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

Abstract

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Keywords: cancer-risk reduction; dulaglutide; liraglutide; personalized medicine; semaglutide.

Figure 1

Flowchart representation of summarized study methods.

Figure 2

Five-year risk of malignant neoplasms. Cox regression analysis was performed in propensity-matched cohorts. Hazards ratio and 95% confidence interval (CI) are reported. Vertical dot line at HR of 1. Blue horizontal bars demonstrated significant protection against cancer in treated versus control groups. CNS: central nervous system, NET: malignant neuroendocrine tumors.

Figure 3

Sex-specific risk of cancer in patients treated with GLP-1R agonists. The magnitude of risk reduction in (A) female and (B) male patients treated with GLP-1R agonists compared to controls. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. The forest plots illustrate the cancer-risk reduction across various organ systems, with HR less than 1 indicating a protective effect of GLP-1R agonist treatment. CNS: central nervous system, NET: malignant neuroendocrine tumors.