TY - JOUR

T1 - Exendin(9-39)NH2

T2 - Recommendations for clinical use based on a systematic literature review

AU - Gasbjerg, Lærke Smidt

AU - Bari, Emilie Johanning

AU - Christensen, Mikkel

AU - Knop, Filip Krag

PY - 2021

Y1 - 2021

N2 - BackgroundThe 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.MethodsWe 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.ResultsExendin(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 ~30 minutes, requiring ~2.5 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.ConclusionsExendin(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.

AB - BackgroundThe 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.MethodsWe 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.ResultsExendin(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 ~30 minutes, requiring ~2.5 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.ConclusionsExendin(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.

U2 - 10.1111/dom.14507

DO - 10.1111/dom.14507

M3 - Journal article

C2 - 34351033

VL - 23

SP - 2419

EP - 2436

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 11

ER -