Glucagon-like peptide-1 receptor agonists and incidence of obesity-related cancer in adults with diabetes: A target-trial emulation study.

10507 Background: Obesity is a major risk factor for cancer development. However, whether glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of diabetes medication which causes weight loss, reduce cancer incidence is unknown. This study investigated whether GLP-1RAs reduce the risk of obesity-related cancer in adults with diabetes and obesity compared to dipeptidyl peptidase-4 inhibitors (DPP-4is), a weight-neutral class of diabetes medication. Methods: 85,015 adult patients from 43 U.S. health systems with a body mass index ≥ 30 kg/m2 and a diagnosis of diabetes, who newly initiated a GLP-1RA or DPP-4i between 2013 and 2023 were included. Patients prescribed GLP-1RAs (mean age, 56.8 years) were matched 1:1 on propensity score for GLP-1RA prescription and prescription year with patients prescribed DPP-4is (mean age, 56.8 years). Obesity-related cancer incidence was compared between groups. Results: Over a mean follow-up of 3.9 years, there was a lower risk of obesity-related cancers (adjusted HR, 0.93; 95% CI, 0.88-0.98; P=0.005) and all-cause death (adjusted HR, 0.92; 95% CI 0.87-0.97; P=0.001) associated with GLP-1RA use versus DPP-4i use. Assessments of cancer subtypes showed protective associations between GLP-1RA use and colon and rectal cancers. Conclusions: GLP-1RAs were associated with a lower risk of obesity-related cancer compared with DPP-4is in a large, real-world cohort of patients with diabetes and obesity. Future studies should prospectively assess the role of GLP-1RAs in cancer prevention. Adjusted hazard ratios of incidence of composite obesity-related cancer and all-cause death in propensity-matched patients prescribed GLP-1RAs versus DPP-4is (n=85,015 pairs). Outcome Sex Events/N at risk (GLP-1RA) Events/N at risk (DPP-4i) HR (GLP-1RA/DPP-4i) P P interaction Obesity-related cancer (composite) Overall 2,501/85,015 (2.9%) 2,671/85,015 (3.1%) 0.93; 95% CI, 0.88-0.98 0.005 NA Obesity-related cancer (composite) Female 1,754/44,762 (3.9%) 1,898/45,182 (4.2%) 0.92; 95% CI, 0.86-0.98 0.01 0.63 Obesity-related cancer (composite) Male 747/40,253 (1.9%) 773/39,833 (1.9%) 0.95; 95% CI, 0.86-1.05 0.29 0.63 All-cause death Overall 2,783/85,015 (3.3%) 2,961/85,015 (3.5%) 0.92; 95% CI, 0.87-0.97 0.001 NA All-cause death Female 1,219/44,762 (2.7%) 1,514/45,182 (3.4%) 0.80; 95% CI, 0.74-0.86 <0.001 <0.001 All-cause death Male 1,564/40,253 (3.9%) 1,447/39,833 (3.6%) 1.04, 95% CI, 0.96-1.11 0.34 <0.001 Adjusted hazards ratios calculated using Cox regression represent ratios of the incidence of composite obesity-related cancer and all-cause death in matched pairs of patients prescribed GLP-1RA versus DPP-4i over average follow-up durations of 3.8 years (GLP-1RA) and 3.9 years (DPP-4i). Results of sex-stratified and sex interaction analyses are also displayed. The threshold for statistical significance is P<0.05.