Genetically Proxied GLP-1RAs Linked to Reduced Breast/Prostate Cancer, Increased Head/Neck/Thyroid Risks

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely prescribed for type 2 diabetes and obesity, yet their long-term cancer risks remain a significant controversy in observational studies. The challenge lies in distinguishing direct causal effects from confounding factors inherent in these populations. Understanding the true causal influence of GLP-1RAs on various cancer types is crucial for patient safety and treatment guidelines, especially given the established links between metabolic dysfunction and malignancy.

Researchers conducted a drug-target Mendelian randomization (MR) analysis using genetic variants within the GLP1R gene region as instruments to proxy GLP-1RA exposure. Summary-level data for 21 cancer types were obtained from public GWAS consortia. The primary analytical method was Inverse-Variance Weighted (IVW) MR, supplemented by sensitivity analyses, Cox proportional hazards regression using UK Biobank data, and mediation testing for BMI and HbA1c levels.

Genetically proxied GLP-1RA use showed a significant association with altered risks for several cancers. A reduced risk was observed for breast cancer [log(OR) = -0.343, P = 6.46 × 10-4] and prostate cancer [log(OR) = -0.004, P = 2.25 × 10-4]. Conversely, an increased risk was found for head and neck cancer [log(OR) = 0.350, P = 1.17 × 10-4] and thyroid cancer [log(OR) = 1.016, P = 9.12 × 10-4].

The directions of these effects were validated by Cox proportional hazards regression models using UK Biobank data, though these associations did not reach statistical significance (P > 0.05). Mediation analyses indicated that BMI explained approximately 3% of the causal effects on endometrial cancer, while HbA1c level explained 3% on head and neck cancer and 4% on thyroid cancer.