GLP-1 receptor agonists and breast cancer risk in type 2 diabetes.

Abstract

10557 Background: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of breast cancer. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which improve glucose metabolism and promote weight loss, are widely used to treat T2DM. However, the trophic activity of GLP-1RAs is concerning. In diabetic patients, GLP-1 receptors are highly expressed in breast cancer tissues and their activation can lead to breast cancer cell proliferation. Combining GLP-1RAs and dipeptidyl-peptidase IV inhibitors (DPP4i), which also enhance GLP-1 pathway, was associated with more cases of breast cancer in the FDA Adverse Event Reporting system. We investigated the relationship of GLP-1RAs with breast cancer in T2DM patients using Epic Cosmos, a HIPPA law-compliant dataset with longitudinal records of 289 million de-identified patients. Methods: A retrospective cohort study was performed on patients with T2DM but without breast cancer. Patients treated with GLP1-1RAs between 1/1/2010 and 12/31/2020 were compared to those treated with metformin, sodium-glucose cotransporter-2 inhibitor (SGLT2i), sulfonylurea (SU), DPP4i, thiazolidinediones (TZD) or insulin. The incidence of breast cancer was tracked from 1/1/2021 to 12/12/2024. Subgroup analysis was conducted on White patients, African American patients, and five subgroups with different BMI ranges. Risk ratio (RR) and 95% confidence interval (CI) were calculated via RStudio (version 2024.09.1). Results: Patients with T2DM and treated with GLP-1RAs had a higher incidence of breast cancer compared to patients treated with each of the other antidiabetics (Table). Results of subgroup analysis were consistent with the overall effect; except that in the obese subgroups, GLP-1RA exposure was not associated with breast cancer compared with DPP4i. Weight and age were not significantly different between each pair of cohorts. Conclusions: GLP-1RAs was associated with an increased incidence of breast cancer compared to other antidiabetic regimens in patients with T2DM in a long-term observation. Acting on identical pathway, GLP-1RAs may show a blunt effect versus DPP4i in obese patients. The study is empowered by an enormous sample size in Epic Cosmos. Future improvements include stratifying exposure levels and stringently matching confounders. GLP-1RAs cohorts Non-GLP-1RAs cohorts GLP-1RAs cohortscancer cases (%) Non-GLP-1RAs cohortscancer cases (%) RR (95% CI) (-) Metformin (N=209090) (+) Metformin (N=4989038) 1406 (0.67%) 25037 (0.50%) 1.34 (1.27-1.41) (-) SGLT2i (N=639303) (+) SGLT2i (N=826786) 4014 (0.63%) 4380 (0.53%) 1.19 (1.14-1.24) (-)SU (N=497603) (+) SU (N=2465377) 3109 (0.63%) 11271 (0.46%) 1.37 (1.31-1.42) (-)DPP4i (N=716984) (+) DPP4i (N=1123264) 4220 (0.59%) 5966 (0.53%) 1.11 (1.07-1.15) (-)TZD (N=838249) (+) TZD (N=464680) 5212 (0.62%) 2141 (0.46%) 1.35 (1.28-1.42) (-) Insulin (N=467130) (+) Insulin (N=2757742) 2921 (0.63%) 9895 (0.36%) 1.74 (1.67-1.82)