139 Type 2 Diabetes Mellitus 92 82 0 0 Fixed 0 NA Change in HbA₁c from baseline Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 6 6 0 0 Random 0.79 NA Change in fasting plasma glucose from baseline Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 6 6 0 0 Random 0 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Change in weight from baseline Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 6 6 0 0 Random 0 NA Change in systolic blood pressure from baseline Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 6 6 0 0 Random 0 NA Change in diastolic blood pressure from baseline Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 NA Proportion of participants achieving HbA₁c Sodium-glucose cotransporter-2 inhibitors Placebo De Buitléir et al. 202135 1661 Type 2 Diabetes Mellitus 6 6 0 0 Random 0.2 NA Change in C-reactive protein (CRP) from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellits 14 14 0 0 Random 0.5 NA Change in tumor necrosis factor-alpha (TNF-α) from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellitus 7 7 0 0 Random 0 NA Change in interleukin-6 (IL-6) from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellitus 6 6 0 0 Random 0.88 NA Change in leptin from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellitus 9 9 0 0 Random 0.6 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Change in adiponectin from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellitus 17 17 0 0 Random 0.26 NA Change in ferritin from baseline Sodium-glucose cotransporter-2 inhibitors Placebo Wang et al. 202236 6261 Type 2 Diabetes Mellitus 6 6 0 0 Random 0.97 NA Composite renal outcome Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 9 9 0 0 Random 0.29 NA Decline in estimated glomerular filtration rate ≥40% Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 4 4 0 0 Random 0.59 NA Doubling of serum creatinine Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 3 3 0 0 Random 0.34 NA Dialysis or renal replacement therapy Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 5 5 0 0 Random 0 NA Sustained estimated glomerular filtration rate <15 ml/min/1.73㎡ for ≥30 days Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 3 3 0 0 Random 0 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint End-stage renal disease Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 3 3 0 0 Random 0 NA Acute kidney injury Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 6 6 0 0 Random 0 NA Renal death Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 6 6 0 0 Random 0 NA Progression to macroalbuminuria Sodium-glucose cotransporter-2 inhibitors Placebo Bose et al. 202337 71553 Type 2 Diabetes Mellitus 2 2 0 0 Random 0.91 NA Composite renal outcome Sodium-glucose cotransporter-2 inhibitors Placebo Zhang et al. 202038 28529 Type 2 Diabetes Mellius 3 3 0 0 Random 0.51 NA Acute renal failure or injury Sodium-glucose cotransporter-2 inhibitors Placebo Zhang et al. 202038 48731 Type 2 Diabetes Mellitus 15 15 0 0 Random 0 0.029 Renal impairment Sodium-glucose cotransporter-2 inhibitors Placebo Zhang et al. 202038 28865 Type 2 Diabetes Mellitus 17 17 0 0 Random 0 NA Change in estimated glomerular filtration rate Sodium-glucose cotransporter-2 inhibitors Placebo Zhang et al. 202038 15556 Type 2 Diabetes Mellitus 46 46 0 0 Random 0.99 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Change in urine albumin-creatinine ratio Sodium-glucose cotransporter-2 inhibitors Placebo Zhang et al. 202038 10129 Type 2 Diabetes Mellitus 18 18 0 0 Random 0.98 NA Composite renal outcome Sodium-glucose cotransporter-2 inhibitors Placebo Heerspink et al. 202039 38612 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 NA Acute kidney injury Sodium-glucose cotransporter-2 inhibitors Placebo Heerspink et al. 202039 38625 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 0.42 Progression to macroalbuminuria Sodium-glucose cotransporter-2 inhibitors Placebo Heerspink et al. 202039 38598 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 NA Decline