The investigators conducted a retrospective cohort analysis in the global TriNetX network, which pools real-world data from several healthcare systems. Patients with type 2 diabetes were assigned to one of three treatment cohorts: metformin alone, GLP-1 receptor agonist alone, and dual metformin + GLP-1 RA therapy, each compared against a referent group receiving DPP4 inhibitors (DPP4i).
The study population consisted of adult patients with confirmed type 2 diabetes and documented exposure to medication. After matching, the groups remained balanced for age, sex, race, comorbidities, obesity status, diabetes duration, and concurrent medications. Cancer events and mortality outcomes were recorded over 5 years; hazard ratios (HRs) with 95% confidence intervals were used to quantify relative risk reductions. Particular attention was paid to subgroup differences, especially among younger and obese individuals.
Results
Both metformin and GLP-1 RA therapy individually lowered the risk of adiposity-related cancers and mortality compared with DPP4 inhibitors.
Metformin users experienced a 4% reduction in cancer incidence (HR 0.96, 95% CI 0.92–0.99) and a 22% reduction in mortality (HR 0.78, 95% CI 0.76–0.80).
GLP-1 RA users had even stronger associations, with a 14% reduction in cancer incidence (HR 0.86, 95% CI 0.82–0.89) and a 39% reduction in mortality (HR 0.61, 95% CI 0.59–0.63).
Dual therapy showed the greatest benefit, with a 39% reduction in cancer incidence (HR 0.61, 95% CI 0.57–0.65) and a 67% reduction in all-cause mortality (HR 0.33, 95% CI 0.32–0.35).
Benefits were more pronounced in younger, male, and obese individuals, suggesting potential interactions with metabolic risk profiles.
In this large real-world cohort of patients with type 2 diabetes, dual metformin and GLP-1 RA therapy was associated with a 39% lower incidence of adiposity-related cancers and a 67% lower all-cause mortality, showing a powerful combined impact on cancer prevention and survival. These findings support the potential value of combination therapy in reducing long-term cancer burden among individuals with type 2 diabetes, especially those who are younger or obese.
Reference:
Henney, A. E., Heague, M., Riley, D. R., Hydes, T. J., Anson, M., Alam, U., & Cuthbertson, D. J. (2025). Synergistic associations of metformin and GLP-1 receptor agonist use with adiposity-related cancer incidence in people living with type 2 diabetes. Diabetes, Obesity & Metabolism. https://doi.org/10.1111/dom.70267
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