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Introduction <p>While glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are established for cardiorenal benefits in type 2 diabetes mellitus (T2DM), prior meta-analyses have not fully integrated cross-class comparisons or net benefit analyses with updated cardiovascular outcome trials (CVOTs).</p> Methods <p>We conducted a systematic review and meta-analysis of 17 CVOTs (<i>N</i> = 132,038; GLP-1RA: <i>N</i> = 73,263; SGLT-2i: <i>N</i> = 58,775) using PubMed and Cochrane CENTRAL. We uniquely synthesized major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), renal composites, and safety outcomes (e.g., retinopathy, genitourinary infections) with random-effects models for hazard ratios (HRs) and relative risks (RRs). Innovative graphical syntheses (tornado/scatter plots, risk curves) and net benefit calculations (absolute risk reductions [ARRs] minus absolute excess risks [AERs]) were employed. Risk of bias (RoB 2) and GRADE certainty were assessed.</p> Results <p>Both classes reduced MACE (HR 0.87, 95% CI 0.84–0.90; <i>p</i> = 0.73 for class difference). SGLT-2is were superior for hHF (HR 0.69 vs. 0.88, <i>p</i> &lt; 0.0001) and renal outcomes (HR 0.68 vs. 0.79, <i>p</i> = 0.026). GLP-1RAs increased retinopathy (RR 1.18, AER + 6.5/1000); SGLT-2is increased genitourinary infections (RR 3.34, AER + 19.9/1000) and DKA (RR 2.67, AER + 1.2/1000). Amputation signals attenuated post-sensitivity analysis. Net benefits favored GLP-1RAs for MACE (+ 2.5/1000). For SGLT-2is, base-case estimates using genital-mycotic infections as the sentinel harm were marginal (hHF: − 4.9/1000; renal: − 1.9/1000), whereas sensitivity scenarios with alternative harms (e.g., volume depletion, amputation, DKA) yielded positive net benefits. GRADE certainty was high for efficacy, moderate for harms.</p> Conclusions <p>Our innovative integration of updated CVOTs, cross-class comparisons, and graphical risk–benefit tools refines therapeutic decision-making, highlighting tailored T2DM management based on patient-specific cardiorenal risks.</p> Trial Registration <p> PROSPERO (CRD420251146788).</p>

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Risk–Benefit Trade-offs of GLP-1RAs and SGLT-2is in Type 2 Diabetes Mellitus (T2D): Systematic Review, Meta-Analysis, and Net Benefit Modeling

  • 期刊论文

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  • 发表日期：

    2025年11月7日

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  • Samit Ghosal,
  • Anuradha Ghosal

摘要

Introduction

While glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are established for cardiorenal benefits in type 2 diabetes mellitus (T2DM), prior meta-analyses have not fully integrated cross-class comparisons or net benefit analyses with updated cardiovascular outcome trials (CVOTs).

Methods

We conducted a systematic review and meta-analysis of 17 CVOTs (N = 132,038; GLP-1RA: N = 73,263; SGLT-2i: N = 58,775) using PubMed and Cochrane CENTRAL. We uniquely synthesized major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), renal composites, and safety outcomes (e.g., retinopathy, genitourinary infections) with random-effects models for hazard ratios (HRs) and relative risks (RRs). Innovative graphical syntheses (tornado/scatter plots, risk curves) and net benefit calculations (absolute risk reductions [ARRs] minus absolute excess risks [AERs]) were employed. Risk of bias (RoB 2) and GRADE certainty were assessed.

Results

Both classes reduced MACE (HR 0.87, 95% CI 0.84–0.90; p = 0.73 for class difference). SGLT-2is were superior for hHF (HR 0.69 vs. 0.88, p < 0.0001) and renal outcomes (HR 0.68 vs. 0.79, p = 0.026). GLP-1RAs increased retinopathy (RR 1.18, AER + 6.5/1000); SGLT-2is increased genitourinary infections (RR 3.34, AER + 19.9/1000) and DKA (RR 2.67, AER + 1.2/1000). Amputation signals attenuated post-sensitivity analysis. Net benefits favored GLP-1RAs for MACE (+ 2.5/1000). For SGLT-2is, base-case estimates using genital-mycotic infections as the sentinel harm were marginal (hHF: − 4.9/1000; renal: − 1.9/1000), whereas sensitivity scenarios with alternative harms (e.g., volume depletion, amputation, DKA) yielded positive net benefits. GRADE certainty was high for efficacy, moderate for harms.

Conclusions

Our innovative integration of updated CVOTs, cross-class comparisons, and graphical risk–benefit tools refines therapeutic decision-making, highlighting tailored T2DM management based on patient-specific cardiorenal risks.

Trial Registration

PROSPERO (CRD420251146788).