in eGFR ≥ 40% Sodium-glucose cotransporter-2 inhibitors Placebo Heerspink et al. 202039 38581 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 NA End-stage kidney disease Sodium-glucose cotransporter-2 inhibitors Placebo Heerspink et al. 202039 38671 Type 2 Diabetes Mellitus 4 4 0 0 Random 0 NA All-cause mortality Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 18 18 0 0 Random 0 NA Major adverse cardiac events Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 31 31 0 0 Random 0 NA Non-fatal myocardial infarction Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 27 27 0 0 Random 0 NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Heart failure/hospitalisation for heart failure Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 14 14 0 0 Random 0 NA Non-fatal stroke Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 28 28 0 0 Random 0 NA Atrial fibrillation Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 16 16 0 0 Random 0 NA Unstable angina Sodium-glucose cotransporter-2 inhibitors Placebo Usman et al. 201822 34987 Type 2 Diabetes Mellitus 18 18 0 0 Random 0 NA Change in glycated hemoglobin (HbA1c, %) Sodium-glucose cotransporter-2 inhibitors Placebo Tang et al. 201740 4235 Type 2 Diabetes Mellitus 7 7 0 0 Random 0.79 >0.05 Change in fasting plasma glucose (FPG, mmol/L) Sodium-glucose cotransporter-2 inhibitors Placebo Tang et al. 201740 4235 Type 2 Diabetes Mellitus 7 7 0 0 Random 0.68 >0.05 Change in body weight (kg) Sodium-glucose cotransporter-2 inhibitors Placebo Tang et al. 201740 4235 Type 2 Diabetes Mellitus 7 7 0 0 Random 0.75 >0.05 Change in insulin dose (IU) Sodium-glucose cotransporter-2 inhibitors Placebo Tang et al. 201740 4235 Type 2 Diabetes Mellitus 6 6 0 0 Random 0.91 <0.01 . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Diabetic ketoacidosis Sodium-glucose co-transporter-2 inhibitors Placebo Liu et al. 202024 51701 Type 2 Diabetes Mellitus 30 30 0 0 Fixed 10% NA . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint 2.2 Blood Glucose Control and Metabolic Parameters SGLT2 inhibitors demonstrated significant improvements in blood glucose control and metabolic parameters. In patients with type 2 diabetes, the weighted mean difference (WMD) in glycated hemoglobin (HbA ₁c) levels was -0.56 (95% CI: -0.67 to -0.44); the WMD in fasting plasma glucose (FPG) was -18.28 mg/dL (95% CI: -20.66 to -15.89) (additionally, the WMD in change in FPG was -0.95 mmol/L, 95% CI: -1.21 to -0.70). The standardized mean difference (SMD) for insulin sensitivity/resistance was 0.72 (95% CI: 0.32 to 1.12). The odds ratio (OR) for achieving the HbA ₁c target was 3.07 (95% CI: 2.29 to 4.12). The WMD for changes in insulin dosage was -8.79 IU (95% CI: -13.36 to -4.22). The odds ratio (OR) for the occurrence of diabetic ketoacidosis was 2.19 (95% CI: 1.41 to 3.39) (Figure 3). Figure 3: Forest Plot of the Effects of SGLT2 on Blood Glucose Control and Metabolic Parameters in Multiple Populations 2.3 Weight and Body Composition SGLT2 inhibitors have a significant effect on improving body weight and body composition. In patients with type 2 diabetes, the weighted mean difference (WMD) in body mass index (BMI) was -1.17 (95% CI: -1.41 to -0.92); the weighted mean difference (WMD) in waist circumference was -1.20 cm (95% CI: -2.00 to -0.43). The mean difference (MD) in body weight change was -1.76 kg (95% CI: -2.04 to -1.48); the weighted mean difference (WMD) in body weight change was -2.63 (95% CI: -3.10 to -2.16) (Figure 4). Figure 4: Forest Plot of the Effects of SGLT2 on Weight and Body Composition 2.4 Cardiovascular Outcomes and Blood Pressure SGLT2 inhibitors have significant benefits in cardiovascular outcomes and blood pressure control. The weighted mean difference (WMD) in systolic blood pressure was -4.08 mmHg (95% CI: -4.91 to -3.24); the WMD in diastolic blood pressure was -1.16 mmHg (95% CI: -1.67 to -0.66) (additionally, the MD in change in SBP was -3.6 mmHg, 95% CI: -4.8 to -2.4; the MD in change in DBP was -1.5 