title: Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.
abstract: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.
  
  
  
  A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m2; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236).
  
  
  
  Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008].
  
  
  
  Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Smits
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Lennart
authors.initials: L
authors.lastname: Tonneijck
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marcel H A
authors.initials: MH
authors.lastname: Muskiet
authors.affiliation: Department of Health Sciences and the EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, the Netherlands.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Trynke
authors.initials: T
authors.lastname: Hoekstra
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.|Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.|Wallenberg Laboratory, University of Gothenberg, Gothenberg, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.|Department of Pediatrics, Laboratory of Metabolic Diseases, University of Groningen, UMCG, Groningen, the Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Djuna L
authors.initials: DL
authors.lastname: Cahen
authors.affiliation: Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Daniël H
authors.initials: DH
authors.lastname: van Raalte
mesh_terms: D000368:Aged; D001647:Bile Acids and Salts / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D003840:Deoxycholic Acid / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005215:Fasting; D005243:Feces / Q000737:chemistry; D005260:Female; D005704:Gallbladder / Q000000981:diagnostic imaging* / Q000473:pathology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000069450:Liraglutide / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009929:Organ Size; D019518:Postprandial Period; D000068900:Sitagliptin Phosphate / Q000627:therapeutic use*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D014463:Ultrasonography; D014580:Ursodeoxycholic Acid / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D002635:Chenodeoxycholic Acid; D019826:Cholic Acid; D003840:Deoxycholic Acid; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D008687:Metformin; D000068900:Sitagliptin Phosphate; D013453:Sulfonylurea Compounds; D014580:Ursodeoxycholic Acid; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C517652:hemoglobin A1c protein, human
keywords: DPP-4; GLP-1; bile acids; dipeptidyl peptidase 4; gallbladder emptying; gastric emptying; glucagon-like peptide 1