Cardiorenal Mortality and Safety Outcomes of GLP-1 Receptor Agonists in Type 2 Diabetes With BMI Below 27 kg/m2: A Target Trial Emulation.

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/m2 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/m2 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/m2, 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.