mmHg, 95% CI: -2.4 to -0.6). The risk ratio (RR) for major cardiovascular events was 0.85 (95% CI: 0.77 to 0.93); the RR for cardiovascular death was 0.75 (95% CI: 0.65 to 0.87). The RR for nonfatal myocardial infarction was 0.84 (95% CI: 0.73 to 0.98); the RR for hospitalization for heart failure was 0.67 (95% CI: 0.55 to 0.80) (additionally, the OR for heart failure hospitalization was 0.67, 95% CI: 0.59 to 0.76). No significant improvement was observed in nonfatal stroke (RR = 1.03, 95% CI: 0.86 to 1.24; OR = 1.02, 95% CI: 0.85 to 1.21) and hospitalization for unstable angina (RR = 0.95, 95% CI: 0.73 to 1.24; OR = 0.95, 95% CI: 0.73 to 1.25) (Figure 5). . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Figure 5: Forest Plot of the Effects of SGLT2 on Cardiovascular Outcomes and Blood Pressure 2.5 Hematological Parameters SGLT2 inhibitors affect certain hematological parameters. The weighted mean difference (WMD) in serum uric acid levels was -41.50 μmol/L (95% CI: -47.22 to -35.79). The mean difference (MD) in hemoglobin levels was 5.60 g/L (95% CI: 3.73 to 7.47); the MD in hematocrit levels was 1.32% (95% CI: 1.21 to 1.44). The standardized mean difference (SMD) in ferritin change was -1.15 (95% CI: -2.87 to 0.57), which was not statistically significant (Figure 6). Figure 6: Forest Plot of the Effects of SGLT2 on Hematological Parameters 2.6 Safety and Adverse Events Certain safety indicators of SGLT2 inhibitors warrant attention. The odds ratio (OR) for the occurrence of hypoglycemic events was 1.27 (95% CI: 1.05 to 1.53). The odds ratio (OR) for urinary tract infections was 1.34 (95% CI: 1.05 to 1.71); the odds ratio (OR) for genital tract infections was 3.57 (95% CI: 2.59 to 4.93) (Figure 7). Figure 7: Forest Plot of the Effects of SGLT2 on Safety and Adverse Events 2.7 Inflammatory and Adipokine Biomarkers SGLT2 inhibitors have a regulatory effect on certain inflammatory and adipokine factors. The standardized mean difference (SMD) for changes in C-reactive protein was -0.25 (95% CI: -47 to -0.03); the standardized mean difference (SMD) for changes in tumor necrosis factor- α was -0.05 (95% CI: -0.35 to 0.26), not statistically significant; the standardized mean difference (SMD) for changes in interleukin-6 was -0.57 (95% CI: -1.36 to 0.22), not statistically significant. The standardized mean difference (SMD) for changes in leptin was -0.22 (95% CI: -0.43 to -0.01); the standardized mean difference (SMD) for changes in adiponectin was 0.28 (95% CI: 0.15 to 0.41) (Figure 8). . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Figure 8: Forest Plot of the Effects of SGLT2 on Inflammatory and Adipokine Biomarkers 2.8 Renal Outcomes SGLT2 inhibitors have shown significant effects in renal protection. The risk ratio (RR) for composite renal outcomes was 0.59 (95% CI: 0.49 to 0.71) (additionally, the RR for composite renal outcomes was 0.64, 95% CI: 0.58 to 0.72; the OR for composite renal outcomes was 0.48, 95% CI: 0.40 to 0.59; the RR for composite renal outcomes was 0.61, 95% CI: 0.45 to 0.82). The RR for progression of albuminuria was 0.72 (95% CI: 0.67 to 0.77); the RR for progression to macroalbuminuria was 0.79 (95% CI: 0.62 to 1.00); the RR for a reduction in estimated glomerular filtration rate (eGFR) ≥40% was 0.62 (95% CI: 0.50 to 0.77) (additionally, the RR for eGFR decline ≥ 40% was 0.58, 95% CI: 0.48 to 0.70); the RR for doubling of serum creatinine was 0.67 (95% CI: 0.56 to 0.81); the RR for dialysis or renal replacement therapy was 0.71 (95% CI: 0.59 to 0.86); the RR for end-stage renal disease was 0.70 (95% CI: 0.56 to 0.87) (additionally, the RR for end-stage kidney disease was 0.65, 95% CI: 0.53 to 0.80); the RR for acute kidney injury was 0.79 (95% CI: 0.71 to 0.89) (additionally, the RR for acute kidney injury was 0.75, 95% CI: 0.66 to 0.85; the OR for acute renal failure or injury was 0.77, 95% CI: 0.66 to 0.91); the RR for sustained eGFR <15 ml/min was 0.66 (95% CI: 0.55 to 0.81); the RR for renal death was 0.53 (95% CI: 0.26 to 1.09); the OR for renal impairment was 1.48 (95% CI: 1.07 to 2.04); the MD for change in eGFR was 0.16 (95% CI: -0.83 to 1.14); the SMD for change in urinary albumin-creatinine ratio (UACR) was -0.21 (95% CI: -0.49 to 0.07)(Figure 9). Figure 9: Forest Plot of the Effects of SGLT2 on Renal Outcomes 2.9 All-Cause Mortality Rate SGLT2 inhibitors can significantly reduce all-cause mortality. The risk ratio (RR) for all-cause mortality was 0.79 (95% CI: 0.70 to 0.88); the odds ratio (OR) for all-cause mortality was 0.79 (95% CI: 0.70 to 0.89) (Figure 10). . