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

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.

The objective of this study was to evaluate the association between GLP-1RA exposure and incident malignancy in patients with CS.

This was a nationwide cohort study using the Clalit Health Services database in Israel, including patients with endogenous CS diagnosed between 2000 and 2023. Patients with adrenal carcinoma or ectopic CS were excluded. Glucagon-like peptide-1 receptor agonist exposure was defined as ≥3 prescription dispensations and modeled as a time-varying variable. The main outcome was incident malignancy following a CS diagnosis in GLP-1RA-exposed vs nonexposed patients. Sensitivity analyses included a 12-month lag-period approach and stratification by remission.

The cohort included 609 patients with CS (mean age ± SD, 48.05 ± 17.17 years; 65.02% women). During a 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 8159.69 nonexposed and 795.88 exposed person-years were accrued, with cancer incidence rates of 12.50 and 17.59 per 1000 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.

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.