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Introduction <p>Type&#xa0;2 diabetes mellitus (T2DM) necessitates long-term pharmacological management, with drug safety now a pivotal factor in therapy selection. Sodium‒glucose cotransporter&#xa0;2 inhibitors (SGLT2is) and dipeptidyl peptidase&#xa0;4 inhibitors (DPP4is) are widely prescribed oral antidiabetic agents; however, their comparative safety profiles remain under debate.</p> Methods <p>A systematic search of PubMed, Embase, the Cochrane Library, and Web of Science was performed up to June 2, 2025. Forty-two randomized controlled trials (RCTs) that compared SGLT2is with DPP4is in adults with T2DM were included. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using Review Manager (RevMan) 5.3. Heterogeneity was assessed with <i>I</i><sup>2</sup>, and publication bias with funnel plots and Egger’s test.</p> Results <p>SGLT2is were associated with a higher overall risk of total adverse events (AEs) (RR&#xa0;1.05, 95%&#xa0;CI 1.01–1.08). Infection-related risks included increased genital infections (RR&#xa0;5.31, 95%&#xa0;CI 3.93–7.18) and urinary tract infections (UTIs) (RR&#xa0;1.45, 95%&#xa0;CI 1.25–1.70), with no difference in upper respiratory tract infections (URTIs) (RR&#xa0;0.78, 95%&#xa0;CI 0.61–1.02). For organ injury, a non-significant trend toward renal injury was noted (RR&#xa0;1.83, 95%&#xa0;CI 0.92–3.67), with no difference in liver injury (RR&#xa0;0.64, 95%&#xa0;CI 0.28–1.46) or fracture (RR&#xa0;0.83, 95%&#xa0;CI 0.25–2.70). Severe outcomes—including hypoglycemia (RR&#xa0;1.07, 95%&#xa0;CI 0.88–1.29), mortality (RR&#xa0;1.48, 95%&#xa0;CI 0.59–3.71), diabetic ketoacidosis (DKA) (RR&#xa0;2.99, 95%&#xa0;CI 0.31–28.45), and major adverse cardiovascular events (MACEs) (RR&#xa0;1.21, 95%&#xa0;CI 0.35–4.19)—did not differ. Hypersensitivity risk was also comparable (RR&#xa0;1.25, 95%&#xa0;CI 0.65–2.42).</p> Conclusion <p>SGLT2is have an overall favorable safety profile but increase the risks of genitourinary infections and transient renal impairment. Risk stratification and monitoring are essential for high-risk individuals, for whom DPP4is may be safer. These findings provide robust RCT-based evidence to inform individualized treatment and guideline updates.</p> Trial Registration <p>This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251115623).</p>

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Comparative Safety of SGLT2 Versus DPP4 Inhibitors in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Yue Li,
  • Jie Chen,
  • Yuying Gao,
  • Jun Zhang,
  • Siqiong Deng,
  • Hao Li,
  • Xin Zhang,
  • Rui Li

摘要

Introduction

Type 2 diabetes mellitus (T2DM) necessitates long-term pharmacological management, with drug safety now a pivotal factor in therapy selection. Sodium‒glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) are widely prescribed oral antidiabetic agents; however, their comparative safety profiles remain under debate.

Methods

A systematic search of PubMed, Embase, the Cochrane Library, and Web of Science was performed up to June 2, 2025. Forty-two randomized controlled trials (RCTs) that compared SGLT2is with DPP4is in adults with T2DM were included. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using Review Manager (RevMan) 5.3. Heterogeneity was assessed with I2, and publication bias with funnel plots and Egger’s test.

Results

SGLT2is were associated with a higher overall risk of total adverse events (AEs) (RR 1.05, 95% CI 1.01–1.08). Infection-related risks included increased genital infections (RR 5.31, 95% CI 3.93–7.18) and urinary tract infections (UTIs) (RR 1.45, 95% CI 1.25–1.70), with no difference in upper respiratory tract infections (URTIs) (RR 0.78, 95% CI 0.61–1.02). For organ injury, a non-significant trend toward renal injury was noted (RR 1.83, 95% CI 0.92–3.67), with no difference in liver injury (RR 0.64, 95% CI 0.28–1.46) or fracture (RR 0.83, 95% CI 0.25–2.70). Severe outcomes—including hypoglycemia (RR 1.07, 95% CI 0.88–1.29), mortality (RR 1.48, 95% CI 0.59–3.71), diabetic ketoacidosis (DKA) (RR 2.99, 95% CI 0.31–28.45), and major adverse cardiovascular events (MACEs) (RR 1.21, 95% CI 0.35–4.19)—did not differ. Hypersensitivity risk was also comparable (RR 1.25, 95% CI 0.65–2.42).

Conclusion

SGLT2is have an overall favorable safety profile but increase the risks of genitourinary infections and transient renal impairment. Risk stratification and monitoring are essential for high-risk individuals, for whom DPP4is may be safer. These findings provide robust RCT-based evidence to inform individualized treatment and guideline updates.

Trial Registration

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251115623).