GLP-1 Receptor Agonist Exposure Not Linked to Increased Malignancy Risk in Cushing's Syndrome Patients

Patients diagnosed with endogenous Cushing's Syndrome (CS) face an inherently elevated risk of developing malignancies, a critical concern for their long-term health. While Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for managing type 2 diabetes and obesity, their long-term oncologic safety, particularly within high-risk populations like those with CS, remains largely understudied. This knowledge gap creates uncertainty for clinicians considering GLP-1RA therapy in CS patients, necessitating robust real-world evidence.

This nationwide cohort study utilized the Clalit Health Services database in Israel, enrolling 609 patients diagnosed with endogenous Cushing's Syndrome between 2000 and 2023. Patients with adrenal carcinoma or ectopic CS were excluded. GLP-1RA exposure was defined as ≥3 prescription dispensations and modeled as a time-varying variable to account for changes in exposure over time. The primary endpoint was incident malignancy following a CS diagnosis, comparing GLP-1RA-exposed versus non-exposed patients. Sensitivity analyses included a 12-month lag-period approach and stratification by CS remission status.

The cohort comprised 609 patients (mean age 48.05±17.17 years; 65.02% women) with a mean follow-up of 14.7±6.4 years. During this period, 116 patients developed cancer, and 141 died. Overall, 137 patients (22.5%) received GLP-1RA therapy. A total of 8,159.69 non-exposed and 795.88 exposed person-years were accrued, with cancer incidence rates of 12.50 and 17.59 per 1,000 person-years, respectively. In the time-varying competing-risk analysis, GLP-1RA exposure was not significantly associated with increased malignancy risk (hazard ratio [HR] 1.65; 95% CI, 0.94-2.90).