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Background <p>The GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial assessed the effectiveness of four glucose-lowering medication classes in reducing hemoglobin A1c (HbA1c) in individuals with type 2 diabetes mellitus (T2DM) on metformin monotherapy but did not include sodium-glucose cotransporter-2 inhibitors (SGLT-2is).</p> Objective <p>To replicate and extend GRADE findings by emulating a modified trial including SGLT-2is in a GRADE-eligible population, i.e., with low-to-moderate cardiovascular risk.</p> Design <p>A 4-arm target trial emulation—an observational design that mimics a randomized trial— comparing SGLT-2is, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in a modified GRADE trial framework, excluding insulin. Optum's de-identified Clinformatics® Data Mart, a commercial claims database in the US, from January 01, 2014-August 31, 2023 was used.</p> Participants <p>GRADE-eligible patients (T2DM, age ≥ 30&#xa0;years, on metformin monotherapy, no recent cardiovascular events, baseline HbA1c 6–9%).</p> Interventions <p>Incident use of SGLT-2i, SU, GLP-1RA or DPP-4i.</p> Main Measures <p>The primary outcome was the first occurrence of HbA1c ≥ 7.0%. Propensity score weights emulated random treatment assignment; hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models.</p> Key Results <p>The weighted cohort included 2,065 SGLT-2i, 2,015 SU, 2,006 GLP-1RA, and 2,006 DPP-4i initiators. GLP-1RAs had a lower risk of HbA1c ≥ 7.0% vs. SUs (HR 0.73; 95% CI 0.68–0.78) and DPP-4is (HR 0.65; 95% CI 0.60–0.70). SGLT-2is had risk of HbA1c ≥ 7.0% comparable to DPP-4is (HR 1.04; 95% CI 0.97–1.10) but higher than GLP-1RAs (HR 1.60; 95% CI 1.48–1.72) and SUs (HR 1.17; 95% CI 1.11–1.23). Subgroups and sensitivity analyses showed consistent results.</p> Conclusions <p>In this target trial emulation, GLP-1RAs were most effective for glycemic control, aligning with GRADE, and superior to SGLT-2is in combination with metformin for T2DM in patients with low-to-moderate cardiovascular risk.</p> Graphical Abstract <p></p>

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Comparative Effectiveness of Current Glucose-lowering Medications in Type 2 Diabetes Mellitus: Emulation of a Modified GRADE Trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Avik Ray,
  • Sushama K. Sreedhara,
  • Julie M. Paik,
  • Sara J. Cromer,
  • Katsiaryna Bykov,
  • Georg Hahn,
  • Robert J. Glynn,
  • Deborah J. Wexler,
  • Elisabetta Patorno

摘要

Background

The GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial assessed the effectiveness of four glucose-lowering medication classes in reducing hemoglobin A1c (HbA1c) in individuals with type 2 diabetes mellitus (T2DM) on metformin monotherapy but did not include sodium-glucose cotransporter-2 inhibitors (SGLT-2is).

Objective

To replicate and extend GRADE findings by emulating a modified trial including SGLT-2is in a GRADE-eligible population, i.e., with low-to-moderate cardiovascular risk.

Design

A 4-arm target trial emulation—an observational design that mimics a randomized trial— comparing SGLT-2is, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in a modified GRADE trial framework, excluding insulin. Optum's de-identified Clinformatics® Data Mart, a commercial claims database in the US, from January 01, 2014-August 31, 2023 was used.

Participants

GRADE-eligible patients (T2DM, age ≥ 30 years, on metformin monotherapy, no recent cardiovascular events, baseline HbA1c 6–9%).

Interventions

Incident use of SGLT-2i, SU, GLP-1RA or DPP-4i.

Main Measures

The primary outcome was the first occurrence of HbA1c ≥ 7.0%. Propensity score weights emulated random treatment assignment; hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models.

Key Results

The weighted cohort included 2,065 SGLT-2i, 2,015 SU, 2,006 GLP-1RA, and 2,006 DPP-4i initiators. GLP-1RAs had a lower risk of HbA1c ≥ 7.0% vs. SUs (HR 0.73; 95% CI 0.68–0.78) and DPP-4is (HR 0.65; 95% CI 0.60–0.70). SGLT-2is had risk of HbA1c ≥ 7.0% comparable to DPP-4is (HR 1.04; 95% CI 0.97–1.10) but higher than GLP-1RAs (HR 1.60; 95% CI 1.48–1.72) and SUs (HR 1.17; 95% CI 1.11–1.23). Subgroups and sensitivity analyses showed consistent results.

Conclusions

In this target trial emulation, GLP-1RAs were most effective for glycemic control, aligning with GRADE, and superior to SGLT-2is in combination with metformin for T2DM in patients with low-to-moderate cardiovascular risk.

Graphical Abstract