GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration

NCT03739268 | Completed

• 1 other identifier: SeveX2018
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this study is to investigate the potential GLP-1-mediated contribution to the well-established glucose-lowering effect of sevelamer-induced bile acid sequestration . Exendin9-39 has been demonstrated to act as a potent and specific GLP-1 receptor antagonist with no partial agonistic potential and is considered a useful tool in the assessment of GLP-1 physiology. The aim is to evaluate any contribution of sevelamer-induced GLP-1 secretion to the reduced plasma glucose concentrations observed after treatment with sevelamer. A randomised placebo-controlled cross-over study involving two 17-day treatment periods with sevelamer and placebo, respectively, in metformin-treated patients with type 2 diabetes, will be conducted. The impact of bile acid sequestration on GLP-1 secretion and effect will be examined during two randomised experimental days after 15 and 17 days of treatment with sevelamer (1,600 mg three times a day) and placebo, respectively. During each of these two experimental days, a meal test with concomitant exendin9-39 infusion or placebo will be performed (for evaluation of any GLP-1-mediated effects). Postprandial plasma glucose excursion is the primary endpoint, and secondary endpoints include postprandial plasma/serum excursions of insulin, C-peptide, GLP-1, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY (PYY), oxyntomodulin, ghrelin, fibroblast growth factor (FGF)-19, FGF-21, C4 (an intermediate in the de novo synthesis of bile acids), cholecystokinin (CCK), bile acids and plasma lipids. Furthermore, gastric emptying, gallbladder emptying, liver fat content, appetite and ad libitum food intake will be examined.

Conditions

Type 2 Diabetes Mellitus

Keywords

bile acid

Outcome Measures

Primary Outcomes (1)

• plasma glucose

  Postprandial plasma glucose (PG) excursion (AUC240 min)

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

Secondary Outcomes (17)

• Postprandial responses of glucagon-like peptide-1 (GLP-1)

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

• Postprandial responses of glucose-dependent insulinotropic polypeptide (GIP)

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

• Postprandial responses of glucagon-like peptide-2 (GLP-2)

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

• Postprandial responses of Glucagon

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

• Postprandial responses of peptide YY (PYY)

  -30 minutes to 240 minutes with ingestion of a meal at 0 minutes

Study Arms (2)

sevelamer

ACTIVE COMPARATOR

Patients with type 2 diabetes treated with sevelamer

Drug: Sevelamer

placebo

PLACEBO COMPARATOR

Patients with type 2 diabetes treated with placebo

Drug: Placebo

Interventions

Sevelamer DRUG

Sevelamer powder dissolved in water 1,600 mg three times a day for 17 days

Also known as: Renvela

sevelamer

Placebo DRUG

placebo powder dissolved in water 1,600 mg three times a day for 17 days

placebo

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO))
• Men and postmenopausal women
• Metformin applied as the only glucose-lowering drug
• Caucasian ethnicity
• Normal haemoglobin
• Age above 40 years and below 75 years
• BMI \>23 kg/m2 and \<35 kg/m2
• Informed and written consent

You may not qualify if:

• Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) \>2 times normal values) or history of hepatobiliary disorder
• Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery
• Nephropathy (serum creatinine \>150 µM and/or albuminuria)
• Hypo- or hyperthyroidism
• Hypo- or hypercalcaemia
• Hypo- or hyperphosphataemia
• Active or recent malignant disease
• Treatment with medicine that cannot be paused for 12 hours
• Treatment with oral anticoagulants
• Any treatment or condition requiring acute or sub-acute medical or surgical intervention
• Any condition considered incompatible with participation by the investigators

Sponsors & Collaborators

• Steno Diabetes Center Copenhagen: lead
• Sanofi: collaborator

Study Sites (1)

Steno Diabetes Center Copenhagen, Gentofte Hospital

Hellerup, 2900, Denmark

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Sevelamer

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Polyamines; Amines; Organic Chemicals

Study Officials

• Filip K Knop, M.D. PhD

  Steno Diabetes Center Copenhagen

  STUDY DIRECTOR

• Henriette H Nerild, M.D.

  Steno Diabetes Center Copenhagen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 11, 2018
• First Posted: November 13, 2018
• Study Start: September 1, 2018
• Primary Completion: September 3, 2020
• Study Completion: September 1, 2021
• Last Updated: October 13, 2021

Record last verified: 2020-09

Locations

DK (1)