Differential Effects of GLP-1 Receptor Agonists on Cancer Risk in Obesity: A Nationwide Analysis of 1.1 Million Patients

<b>Background</b>: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated significant efficacy in obesity treatment beyond their original development for type-2 diabetes management. This comprehensive study investigated the relationship between GLP-1RA use and cancer incidence in individuals with obesity across a 5-year follow-up period. <b>Methods</b>: We conducted a large-scale cohort study using the TriNetX US Collaborative Network database (2013-2023) examining adult patients with obesity. The study utilized propensity score matching to pair GLP-1RA-treated patients with controls (1:1) using the nearest neighbor method. Cancer incidence served as the primary outcome measure over the 5-year follow-up, with subgroup analyses considering individual GLP-1RA agents, patient sex, and BMI categories. <b>Results</b>: Analysis revealed significant cancer-risk reductions associated with GLP-1RA use across multiple cancer types compared to matched controls. Notable risk reductions were observed in gastrointestinal (HR 0.67, 95% CI 0.59-0.75), skin (HR 0.62, 95% CI 0.55-0.70), breast (HR 0.72, 95% CI 0.64-0.82), female genital (HR 0.61, 95% CI 0.53-0.71), prostate (HR 0.68, 95% CI 0.58-0.80), and lymphoid/hematopoietic cancers (HR 0.69, 95% CI 0.60-0.80). Semaglutide demonstrated superior protective effects, particularly in gastrointestinal cancers (HR 0.45, 95% CI 0.37-0.53). Conversely, liraglutide showed increased risks for thyroid (HR 1.70, 95% CI 1.03-2.82) and respiratory cancers (HR 1.62, 95% CI 1.13-2.32). <b>Conclusions</b>: This research provides compelling evidence for GLP-1RA's potential role in cancer-risk reduction, with semaglutide showing particularly promising results. The differential effects observed among GLP-1RA agents emphasize the importance of personalized medicine approaches. These findings suggest significant implications for clinical practice and future research in both obesity management and cancer prevention.