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

BACKGROUND

A high proportion of patients with pheochromocytomas and paragangliomas (PPGLs) show glycemic dysregulation. However, studies on the effects of anti-diabetic drugs on PPGL tumor growth are still lacking.

METHODS

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).

RESULTS

We found cluster-dependent effects of semaglutide in patient primary cultures, with significant anti-tumor effects in cluster 1 PPGLs. Interestingly, we found tumor-promoting effects of high-dose semaglutide in 3 PPGLs with germline RET PVs (MEN2 syndrome), but not in a PPGL with a somatic RET PV. Metformin displayed overall anti-tumor effects while insulin showed individual tumor-promoting effects in the patient primary cultures. Consistently, clinical data confirmed larger median tumor sizes of PPGL patients receiving insulin therapy compared to patients receiving metformin/GLP-1RA therapy or patients without anti-diabetic therapy.

CONCLUSION

Overall, we provide novel data on the effects of anti-diabetic drugs on PPGL tumor growth including significant anti-tumor 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.