UNASSIGNED: Recently, the European Medicines Agency (EMA) received reports of suicidal thoughts and self-injury associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide.
UNASSIGNED: Herein, we sought to evaluate suicidality associated with all GLP-1 RAs relative to other glucose-lowering agents currently approved by the United States Food and Drug Administration (FDA). Reports of suicidal ideation, \"depression/suicidal\", suicidal behavior, suicidal attempts, and completed suicide associated with GLP-1 RA exposure reported to the FDA between 2005 and October 2023 were obtained from the FDA Adverse Event Reporting System (FAERS). We present data using the reporting odds ratio (ROR). The ROR was considered significant when the lower limit of the 95% confidence interval (CI) was greater than 1.0.
UNASSIGNED: Disproportionate reporting of suicidal ideation and \"depression/suicidal\" was observed with semaglutide and liraglutide. Disproportionate reporting of suicidal behavior, suicide attempts, and completed suicide was not observed for any of the FDA-approved GLP-1 RAs.
UNASSIGNED: Using the Bradford Hill criteria, however, and taking into consideration confounders, no causal link between GLP-1 RAs and suicidality exists.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) are the newest treatment for diabetes mellitus (DM). These drugs can down-regulate fasting glucose more than oral drugs and lead to more constant glucose levels compared to regular insulin. Acute pancreatitis is a serious condition that may have a fatal outcome. It has been shown that long term and high doses of GLP-1RA can cause pancreatic changes in animals, but no connection has been proven in humans. We present the case of a 67 years old man with DM treated with oral drugs for 10 years until 3 months before, when GLP-1RA was added. He presented progressive abdominal pain, vomiting, and increased level of serum lipase and amylase were found. Ultrasonography and computed tomography found pancreatic and peripancreatic fatty tissue inflammation (inflammation score 2, necrosis score 0). All the etiologies of acute pancreatitis (lithiasis, alcohol, autoimmune, or trauma) were excluded. After GLP-1RA cessation and supportive treatment the evolution was self-limited with full recovery within 5 days. We concluded that acute pancreatitis can be considered a side effect of the GLP-1 treatment.

The experimental protocol of the perfused rat pancreas is commonly used to evaluate β-cell function. In this context, mathematical models become useful tools through the determination of indexes that allow the assessment of β-cell function in different experimental groups and the quantification of the effects of antidiabetic drugs, secretagogues, or treatments. However, a minimal model applicable to the isolated perfused rat pancreas has so far been unavailable. In this work, we adapt the C-peptide minimal model applied previously to the intravenous glucose tolerance test to obtain a specific model for the experimental settings of the perfused pancreas. Using the model, it is possible to estimate indexes describing β-cell responsivity for first (ΦD) and second phase (ΦS, T) of insulin secretion. The model was initially applied to untreated pancreata and afterward used for the assessment of pharmacologically relevant agents (the gut hormone GLP-1, the potent GLP-1 receptor agonist lixisenatide, and a GPR40/FFAR1 agonist, SAR1) to quantify and differentiate their effect on insulin secretion. Model fit was satisfactory, and parameters were estimated with good precision for both untreated and treated pancreata. Model application showed that lixisenatide reaches improvement of β-cell function similarly to GLP-1 (11.7- vs. 13.1-fold increase in ΦD and 2.3- vs. 2.8-fold increase in ΦS) and demonstrated that SAR1 leads to an additional improvement of β-cell function in the presence of postprandial GLP-1 levels.