Weight loss interventions and obesity-associated cancers in people with type 2 diabetes and overweight/obesity: A real-world observational study.

AIMS: To evaluate whether weight-loss interventions are associated with obesity-associated cancers (OAC) in individuals with overweight/obesity and type 2 diabetes (T2D). MATERIALS AND METHODS: This retrospective cohort study utilised the TriNetX federated research network. Three cohorts of adults with overweight/obesity and T2D, treated with either semaglutide, tirzepatide or bariatric surgery (BS) between June 2005 and June 2025, were propensity score matched (1:1) to cohorts treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) using potential confounding factors. Using Cox regression analysis, we estimated hazard ratios (HRs) of composite and individual OAC: breast, colorectal, gallbladder, liver, multiple myeloma, oesophageal, ovarian, pancreatic, renal, gastric cardia, thyroid and uterine cancers. RESULTS: In 64,178 matched pairs (mean follow-up 911 days), semaglutide (vs. DPP-4i) was associated with lower rates of composite OAC (HR: 0.88; 95% CI: 0.82-0.95), colorectal (0.80; 0.67-0.97), liver (0.75; 0.60-0.95) and pancreatic (0.76; 0.60-0.96) cancers. In 19,682 matched pairs (mean follow-up 435 days), tirzepatide (vs. DPP-4i) was associated with a non-significant lower rate of composite OAC (0.84; 0.69-1.01) but a significant lower rate of ovarian cancer (0.31; 0.10-0.95). In 9642 matched pairs (mean follow-up 1746 days), BS (vs. DPP-4i) was associated with lower rates of composite OAC (0.85; 0.74-0.98), liver (0.56; 0.32-0.97) and uterine cancers (0.59; 0.38-0.90), and higher rates of gastric cardia cancer (10.54; 1.35-82.38) and oesophageal cancer (4.78; 1.04-21.87). CONCLUSIONS: Semaglutide and BS were associated with lower cancer rates in individuals with overweight/obesity and T2D, with non-significant lower rates also observed with tirzepatide. These findings suggest weight-loss interventions may contribute to cancer prevention in this population.