GLP-1 receptor agonist use and cancer risk in obese nondiabetic adults

Background: Recent data show that glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with decreased cancer incidence in diabetic and obese patients. However, there have been no studies exclusively investigating the association of obesity-associated cancer (OAC) risks and GLP-1RAs in obese, nondiabetic patients.

Patients and methods: We conducted a target trial emulation to evaluate the association between GLP-1RA use and risk of 13 OACs. Using TriNetX, a nationwide database of 113 million US patients, we identified obese, nondiabetic adults without prior OAC diagnosis from December 2014 to June 2025. Patients prescribed GLP-1RAs were 1:1 propensity score matched to those receiving diet or exercise counseling and validated using inverse probability of treatment weighting. The primary outcome compared the cumulative incidence of OACs among treatment groups. The secondary outcome analyzed cancer incidence across sex (female, male), body mass index (<40, ≥40 kg/m 2 ), race (white, black), and drug (semaglutide, tirzepatide).

Results: The cohort included 229 467 patients; 86 422 (37.7%) received GLP-1RAs, while 143 045 (62.3%) received diet or exercise consultation. After 1:1 propensity score matching, the study cohort included 161 798 patients: 80 899 GLP 1RA users versus 80 899 patients on diet or exercise consultation. Mean age of patients was 47.2 years (standard deviation 14.8). With a median follow-up of 2 years (interquartile range 1-2 years), the propensity score matching analysis showed a significantly lower incidence of any OACs among GLP-1RA users (hazard ratio 0.59, 95% confidence interval 0.53-0.67). Secondary analyses showed that in all subgroups, except for black race, GLP-1RA use was associated with a lower cumulative incidence of OACs. The inverse probability of treatment weighting
analysis confirmed the findings.

Conclusions: GLP-1RA use was associated with a significantly lower short-term incidence of OACs among obese,nondiabetic patients, with consistent results observed in subgroups, except for race. Prospective trials are needed to confirm causality.

Key words: cancer incidence, GLP-1 receptor agonists, obesity, obesity-associated cancers, pharmacoepidemiology