Effects of a GLP-1 agonist and antidiabetic therapies on pheochromocytoma/paraganglioma growth.

Abstract

A high proportion of patients with pheochromocytomas and paragangliomas (PPGLs) show glycemic dysregulation. However, studies on the effects of antidiabetic drugs on PPGL tumor growth are still lacking. We evaluated the effects of glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide, metformin, and insulin on fresh patient-derived PPGL primary cultures (n = 54), including 8 cluster 1 tumors and 18 cluster 2/3 tumors (n = 4 tumors with RET pathogenic variants (PVs)). We correlated the primary culture data with clinical data from 67 patients enrolled in the prospective clinical trial PROSPHEO (NCT03344016). We found cluster-dependent effects of semaglutide in patient primary cultures, with significant antitumor effects in cluster 1 PPGLs. Interestingly, we found tumor-promoting effects of high-dose semaglutide in three PPGLs with germline RET PVs (MEN2 syndrome), but not in a PPGL with a somatic RET PV. Metformin displayed overall antitumor effects, whereas insulin showed individual tumor-promoting effects in the patient primary cultures. Consistently, clinical data confirmed larger median tumor sizes in PPGL patients receiving insulin therapy compared with those receiving metformin/GLP-1RA therapy or those without antidiabetic therapy. Overall, we provide novel data on the effects of antidiabetic drugs on PPGL tumor growth, including significant antitumor effects of the GLP-1RA semaglutide in cluster 1 PPGLs and tumor-promoting effects in patients with MEN2 syndrome. Further confirmation of our data in prospective clinical studies is required.