Efficacy and Safety of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes: An Umbrella Review Based on Randomized Controlled Trials Dataset

<b>Abstract</b><b>Objective:</b><b> </b>The treatment of type 2 diabetes mellitus (T2DM) still faces challenges due to the limitations of existing hypoglycemic agents. Sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) provide a novel insulin-independent glucose-lowering mechanism by inhibiting renal glucose reabsorption. In addition to lowering blood glucose, these agents offer extra benefits such as weight reduction and blood pressure lowering, and have shown potential cardio-renal protective effects in high-risk patients. However, their long-term effects on renaloutcomes, inflammatory markers, and insulin sensitivity remain inconsistent, and they may be associated with risks such as diabetic ketoacidosis, warranting further investigation. This study aims to synthesize current evidence on the efficacy and safety of SGLT2 inhibitors in patients with T2DM.<b>Methods:</b><b> </b>This study is an umbrella review that systematically searched Embase, Medline, the Cochrane Database of Systematic Reviews, and Web of Science, from their inception to September 2025, for relevant systematic reviews and meta-analyses. A predefined search strategy was used, strictly following the SIGN guidelines, and the AMSTAR 2 and GRADE tools were applied to assess methodological quality and the level of evidence, respectively.<b>Results:</b><b> </b>A number of meta-analyses were included, covering eight categories of outcomes: glycemic control, body weight, cardiovascular outcomes, safety, inflammatory markers, renal outcomes, and all-cause mortality. The results showed that SGLT2 inhibitors significantly reduced glycated hemoglobin (WMD = -0.52% to -0.56%) and fasting blood glucose (WMD = -18.28 mg/dL or -0.95 mmol/L), improved insulin sensitivity (SMD = 0.72), and reduced body weight (MD = -1.76 kg to -2.63 kg) and blood pressure (systolic BP WMD = -4.08 mmHg). In terms of cardiovascular outcomes, they significantly reduced major adverse cardiovascular events (RR = 0.85), hospitalization for heart failure (RR = 0.67), cardiovascular death (RR = 0.75), and the risk of all-cause mortality (RR = 0.79). Renal protective effects included reducing the risk of composite renal outcomes (RR = 0.59–0.64), end-stage renal disease (RR = 0.70), and acute kidney injury (RR = 0.79). In addition, SGLT2 inhibitors increased hemoglobin (MD = 5.60 g/L) and adiponectin (SMD = 0.28) levels, and reduced C-reactive protein (SMD = -0.25) and leptin (SMD = -0.22) levels. However, they were also associated with an increased risk of genital infections (OR = 3.57), urinary tract infections (OR = 1.34), hypoglycemia (OR = 1.27), and diabetic ketoacidosis (OR = 2.19). Most outcomes showed moderate to high heterogeneity (I²= 0–99%), and the overall quality of evidence was generally low to very low.<b>Conclusion:</b><b> </b>SGLT2 inhibitors have demonstrated multiple benefits in the management of T2DM, including blood glucose control, weight loss, blood pressure improvement, and cardio-renal protection, making them particularly suitable for high-risk patients. However, attention should be paid to the risk of specific adverse reactions. Current evidence is limited by heterogeneity, publication bias, and short-term follow-up; therefore, more high-quality, long-term studies are needed in the future to clarify their effects and safety in different populations.<b>Keywords:</b><b> </b>Sodium-glucose cotransporter 2 inhibitors; type 2 diabetes; umbrella review; cardiovascular outcomes; renal protection; safety