Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs

Abstract

Objective: Recent randomized and controlled trials of drugs derived from the gut hormone glucagon-like peptide-1 (GLP-1) show that the most frequent adverse symptoms are gastrointestinal, including gallbladder-related side effects such as cholithiasis and cholecystitis. Since the gut hormone cholecystokinin (CCK) stimulates bile secretion and regulates gallbladder motility and emptying, we examined the effect of GLP-1 on the secretion of CCK in normal subjects and patients with type 1 diabetes mellitus.

Materials and methods: Plasma was sampled from 10 healthy subjects and 10 patients with diabetes. With plasma glucose concentrations clamped between 6 and 9 nmol/l, GLP-1 or saline was infused for 240 min during and after a meal. The plasma concentrations of CCK were measured with a highly specific radioimmunoassay.

Results: Basal plasma concentrations of CCK were similar in the normal subjects and in the diabetes patients. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the diabetes patients.

Conclusions: The results show that GLP-1 suppresses the secretion of CCK after a meal in normal and diabetic subjects. The suppression attenuates the gallbladder contractility. Our data, therefore, offer an explanation for the increased risk of adverse gallbladder events during treatment with GLP-1-derived drugs.

Keywords:

• Cholecystokinin
• cholecystitis
• cholelithiasis
• diabetes mellitus
• glucagon-like peptide 1
• side effects

Acknowledgements

The skillful and patient secretarial assistance of Connie Bundgaard, and the skillful technical assistance of Alice von der Lieth are gratefully acknowledged.

Disclosure statement

F. K. K. has served on advisory panels and as consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gubra, MSD/Merck, Novo Nordisk, Sanofi, and Zealand Pharma. S. M. has served on advisory boards and/or received lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi Aventis. He has also received research support from Novo Nordisk and Boehringer Ingelheim.

Additional information

Funding

This study was supported by the Danish Biotechnology Center for Cellular Communication.