Written By: Smaiksha Benke, M.Pharm Pharmacology
Obesity is a major global health concern and a known risk factor for at least 13 different types of cancer. The increasing prevalence of obesity-related cancers highlights the urgent need for effective and widely accessible prevention strategies. Conventional weight loss approaches often provide only transitory benefits, while bariatric surgery though effective is invasive and not appropriate for everyone. However, first-generation GLP-1 receptor agonists (GLP-1 RAs) such as liraglutide and exenatide, initially designed to manage type 2 diabetes and obesity, are now showing encouraging anti-cancer potential, according to a recent study published in eClinicalMedicine, part of The Lancet Discovery Science series. This discovery indicates that the benefits of these medications may go beyond weight control. They appear to exert anti-cancer effects through mechanisms such as reducing inflammation, inhibiting the growth of cancer cells, and promoting programmed cell death (apoptosis).
Study Design
The study was a retrospective, observational cohort study using electronic medical records from Clalit Health Services in Israel. Researchers compared adults aged ≥24 years with obesity and type 2 diabetes who received either bariatric metabolic surgery (BMS) or first-generation glucagon-like peptide-1 receptor agonists (GLP-1RAs), primarily liraglutide, between 2010 and 2018. A total of 3178 matched pairs (N=6356) were followed for a median of 7.5 years (up to 12.9 years). Matching was based on age, sex, BMI, treatment initiation year, and smoking status. The primary endpoint was the incidence of obesity-related cancers (ORCs), including colorectal, postmenopausal breast, pancreatic, and other specified malignancies. Secondary analysis assessed mediation effects through changes in BMI and HbA1c.
Results
The final study cohort consisted of 6356 individuals (3178 pairs), matched on sex, age, baseline BMI, year of treatment initiation, and smoking status. At baseline, the mean age was 52.3 years, and the average BMI was 41.5 kg/m². The median follow-up time was 7.5 years, with some individuals followed for up to 12.9 years.
During the follow-up period, obesity-related cancers (ORCs) were diagnosed in 298 individuals:
150 cases occurred among those who underwent bariatric metabolic surgery (BMS), with an incidence rate of 5.76 cases per 1000 person-years.
148 cases occurred among those treated with GLP-1 receptor agonists (GLP-1RAs), with an incidence rate of 5.64 per 1000 person-years.
The adjusted hazard ratio (HR) for developing ORC in the GLP-1RA group compared to the BMS group was 1.03, indicating no statistically significant difference in overall cancer risk between the two treatment modalities.
Mediation Analysis
To explore potential mechanisms beyond weight loss, a mediation analysis was conducted:
Patients in the BMS group experienced a mean BMI reduction of 31.1%, whereas those in the GLP-1RA group had a mean decrease of 12.9%.
When the change in BMI was included in the adjusted model, the hazard ratio for GLP-1RA vs. BMS shifted to 0.59, indicating a direct effect of GLP-1RA therapy beyond weight loss, equivalent to a 41% relative risk reduction.
In contrast, when the change in HbA1c levels was tested as a mediator, it did not alter the main association. The adjusted HR remained non-significant, suggesting glycemic control alone does not explain the protective effect of GLP-1RAs.
Subgroup Observations
Among all diagnosed ORC cases:
Breast cancer (postmenopausal) was the most common (26%),
Followed by colorectal (16%) and uterine cancer (15%)
These distributions are aligning with known obesity-related cancer patterns.
Broader Implications
These findings are important in view of the current rising use of newer GLP-1 RAs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). While most attention has focused on weight loss and diabetes control, these early-generation drugs may offer additional therapeutic value as cancer-preventive agents.
Conclusions
The study’s findings suggest that treatment with first-generation GLP-1 receptor agonists (GLP-1RAs) like Liraglutide and exenatide may be doing more than helping patients lose weight or manage blood sugar they could also be reducing cancer risk. Also they are not associated with an increased risk of obesity-related cancers when compared to bariatric metabolic surgery (BMS) in patients with obesity and type 2 diabetes. Despite the greater weight loss achieved through BMS, the incidence of obesity-related cancers was statistically similar between the two groups over a long-term follow-up. Importantly, mediation analysis revealed that GLP-1RAs may exert a protective effect against these cancers independent of weight loss, potentially through other mechanisms such as anti-inflammatory pathways. These results position GLP-1RA therapy as a viable, non-surgical alternative for reducing obesity-associated cancer risk in this population. However, confirmation through larger prospective studies and randomized controlled trials is warranted to strengthen causal inference and explore the underlying biological mechanisms.
Reference
Wolff Sagy, Y., Ramot, N., Battat, E., Arbel, R., Reges, O., Dicker, D., & Lavie, G. (2025). Glucagon-like peptide-1 receptor agonists compared with bariatric metabolic surgery and the risk of obesity-related cancer: An observational, retrospective cohort study. eClinicalMedicine, 83, 103213. https://doi.org/10.1016/j.eclinm.2025.103213
The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com
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