Glucagon-like peptide-1 receptor agonist exposure and malignancy risk in patients with endogenous Cushing’s syndrome

CONTEXT: Patients with endogenous Cushing's syndrome (CS) have increased malignancy risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for diabetes and obesity, yet their oncologic outcomes in CS remains limited. OBJECTIVE: Evaluate association between GLP-1RA exposure and incident malignancy in patients with CS. DESIGN: Nationwide cohort study using the Clalit Health Services database in Israel, including patients with endogenous CS diagnosed between 2000-2023. 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. MAIN OUTCOME: Incident malignancy following a CS diagnosis in GLP-1RA-exposed vs non-exposed patients. Sensitivity analyses included a 12-month lag-period approach and stratification by remission. RESULTS: The cohort included 609 patients with CS (mean age±SD, 48.05±17.17 years; 65.02% women). During mean follow-up of 14.7±6.4 years, 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 time-varying competing-risk analysis, GLP-1RA exposure was not associated with increased malignancy risk (hazard ratio [HR] 1.65; 95% CI, 0.94-2.90), with consistent results after adjustment (adjusted HR 1.22; 95% CI, 0.45-3.29). Findings were similar in lag-period and remission-stratified analyses. CONCLUSION: In this nationwide cohort of patients with CS, GLP-1RA exposure was not associated with altered malignancy risk. These findings provide reassuring evidence regarding the oncologic safety of GLP-1RAs in this high-risk population.