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Figure 10: Forest Plot of the Effects of SGLT2 on All-Cause Mortality Rate 2.10 Heterogeneity The heterogeneity of the included studies varied depending on the outcome indicators. Some outcome indicators showed low to moderate heterogeneity, such as glycated hemoglobin (I ² = 0.14), fasting blood glucose (I ² = 0.18), systolic blood pressure (I² = 0), and several cardiovascular hard endpoints (I ² mostly below 0.1). However, some outcome indicators exhibited high heterogeneity, such as body mass index (I² = 0.9), insulin sensitivity (I ² = 0.848), weight change (I ² = 0.75), and certain inflammatory markers (e.g., change in ferritin I ² = 0.97). The high heterogeneity may stem from differences in intervention protocols, follow-up duration, baseline population characteristics, or measurement methods across studies. 2.11 Publication Bias Egger's test results showed no significant publication bias (P > 0.05) in most outcome indicators of the meta-analyses. For example, changes in glycated hemoglobin (P > 0.05), changes in fasting blood glucose (P > 0.05), and major cardiovascular events (P > 0.05) all did not indicate the presence of small-study effects. Only a few outcome indicators, such as changes in insulin dosage (P < 0.01) and acute kidney injury (P = 0.029), had Egger's test P values < 0.1, suggesting possible publication bias. Overall, no significant publication bias was reported in all meta-analyses. 2.12 Assessment of Evidence Quality and Risk of Bias The AMSTAR 2.0 tool was used to assess the methodological quality of the included systematic reviews/meta-analyses. The results showed that most studies performed well in terms of search strategy, bias risk control, and statistical analysis, with the overall quality of evidence rated as moderate to high. The main limitations were that some studies did not have a pre-registered protocol or did not adequately report the list and reasons for excluded studies. The risk of bias assessment indicated that the included original studies were mainly randomized controlled trials, with an overall low risk of bias. Sensitivity analysis results showed that after excluding low-quality studies, the pooled effect size remained robust, indicating a high level of credibility for the evidence of the main outcome measures (Table 2). . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Table 2. Analysis table of research methodological quality and evidence reliability in SGLT2 based on AMSTAR 2 scores and GRADE grading Outcome group AMSTAR2 GRADE Body Weight & Composition Body Mass Index SGLT2 inhibitors Critically low very low Waist Circumference SGLT2 inhibitors low low Change in weight from baseline SGLT2 inhibitors low low Change in body weight SGLT2 inhibitors low low Cardiovascular Outcomes & Blood Pressure Systolic Blood Pressure SGLT2 inhibitors low low Diastolic Blood Pressure SGLT2 inhibitors low low Major Cardiovascular Events SGLT2 inhibitors Critically low very low Cardiovascular Death SGLT2 inhibitors Critically low low Non-fatal Myocardial Infarction SGLT2 inhibitors Critically low very low Non-fatal Stroke SGLT2 inhibitors low low Hospitalisation for Unstable Angina SGLT2 inhibitors low low Hospitalisation for Heart Failure SGLT2 inhibitors low low Change in systolic blood pressure from baseline SGLT2 inhibitors low low Change in diastolic blood pressure from baseline SGLT2 inhibitors low low Major adverse cardiac events SGLT2 inhibitors low low Non-fatal myocardial infarction SGLT2 inhibitors low low Heart failure/hospitalisation for heart failure SGLT2 inhibitors Critically low low Non-fatal stroke SGLT2 inhibitors Critically low low Atrial fibrillation SGLT2 inhibitors Critically low low Unstable angina SGLT2 inhibitors low low Glycemic Control & Metabolic Parameters Glycated Hemoglobin SGLT2 inhibitors low low . