GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration (SeveX)

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sevelamer; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Steno Diabetes Center Copenhagen, Gentofte Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / 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: Renvela
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
plasma glucose	Postprandial plasma glucose (PG) excursion (AUC240 min)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Postprandial responses of Glucagon	Meal response of Glucagon	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
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
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
Postprandial responses of Ghrelin	Meal response of Ghrelin	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
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
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
Postprandial responses of Bile acids	Meal response of Bile acids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Postprandial responses of cholecystokinin (CCK)	Meal response of cholecystokinin (CCK)	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Postprandial responses of plasma lipids	Meal response of plasma lipids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
Postprandial responses of Amino acids	Meal response of Amino acids	-30 minutes to 240 minutes with ingestion of a meal at 0 minutes
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
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
Liver stiffness and fat	Liver stiffness and fat content measured by fibroscan	At initiation and after 15 days of treatment with sevelamer/placebo
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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: 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 record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2018
• Primary Completion (ACTUAL): September 3, 2020
• Study Completion (ACTUAL): September 1, 2021

Study Registration Dates

• First Submitted: October 11, 2018
• First Submitted That Met QC Criteria: November 8, 2018
• First Posted (ACTUAL): November 13, 2018

Study Record Updates

• Last Update Posted (ACTUAL): October 13, 2021
• Last Update Submitted That Met QC Criteria: October 12, 2021
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: bile acid
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Sevelamer
• Other Study ID Numbers: SeveX2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No