SeveX: GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: sevelamer Patients with type 2 diabetes treated with sevelamer |
Drug: Sevelamer
Sevelamer powder dissolved in water 1,600 mg three times a day for 17 days
Other Names:
|
| Placebo Comparator: placebo Patients with type 2 diabetes treated with placebo |
Drug: Placebo
placebo powder dissolved in water 1,600 mg three times a day for 17 days
|
Outcome Measures
Primary Outcome Measures
- plasma glucose [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Postprandial plasma glucose (PG) excursion (AUC240 min)
Secondary Outcome Measures
- Postprandial responses of glucagon-like peptide-1 (GLP-1) [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of GLP-1
- Postprandial responses of glucose-dependent insulinotropic polypeptide (GIP) [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of glucose-dependent insulinotropic polypeptide (GIP)
- Postprandial responses of glucagon-like peptide-2 (GLP-2) [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of glucagon-like peptide-2 (GLP-2)
- Postprandial responses of Glucagon [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of Glucagon
- Postprandial responses of peptide YY (PYY) [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of peptide YY (PYY)
- Postprandial responses of Insulin and c-peptide [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of Insulin and c-peptide as a insulin/c-peptide ratio
- Postprandial responses of Ghrelin [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of Ghrelin
- Postprandial responses of fibroblast growth factor (FGF)-19 [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of fibroblast growth factor (FGF)-19
- Postprandial responses of fibroblast growth factor (FGF)-21 [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of fibroblast growth factor (FGF)-21
- Postprandial responses of Bile acids [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of Bile acids
- Postprandial responses of cholecystokinin (CCK) [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of cholecystokinin (CCK)
- Postprandial responses of plasma lipids [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of plasma lipids
- Postprandial responses of Amino acids [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Meal response of Amino acids
- Gastric emptying [-30 minutes to 240 minutes with ingestion of a meal and paracetamol at 0 minutes]
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.
- Rate of gall bladder emptying [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
Gall bladder volumen measured by ultrasound over time after a meal (see time frame below). The rate of gall bladder emptying will be calculated
- Liver stiffness and fat [At initiation and after 15 days of treatment with sevelamer/placebo]
Liver stiffness and fat content measured by fibroscan
- Appetite measured by visual analog scale [-30 minutes to 240 minutes with ingestion of a meal at 0 minutes]
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)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO))
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Men and postmenopausal women
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Metformin applied as the only glucose-lowering drug
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Caucasian ethnicity
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Normal haemoglobin
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Age above 40 years and below 75 years
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BMI >23 kg/m2 and <35 kg/m2
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Informed and written consent
Exclusion Criteria:
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Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary disorder
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Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery
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Nephropathy (serum creatinine >150 µM and/or albuminuria)
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Hypo- or hyperthyroidism
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Hypo- or hypercalcaemia
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Hypo- or hyperphosphataemia
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Active or recent malignant disease
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Treatment with medicine that cannot be paused for 12 hours
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Treatment with oral anticoagulants
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Any treatment or condition requiring acute or sub-acute medical or surgical intervention
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Any condition considered incompatible with participation by the investigators
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Steno Diabetes Center Copenhagen, Gentofte Hospital | Hellerup | Denmark | 2900 |
Sponsors and Collaborators
- Steno Diabetes Center Copenhagen
- Sanofi
Investigators
- Study Director: Filip K Knop, M.D. PhD, Steno Diabetes Center Copenhagen
- Principal Investigator: Henriette H Nerild, M.D., Steno Diabetes Center Copenhagen
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SeveX2018