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Fasting Plasma Glucose SGLT2 inhibitors low low Insulin Sensitivity/Insulin Resistance in T2DM Population SGLT2 inhibitors Critically low low Change in HbA₁c from baseline SGLT2 inhibitors low low Change in fasting plasma glucose from baseline SGLT2 inhibitors Critically low low Proportion of participants achieving HbA₁c SGLT2 inhibitors Critically low very low Change in glycated hemoglobin SGLT2 inhibitors Critically low low Change in fasting plasma glucose SGLT2 inhibitors low very low Change in insulin dose SGLT2 inhibitors low low Diabetic ketoacidosis SGLT2 inhibitors low low Hematological Parameters Serum Uric Acid SGLT2 inhibitors low low Hemoglobin Level SGLT2 inhibitors Critically low low Hematocrit Level SGLT2 inhibitors low low Change in ferritin from baseline SGLT2 inhibitors low very low Inflammation & Adipokine Biomarkers Change in C-reactive protein (CRP from baseline SGLT2 inhibitors low low Change in tumor necrosis factor-alpha (TNF-α from baseline SGLT2 inhibitors Critically low low Change in interleukin-6 from baseline SGLT2 inhibitors low very low Change in leptin from baseline SGLT2 inhibitors low low Change in adiponectin from baseline SGLT2 inhibitors Critically low very low Incident Hypoglycemia SGLT2 inhibitors low low Urinary Tract Infection SGLT2 inhibitors low low Genital Tract Infection SGLT2 inhibitors low low Mortality All-cause Death SGLT2 inhibitors Critically low low All-cause mortality SGLT2 inhibitors low low Renal Outcomes . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint Composite renal outcomes SGLT2 inhibitors low low Albuminuria Progression SGLT2 inhibitors low very low Composite renal outcome SGLT2 inhibitors low low Decline in estimated glomerular filtration rate ≥40% SGLT2 inhibitors Critically low very low Doubling of serum creatinine SGLT2 inhibitors low low Dialysis or renal replacement therapy SGLT2 inhibitors low very low Sustained estimated glomerular filtration rate <15 ml/min/1.73㎡ for ≥30 days SGLT2 inhibitors Critically low low End-stage renal disease SGLT2 inhibitors low low Acute kidney injury SGLT2 inhibitors low low Renal death SGLT2 inhibitors Critically low very low Progression to macroalbuminuria SGLT2 inhibitors low low Composite renal outcome SGLT2 inhibitors Critically low low Acute renal failure or injury SGLT2 inhibitors low low Renal impairment SGLT2 inhibitors low very low Change in estimated glomerular filtration rate SGLT2 inhibitors low low Change in urine albumin-creatinine ratio SGLT2 inhibitors low low Composite renal outcome SGLT2 inhibitors low low Acute kidney injury SGLT2 inhibitors Critically low very low Progression to macroalbuminuria SGLT2 inhibitors low low Decline in eGFR ≥ 40% SGLT2 inhibitors low low End-stage kidney disease SGLT2 inhibitors low low . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted December 1, 2025. ; https://doi.org/10.1101/2025.11.27.25341177doi: medRxiv preprint 3 Conclusion In summary, this umbrella review demonstrates that SGLT2 inhibitors offer multiple benefits in patients with T2DM, including glycemic control, weight reduction, and cardiorenal protection. This provides a scientific basis for their clinical application and the development of personalized treatment strategies. Additionally, the review suggests the need for further exploration of efficacy differences across various eGFR stages and levels of proteinuria, as well as comparisons of efficacy and safety among different types of SGLT2 inhibitors.

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