Cardiorenal Mortality and Safety Outcomes of GLP ‐1 Receptor Agonists in Type 2 Diabetes With BMI Below 27 kg/m 2 : A Target Trial Emulation

ABSTRACT Aims Cardiorenal evidence for glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) derives mainly from trials in overweight or obesity; data in adults with Type 2 diabetes (T2D) and body mass index (BMI) below 27 kg/m 2 are limited. Materials and Methods We emulated a target trial in the TriNetX US Collaborative Network (index dates 2020 to 2026; maximum follow‐up 24 months). Adults with T2D and BMI < 27 kg/m 2 newly initiating non‐tirzepatide GLP‐1 RAs were compared with new users of dipeptidyl peptidase‐4 inhibitors (DPP‐4i), sodium–glucose cotransporter‐2 inhibitors (SGLT2i) or usual care. Comparisons used separate 1:1 propensity score matching. The primary outcome was all‐cause mortality. Results After matching, 7389, 8969 and 8610 GLP‐1 RA users were matched to DPP‐4i, SGLT2i and usual care. Versus DPP‐4i, GLP‐1 RA was associated with lower all‐cause mortality (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.52–0.71), major adverse cardiovascular events (MACE; HR 0.83; 95% CI 0.71–0.98) and coded heart failure (HR 0.71; 95% CI 0.60–0.85). Versus SGLT2i, MACE (HR 0.81; 95% CI 0.69–0.95) and coded heart failure (HR 0.56; 95% CI 0.47–0.65) were lower, but all‐cause mortality was not (HR 0.89; 95% CI 0.76–1.05). Gastroparesis was more frequent versus DPP‐4i. Conclusion In people with T2D and BMI < 27 kg/m 2 , GLP‐1 RA use was associated with lower coded heart failure risk across all three comparisons, the most consistent finding. The lower all‐cause mortality association versus DPP‐4i and usual care, absent versus SGLT2i, should be interpreted cautiously as likely reflecting residual confounding rather than a benefit of this magnitude.