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

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been in use for 20 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 or multiple endocrine neoplasia type 2. In this review, we have attempted to evaluate the physiological and pathological expression of GLP-1Rs in various endocrine organs and summarize the preclinical and clinical evidence regarding the effect of GLP-1RA exposure and risk of NENs. Glucagon-like peptide-1 receptor expression has not only been found in non-neoplastic tissues such as neurohypophysis, duodenal glands and pancreatic islets, but also in neuroendocrine tumors (NETs). Preclinical studies have demonstrated the proliferative effects of GLP-1RA in cell lines representing pancreatic NETs and small intestinal NETs. The available data from retrospective studies, randomized trials and cancer registries provide conflicting data and do 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 tumor subtypes, long-term prospective studies with NENs as the clinical endpoint and uncertainty regarding patients with multiple endocrine neoplasia type 1. Hence, the initiation of GLP-1RA therapy in patient with predisposition to NENs where a contraindication does not exist, should be approached cautiously with careful monitoring for long-term adverse effects.