GLP-1 Receptor Agonists and Substance Use Disorders in Older Adults With Type 2 Diabetes: A Target Trial Emulation

Abstract

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), approved for type 2 diabetes (T2D) and obesity, may modulate reward pathways and reduce substance-related behaviors. This study assessed the association between GLP-1RA use and substance use-related hospitalization in older adults with coexisting T2D and substance use disorders (SUD). Methods: A retrospective cohort study using 2016-2020 Medicare data compared GLP-1RA initiators with new users of SGLT2 inhibitors (SGLT2is) or DPP-4 inhibitors (DPP4is) among adults aged ≥ 65. The primary outcome was hospitalization for any SUD; secondary outcomes included hospitalizations for alcohol use disorder (AUD) and opioid use disorder (OUD). Propensity score 1:1 matching and Cox proportional hazards models were used under an intention-to-treat approach. Results: In the GLP-1RA versus DPP4i cohort (n = 4920), GLP-1RA users had a lower risk of SUD hospitalization (HR 0.76; 95% CI, 0.67-0.86) and OUD hospitalization (HR 0.64; 95% CI, 0.43-0.96), with a nonsignificant trend for AUD (HR 0.76; 95% CI, 0.53-1.08). No significant differences were observed compared to SGLT2is (n = 4620). Conclusions: Among older adults with T2D, GLP-1RA use was associated with reduced SUD-related hospitalization versus DPP4i use, suggesting potential repurposing for SUD management.