ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study examined glycemic control following treatment with once-weekly exenatide 2 mg (Bydureon, AstraZeneca) in youth with T2D which was not optimally controlled. At 24 weeks, exenatide was superior to placebo in lowering HbA1c (least squares mean change, −0.36% with exenatide vs. +0.49% with placebo), with a between-group difference of −0.85%.

Comment: The story of the development of exenatide is fascinating. It starts with a venomous lizard named the Gila monster (Heloderma suspectum), native to New Mexico and Arizona. H. suspectum, a long-lived and reclusive species, spends a significant portion of its life underground. Its venomous bite causes pain and weakness, but is rarely fatal to adult humans.

The discovery of exendin-4 dates back to 1992, when endocrinologist Dr. John Eng, uncovered this peptide while using chemical assays to identify new hormones. Analysing the venom, she identified a peptide named exendin, which triggers the synthesis and release of insulin from beta cells in the pancreas. Dr. Eng, discovered that exendin-4 closely resembled GLP-1, a hormone that stimulates insulin production in the pancreas, when glucose levels are high. However, while GLP-1 remains active for about two minutes, the prolonged effect of exendin-4 lasts several hours. Preclinical studies revealed that in diabetic mice, a single daily injection of exendin-4 normalized blood glucose concentrations. Furthermore, the effects of exendin-4 lasted for several hours. Following extensive clinical testing, exendin-4 was deemed safe and effective, and received FDA approval in 2005. Exenatide is believed to facilitate glucose control in at least five ways. It increases insulin secretion in response to eating meals; suppresses pancreatic release of glucagon in response to eating, helps slow down gastric emptying, and thus decreases the rate at which meal-derived glucose appears in the bloodstream. Exenatide has a subtle yet prolonged effect on reducing appetite, and promotes satiety via hypothalamic receptors.

In the current study, a mean decrease in HbA1c of 0.36% in the once-weekly exenatide group was demonstrated after 24 weeks, compared with a 0.49% increase in the placebo group (a between-group difference of −0.85%). There were no events of major hypoglycaemia, and the most frequently reported adverse events were gastrointestinal (nausea, diarrhoea, vomiting) and injection site reactions (pruritus, erythema, nodules). Across the trial groups, clinically relevant differences were not observed in changes from baseline, for the exploratory weight variables of the BMI Z-score, body weight or waist circumference.

Of note, spontaneous cases of acute pancreatitis have been reported among adults on prolonged-release exenatide. Also, a 2-year rat carcinogenicity study found that prolonged-release exenatide (at doses ≥2-fold the human systemic exposure) increased incidences of adenomas and C-cell carcinomas. The clinical relevance of these adverse findings is unknown. Nevertheless, individuals with a personal or family history of medullary thyroid carcinoma should not use the therapy.

The prolonged-release suspension for exenatide injection in a pre-filled pen has been approved both by the European Union and the FDA for the treatment of T2DM in children and adolescents aged 10 years and older.