Early Add-On Combination of GLP-1 Receptor Agonist and SGLT2 Inhibitor in People With Cardiovascular-Kidney-Metabolic Stage 2-3

This retrospective observational target-trial emulation uses electronic health record data from the TriNetX US Collaborative Network to compare early treatment intensification strategies in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor. The study compares patients who, within 90 days of starting background therapy, add the alternate agent, add a DPP-4 inhibitor or sulfonylurea, or do not receive early add-on therapy. The primary outcome is all-cause mortality over 36 months, with secondary cardiorenal outcomes also evaluated. Propensity-score methods are used to reduce bias from nonrandom treatment selection.

Inclusion Criteria: * Adults aged 20 years or older. * Obesity, defined by body mass index (BMI) 27 kg/m2 or greater. * Type 2 diabetes mellitus, defined using electronic health record data, including diagnosis codes and/or hemoglobin A1c 6.5% or greater. * Met cardiovascular-kidney-metabolic (CKM) stage 2-3 criteria at baseline. * Initiated a GLP-1 receptor agonist or an SGLT2 inhibitor as background therapy. * Had treatment strategy classification based on early add-on initiation within 90 days after background therapy initiation, or no early add-on with index at the 90-day landmark. Exclusion Criteria: * Prior use of GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas within 6 months before cohort entry. * Major cardiovascular disease or revascularization within 12 months before cohort entry. * Advanced kidney disease within 12 months before cohort entry, including end-stage kidney disease, dialysis, or estimated glomerular filtration rate less than 15 mL/min/1.73 m2. * Major cardiovascular or renal events within 6 months before index. * Any history of non-type 2 diabetes, HIV infection, bariatric surgery, or solid-organ transplantation. * Missing critical baseline covariates.