Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been in use for twenty years. There have been concerns about their safety in patients with neuroendocrine neoplasms (NENs). The reports of GLP-1 receptor (GLP-1R)-driven proliferation of C-cell neoplasms in rodent studies had led to the black-box warning against their use in patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2). In this review, we have attempted to evaluate the physiological and pathological expression of GLP-1 receptors (GLP-1R) in various endocrine organs and summarise the preclinical and clinical evidence regarding the effect of GLP-1RA exposure and risk of NENs. GLP-1R expression has not only been found in nonneoplastic tissues such as neurohypophysis, duodenal glands and pancreatic islets but also in neuroendocrine tumours (NETs). Preclinical studies have demonstrated the proliferative effects of GLP-1RA in cell lines representing pancreatic NETs (panNETs) and small intestinal NETs. The available data from retrospective studies, randomized trials and cancer registries provide conflicting data and does not support a generalized increase in NENs with the use of GLP-1RA. Some epidemiological studies have even shown survival benefits associated with GLP-1RA use. In addition, significant gaps in evidence remain, such as lack of data regarding certain tumour subtypes, long-term prospective studies with NENs as the clinical endpoint and uncertainty regarding patients with multiple endocrine neoplasia type 1 (MEN1). Hence, the initiation of GLP-1RA therapy in patient with predisposition to NEN where a contraindication does not exist, should be approached cautiously with careful monitoring for long-term adverse effects.