AIMS: Chronic kidney disease (CKD) is a common and serious complication of type 2 diabetes, yet the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in non-obese or mildly overweight individuals remains uncertain. This study evaluated renal, cardiovascular, and systemic outcomes associated with GLP-1 RA therapy in adults with type 2 diabetes and body mass index (BMI) ≤ 30 kg/m².
MATERIALS AND METHODS: We conducted a real-world, target trial emulation, retrospective cohort study using the TriNetX US Collaborative Network. Adults with type 2 diabetes and BMI ≤30 kg/m² initiating GLP-1 RAs or dipeptidyl peptidase-4 inhibitors (DPP-4i) between 2016 and 2023 were identified. After exclusions, 23,103 GLP-1 RA and 44,156 DPP-4i users remained; 1:1 propensity score matching yielded two balanced cohorts of 20,928 patients. Outcomes-including major adverse kidney events (MAKE), progression to dialysis, cardiovascular events, hospitalization, and sepsis-were assessed over up to four years. Cox regression and Kaplan-Meier analyses estimated hazard ratios.
RESULTS: GLP-1 RA initiation was associated with lower risks of MAKE (14.8% vs. 16.8%; HR 0.93, p = 0.005) and progression to dialysis (HR 0.78, p < 0.001). Cardiovascular outcomes and all-cause mortality were similar between groups. GLP-1 RAs significantly reduced hospitalization (HR 0.84, p < 0.001) and sepsis (HR 0.88, p = 0.001). Benefits were consistent across BMI strata and clinical subgroups, with no evidence of effect modification.
CONCLUSIONS: In adults with type 2 diabetes and BMI ≤ 30 kg/m², GLP-1 RAs confer clinically meaningful kidney protection and reduce hospitalization and sepsis, despite neutral cardiovascular effects. These findings support the use of GLP-1 RAs in non-obese or mildly overweight diabetic populations.
