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

<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

摘要
## 研究目的：
当前2型糖尿病（type 2 diabetes mellitus, T2DM）的治疗仍面临诸多挑战，这源于现有降糖药物存在局限。钠-葡萄糖协同转运蛋白2抑制剂（sodium-glucose co-transporter 2 inhibitors, SGLT2抑制剂）通过抑制肾脏葡萄糖重吸收，提供了一种全新的非胰岛素依赖型降糖机制。除降低血糖外，此类药物还可带来减重、降压等额外获益，并在高危患者中展现出潜在的心肾保护作用。然而，其对肾脏结局、炎症标志物及胰岛素敏感性的长期效应仍存在争议，且可能伴随糖尿病酮症酸中毒等风险，有待进一步研究验证。本研究旨在综合现有证据，明确SGLT2抑制剂在2型糖尿病患者中的疗效与安全性。
## 研究方法：
本研究为伞状综述（umbrella review），系统检索了建库至2025年9月的Embase、Medline、Cochrane系统评价数据库（Cochrane Database of Systematic Reviews）及Web of Science，以获取相关系统评价与荟萃分析。研究采用预设检索策略，严格遵循SIGN指南（SIGN guidelines），并分别使用AMSTAR 2工具与GRADE工具评估方法学质量及证据等级。
## 研究结果：
本研究共纳入多项荟萃分析，涵盖8类结局指标：血糖控制、体质量、心血管结局、安全性、炎症标志物、肾脏结局及全因死亡率。结果显示，SGLT2抑制剂可显著降低糖化血红蛋白（glycated hemoglobin）水平（加权均数差（weighted mean difference, WMD）=-0.52%~-0.56%）与空腹血糖水平（WMD=-18.28 mg/dL或-0.95 mmol/L），改善胰岛素敏感性（标准化均数差（standardized mean difference, SMD）=0.72），同时减轻体质量（均数差（mean difference, MD）=-1.76 kg~-2.63 kg）并降低血压（收缩压WMD=-4.08 mmHg）。在心血管结局方面，SGLT2抑制剂可显著降低主要不良心血管事件（相对危险度（relative risk, RR）=0.85）、心力衰竭住院风险（RR=0.67）、心血管死亡风险（RR=0.75）及全因死亡率（RR=0.79）。肾脏保护效应方面，其可降低复合肾脏结局风险（RR=0.59~0.64）、终末期肾病（end-stage renal disease, ESRD）风险（RR=0.70）及急性肾损伤（acute kidney injury, AKI）风险（RR=0.79）。此外，SGLT2抑制剂可升高血红蛋白（MD=5.60 g/L）与脂联素（adiponectin）水平，降低C反应蛋白（C-reactive protein）与瘦素（leptin）水平。但此类药物同时会增加生殖器感染（比值比（odds ratio, OR）=3.57）、尿路感染（OR=1.34）、低血糖（OR=1.27）及糖尿病酮症酸中毒的发生风险。多数结局指标存在中至高异质性（I²=0~99%），整体证据质量普遍为低至极低水平。
## 研究结论：
SGLT2抑制剂在2型糖尿病管理中展现出多重获益，包括血糖控制、减重、降压及心肾保护，尤其适用于高危患者。但临床应用中需警惕特定不良反应风险。现有证据受异质性、发表偏倚及随访周期较短的限制，未来需开展更多高质量、长期的研究，以明确其在不同人群中的疗效与安全性。
## 关键词：
钠-葡萄糖协同转运蛋白2抑制剂；2型糖尿病；伞状综述；心血管结局；肾脏保护；安全性