M. Bhatia3, A.G. Pachimatla1, K. Ratnakaram4, S. Kalvapudi2, S. Patnaik1, B. Fitzgerald1, S. Yendamuri1 1Roswell Park Comprehensive Cancer Center, Department Of Thoracic Surgery, Buffalo, NEW YORK, USA 2University of Tennessee, Graduate School Of Medicine, Knoxville, TENNESSEE, USA 3Purdue University, Department Of Biochemistry, West Lafayette, IN, USA 4University Of Florida, Department Of Biology, Gainesville, FL, USA
Introduction:
Glucagon-like peptide-1 receptor agonists (GLP1ra) are oral hypoglycemic drugs used for type 2 diabetes and obesity treatment. Emerging evidence suggests that GLP1ra may exert anticancer effects that are mediated not only by their role in weight loss and glucose tolerance, but also by systemic metabolic and inflammatory properties that induce anti-proliferative and pro-apoptotic effects. In this study, we explored the impact of GLP1ra on lung cancer by analyzing preclinical and clinical outcome data. Our findings aim to elucidate GLP1ra as a therapeutic strategy in lung cancer treatment.
Methods:
In vitro, we evaluated the proliferation of Lewis Lung Carcinoma (LLC) cells treated with liraglutide and semaglutide at concentrations of 0, 10, 30, and 90 nM. In vivo, 150,000 LLC cells were injected subcutaneously into 24 young male mice to induce tumors. The treatment group received daily intraperitoneal injections of 0.2 µg/g liraglutide, while the control group received saline.
We also performed a retrospective cohort analysis of 1185 overweight patients (BMI >25) with early-stage non-small cell lung cancer treated with resection from 2015 to 2024. Using the Cox proportional hazards model, we compared outcomes between patients who received GLP1ra and those who did not.
Results:
The cell proliferation assay showed a significant increase in the viability of LLC cells treated with multiple liraglutide concentrations (day 3 mean absorption values: 0.31, 0.56, 0.58, 0.63 at concentrations of 0, 10, 30, and 90nM respectively, p < 0.001), while semaglutide did not show this trend. In mice, liraglutide treatment significantly decreased body weight, with treated mice losing 1g (paired t-test, p = 0.006) versus a 0.8g gain in control mice (p = 0.001) over 15 days. There was no significant effect on tumor growth (tumor weight: 0.86g vs 0.84g, p = 0.9). In the clinical cohort (n = 1185), patients taking GLP1ra (n = 97) had significantly higher body mass indexes (BMI) than those who did not (n = 1106) – mean BMI: 34.7 ± 6 vs. 30.8 ± 4.9, p = 0.01. A Cox proportional hazards model using age, sex, race, smoking status, stage, and GLP1ra use as covariates showed a trend of improved progression-free survival (HR = 0.47; 95% CI 0.21–1.07, p = 0.07) in patients using GLP1ra. These patients also showed a significant weight loss of 5kg (paired t-test, p < 0.001).
Conclusion:
Although GLP1ra significantly impact cancer cell growth and hold promise as a therapeutic agent, its underlying mechanisms remain inconclusive. The absence of a suppressive effect in the preclinical studies suggests that alterations in the tumor immune microenvironment or obesity-related inflammatory pathways may mediate the effects of GLP1ra.