Glucagon-like peptide-1 receptor agonists compared with bariatric metabolic surgery and the risk of obesity-related cancer: an observational, retrospective cohort study

Background: Both obesity and diabetes are associated with increased risk for specific types of cancer, generally termed obesity-related cancer (ORC). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and bariatric metabolic surgery (BMS) are well established treatments for diabetes and obesity, but their comparative effectiveness for the prevention of ORC is unknown. Here, we compare the incidence of ORC in adults living with obesity and diabetes who were treated with first-generation GLP-1RA or with BMS. Methods: An observational, retrospective cohort study based on electronic medical records data of Clalit health services, Israel. The study included patients aged ≥24 years, with obesity and diabetes, with no prior history of ORC, who received either of the interventions during 2010 through 2018. Overall, 3178 pairs were matched 1:1 based on sex, age, baseline BMI, time of treatment initiation, and smoking status. The study period extended from January 2010 until December 2023. The measured outcome was the incidence of ORC, defined as any of the following diagnoses: multiple myeloma, meningioma, adenocarcinoma of esophagus; stomach, colorectal, liver or bile duct, gallbladder, pancreas, corpus uteri, ovary, renal-cell kidney, thyroid, and postmenopausal breast cancer. Findings: Of the 6356 study participants, 3884 (61.1%) were females. At baseline, the mean age was 52.3 years (SD: 9.28), and the mean BMI was 41.5 kg/m² (SD: 5.10). Participants were followed for a median of 7.5 years and up to 12.9 years. ORC occurred in 5.62 cases per 1000 person-years in BMS patients, and in 5.89 cases per 1000 person-years in GLP-1Ra patients; adjusted HR for GLP1-RA versus BMS 1.11 (95% CI: 0.86–1.44). Moreover, assessment of mediation through weight-loss resulted in an estimated direct effect of 41% (95% CI: 15%–59%) relative risk reduction of the pharmacotherapy. Interpretation: Our finding suggest that first-generation GLP1-RA treatment does not increase ORC risk in patients receiving GLP1-RA treatment for diabetes and weight loss. Moreover, this may point at additional pathways beyond weight loss in which GLP-1RAs might contribute to the decreased risk for ORC, such as reducing inflammation. However, future studies, including randomized controlled trials and larger prospective cohort studies are needed to validate the observed effects and explore the underlying mechanisms. Funding: No financial or in-kind support was provided for the conduct of this study.