The association between genetically proxied GLP-1 receptor agonists and cancer risks

Area of Science:

• Pharmacogenomics
• Oncology
• Endocrinology

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are common treatments for type 2 diabetes and obesity.
• Long-term cancer risks associated with GLP-1RA use are debated, with conflicting evidence from observational studies.
• Understanding the causal relationship between GLP-1RA exposure and cancer risk is crucial for patient safety.

Purpose of the Study:

• To investigate the potential causal effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) exposure on the risk of various cancers.
• To utilize a drug-target Mendelian randomization approach to overcome limitations of observational studies.

Main Methods:

• A drug-target Mendelian randomization (MR) analysis was performed using genetic variants in the GLP1R gene region as instrumental variables for GLP-1RA exposure.
• Summary-level data from 21 cancer types were analyzed using the inverse-variance weighted (IVW) MR method.
• Sensitivity analyses, Cox proportional hazards regression, and mediation analyses (for BMI and HbA1c) were conducted for validation.

Main Results:

• Genetically proxied GLP-1RA use showed a reduced risk 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, GLP-1RA use was associated with an increased risk of 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).
• Mediation analyses suggested BMI partially explained effects on endometrial cancer, while HbA1c influenced head and neck and thyroid cancer risks.

Conclusions:

• This Mendelian randomization study provides evidence suggesting that GLP-1RA use may causally impact the risk of specific cancers.
• Findings indicate a potential dual effect: reduced risk for some cancers (breast, prostate) and increased risk for others (head and neck, thyroid).
• The results highlight the necessity for cancer-specific monitoring in patients prescribed GLP-1RAs and warrant further investigation into underlying mechanisms.