Clinical trial NCT03739268: GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration
Official title: GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Keywords: bile acid
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Sanofi
First posted: 2018-11-13
Enrollment: 17
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: plasma glucose
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary outcomes:
measure: Postprandial responses of glucagon-like peptide-1 (GLP-1)
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of glucose-dependent insulinotropic polypeptide (GIP)
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of glucagon-like peptide-2 (GLP-2)
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of Glucagon
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of peptide YY (PYY)
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of Insulin and c-peptide
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of Ghrelin
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of fibroblast growth factor (FGF)-19
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of fibroblast growth factor (FGF)-21
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of Bile acids
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of cholecystokinin (CCK)
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of plasma lipids
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Postprandial responses of Amino acids
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Gastric emptying
timeFrame: -30 minutes to 240 minutes with ingestion of a meal and paracetamol at 0 minutes
measure: Rate of gall bladder emptying
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
measure: Liver stiffness and fat
timeFrame: At initiation and after 15 days of treatment with sevelamer/placebo
measure: Appetite measured by visual analog scale
timeFrame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Steno Diabetes Center Copenhagen, Gentofte Hospital
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Filip K Knop, M.D. PhD
role: STUDY_DIRECTOR
affiliation: Steno Diabetes Center Copenhagen
name: Henriette H Nerild, M.D.
role: PRINCIPAL_INVESTIGATOR
References: