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

Type 2 Diabetes Mellitus Clinical Trial

— SeveX  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03739268
• Other study ID #: SeveX2018
• Status: Completed
• Phase: N/A
• Start date: September 1, 2018
• Est. completion date: September 1, 2021

Study information

• Verified date: September 2020
• Source: Steno Diabetes Center Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: September 1, 2021
• Est. primary completion date: September 3, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Sevelamer
Sevelamer powder dissolved in water 1,600 mg three times a day for 17 days
• Placebo
placebo powder dissolved in water 1,600 mg three times a day for 17 days

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center Copenhagen, Gentofte Hospital	Hellerup

Sponsors (2)

Lead Sponsor	Collaborator
Steno Diabetes Center Copenhagen	Sanofi

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	plasma glucose	Postprandial plasma glucose (PG) excursion (AUC240 min)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of glucagon-like peptide-1 (GLP-1)	Meal response of GLP-1	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of glucose-dependent insulinotropic polypeptide (GIP)	Meal response of glucose-dependent insulinotropic polypeptide (GIP)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of glucagon-like peptide-2 (GLP-2)	Meal response of glucagon-like peptide-2 (GLP-2)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of Glucagon	Meal response of Glucagon	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of peptide YY (PYY)	Meal response of peptide YY (PYY)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of Insulin and c-peptide	Meal response of Insulin and c-peptide as a insulin/c-peptide ratio	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of Ghrelin	Meal response of Ghrelin	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of fibroblast growth factor (FGF)-19	Meal response of fibroblast growth factor (FGF)-19	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of fibroblast growth factor (FGF)-21	Meal response of fibroblast growth factor (FGF)-21	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of Bile acids	Meal response of Bile acids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of cholecystokinin (CCK)	Meal response of cholecystokinin (CCK)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of plasma lipids	Meal response of plasma lipids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Postprandial responses of Amino acids	Meal response of Amino acids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Gastric emptying	Gastric emptying measured by paracetamol absorption test. Paracetamol is ingested along with meal, the appearance in blood will be calculated as a measure of gastric emptying.	-30 minutes to 240 minutes with ingestion of a meal and paracetamol at 0 minutes
Secondary	Rate of gall bladder emptying	Gall bladder volumen measured by ultrasound over time after a meal (see time frame below). The rate of gall bladder emptying will be calculated	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Secondary	Liver stiffness and fat	Liver stiffness and fat content measured by fibroscan	At initiation and after 15 days of treatment with sevelamer/placebo
Secondary	Appetite measured by visual analog scale	We assessed appetite parameters (hunger, satiety, fullness, prospective food consumption) and well-being, nausea, and thirst by visual analogue scales. Overall appetite score (OAS) will be calculated as (satiety + fullness + (100 - hunger) + (100 - prospective food consumption)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes