Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions

Abstract

Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.

Keywords: Diabetes; Dual GIP/GLP-1R agonists; GLP-1R agonists–DPP-4 inhibitors; Neuroendocrine tumors; SGLT-2 inhibitors.

Fig. 1

Anti- and Pro-Tumor Mechanisms of GLP-1R Agonists, DPP-4 Inhibitors, and SGLT-2 Inhibitors. The diagram illustrates the main pathways activated or inhibited in pancreatic β cells or tumor cells following treatment with GLP-1/GIP receptor agonists (GLP-1/GIPRAs), DPP-4 inhibitors (DPP-4is), and SGLT-2 inhibitors (SGLT-2is). In the bottom left section, under 'Legend,' the symbols used in the diagram are listed. In summary, in healthy pancreatic β cells, all incretin-mimetic drugs enhance insulin secretion, mitigate glucose-induced cellular damage, inhibit apoptosis, and/or stimulate cell proliferation. GLP-1RAs deactivate GLP-1Rs, leading to the inhibition of the cAMP/PKA/ERK1/2 signaling cascade and tumor growth while promoting apoptosis by increasing levels of pro-apoptotic proteins. DPP-4is activate the CXCL12/CXCR4 pathway, which influences AMPK and mTORsignaling, potentially resulting in an increase in epithelial-mesenchymal transition (EMT). SGLT-2is reduce glucose uptake, inhibit glycolysis, and limit ATP production, thereby contributing to decreased cancer cell proliferation

Fig. 2

Flow-chart resuming the proposed algorithm for management of pre-existing and/or iatrogenic diabetes in patients affected by neuroendocrine tumors. Abbreviations: DM: diabetes mellitus, NET: neuroendocrine tumours, HbA1c: hemoglobin glycated, SSA: somatostatin analogue, RLT: radioligand therapy, ADD: antidiabetic drug, SGLT-2i: sodium-glucose cotransporter-2 inhibitor, DPP-4i: dipeptidyl peptidase-4 inhibitor

Fig. 3

Flow-chart resuming the proposed algorithm for diabetes secondary to functioning NETs. Abbreviations: DM: diabetes mellitus, NET: neuroendocrine tumours, HbA1c: hemoglobin glycated, ADD: antidiabetic drug, SGLT-2i: sodium-glucose cotransporter-2 inhibitor, DPP-4i: dipeptidyl peptidase-4 inhibitor