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

The glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39)NH2 has facilitated the description of GLP-1 physiology and the development of GLP-1 receptor agonists for the treatment of obesity and type 2 diabetes. As GLP-1 physiology continues to unfold and the mechanisms behind several therapeutic effects of GLP-1 receptor agonism remain unknown, an increased use of exendin(9-39)NH2 may be anticipated. The aim of this review is to present an overview of exendin(9-39)NH2 usage as a scientific tool in humans and to 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 GLP-1 receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH2 after intravenous administration is textasciitilde30?minutes, requiring textasciitilde2.5?hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilising 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, obesity, and patients, who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but have 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 (i.e., besides GLP-1, also peptide YY, glucagon-like peptide 2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH2 as a tool to study 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.