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

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.