Exendin(9-39)NH2 - recommendations for clinical use based on a systematic literature review

AIM: To present an overview of exendin(9-39)NH2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes.

METHODS: We systematically searched the literature on exendin(9-39)NH2 and included for review 44 clinical studies reporting use of exendin(9-39)NH2 in humans.

RESULTS: Exendin(9-39)NH2 binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH2 after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9-39)NH2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH2 induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH2 as a tool to study the isolated effect of GLP-1.

CONCLUSIONS: Exendin(9-39)NH2 is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH2 to GLP-1 of 2000:1. Highlights Exendin(9-39)NH2 is a competitive antagonist of the human GLP-1 receptor. Exendin(9-39)NH2 has been used as a tool to delineate human GLP-1 physiology since 1998. Exendin(9-39)NH2 induces secretion of GLP-1 and other L cell products. Reported effects of exendin(9-39)NH2 on insulin levels and food intake are inconsistent. Here, we provide recommendations for the use of exendin(9-39)NH2 in clinical studies.