GLP1R Variants and Polygenic Risk Underlie Heterogeneous Response to GLP-1 Receptor Agonists in Type 2 Diabetes

The study investigated genetic and clinical factors influencing the response of type 2 diabetes patients to GLP-1 receptor agonist therapy. The research included 5,784 adults from the All of Us database, classified as good responders (3,194 patients with HbA1c reduction ≥2.5 percentage points) and poor responders (2,590 patients with reduction <0.5 percentage points). Good responders were younger (55.2 vs. 58.6 years) and achieved greater glycemic improvement, with HbA1c declining from 9.2% to 6.3%, while poor responders showed only a decline from 8.4% to 8.1%. Poor responders had higher polygenic risk scores for diabetes (0.38 vs. 0.21), higher frequency of GLP1R variant carriers (10.1% vs. 8.0%), and greater overall GLP1R variant burden (22.8% vs. 19.2%). Specific variants rs2268650 and rs2003132 were enriched in poor responders. The findings indicate that response to GLP-1RA therapy is associated with genetic predisposition and clinical status of patients.