Impaired Fasting Glucose, Prediabetes
Conditions
Keywords
Impaired Fasting Glucose, PreDiabetes
Brief summary
The objective of this study is to determine the effect of 8 weeks of treatment with colesevelam HCl 3.75 g once daily with the evening meal on ß-cell function by evaluating the acute insulin response (AIRg) to an intravenous glucose load in subjects with prediabetes (impaired fasting glucose).
Detailed description
Colesevelam is a bile acid sequestrant that was initially approved for treatment of patients with dyslipidemia. Subsequently it was observed that patients with type 2 diabetes receiving this medication had improved glucose control. However, the mechanism(s) by which it lowers glucose concentrations has not been determined. Glucose metabolism is enhanced following oral nutrient ingestion by the action of the incretin hormones. The two major incretin hormones are the peptides glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are released from the intestinal tract wall in response to a meal. Of these two peptides, GLP-1 appears to be more important in regulating glucose metabolism. In the presence of elevated plasma glucose, GLP-1 promotes insulin release from the ß-cells of the pancreas. GLP-1 also suppresses glucagon release, and thereby inhibits hepatic glucose output. Administration of GLP-1 by infusion or by subcutaneous injection has been shown to improve glucose tolerance in type 2 diabetic patients. The purpose of this study is therefore to determine in a cohort of individuals with prediabetes, who have an elevated fasting plasma glucose and are at increased risk of developing type 2 diabetes, whether the glucose lowering properties of colesevelam occur by it improving insulin sensitivity, islet ß-cell function or both. Further, by assessing the effect of colesevelam on incretin hormone release, it will be possible to determine whether any improvement in islet ß-cell function is due to enhanced incretin stimulation.
Interventions
DRUGColesevelam
colesevelam HCl 3.75 g once daily orally with the evening meal
OTHERplacebo
tablet (s) orally given with evening meal
Sponsors
VA Puget Sound Health Care System
Seattle Institute for Biomedical and Clinical Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Males or females (postmenopausal, surgically sterile or using double-barrier method of contraception), aged 18-75 years, FPG 100-115 mg/dl at screening (average of 2 measurements during screening; no individual measurement outside of the range 92-125 mg/dl) * In good health as determined by past medical history, physical examination, electrocardiogram, laboratory tests and urinalysis * HbA1c \<6.5% at screening * Body mass index (BMI) in the range of 22-40 kg/m2 inclusive and with a stable (+/-2.5 kg) weight for the last 6 months * Subjects must be willing to: * Maintain prior exercise and dietary habits throughout the study * Comply with all study requirements * Provide written informed consent
Exclusion criteria
* Pregnant or lactating females * Patients diagnosed with type 2 diabetes or that have taken glucose-lowering agents or insulin, except during pregnancy * Chronic oral or parenteral corticosteroid treatment (\>7 consecutive days of treatment) within 8 weeks prior to screening * HIV protease inhibitors * Warfarin or phenytoin use * Triglycerides \>500 mg/dl * History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection * History of dysphagia, swallowing disorders or intestinal motility disorder * History of pancreatitis * Uncontrolled hypothyroidism * Individuals with clinical hepatic disease or liver function tests greater than ≥2 times upper limits of normal within 30 days preceding the first dose of study drug * On a weight loss program with ongoing weight loss, or starting an intensive exercise program within 4 weeks of study initiation * Current or prior (within the past 3 months) treatment with a bile acid sequestrant (colesevelam, colestipol, colestimide, or cholestyramine) * Use of any investigational drug in the last 30 days * Donation of one unit (500 ml) or more of blood, significant blood loss equaling at least one unit of blood within the past 2 weeks or a blood transfusion within 8 weeks prior to screening * Employment by the research center
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Insulin Response (AIRg) to Intravenous Glucose | Baseline and 8 weeks | Increase in insulin following glucose injection. AIRg is measured as the magnitude of the insulin response to an intravenous glucose injection calculated over the 10 minutes following glucose administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | Baseline and 8 weeks | Tissue response to circulating insulin in the blood. Insulin sensitivity is measured using a mathematical model that quantifies the fractional rate of change in glucose concentrations per unit of insulin. Low values are insulin resistant and high values are insulin sensitive. \*Please note: the -1 in the Unit of Measure should be a superscripted value. |
| Glucose Disappearance Rate | Baseline and 8 weeks | Rate of fall of glucose in the blood |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam Hydrochloride People with IGT will take 2 weeks of placebo and then 8 weeks of study drug | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Colesevelam Hydrochloride |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age Continuous | 60.7 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 21 |
| serious Total, serious adverse events | 1 / 21 |
Outcome results
Primary
Acute Insulin Response (AIRg) to Intravenous Glucose
Increase in insulin following glucose injection. AIRg is measured as the magnitude of the insulin response to an intravenous glucose injection calculated over the 10 minutes following glucose administration.
Time frame: Baseline and 8 weeks
Population: Subjects who completed the study
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Colesevelam | Acute Insulin Response (AIRg) to Intravenous Glucose | 8 Weeks | 1866 pmol/1*min |
| Colesevelam | Acute Insulin Response (AIRg) to Intravenous Glucose | Baseline | 1752 pmol/1*min |
Secondary
Glucose Disappearance Rate
Rate of fall of glucose in the blood
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Glucose Disappearance Rate | 8 weeks | 1.32 percentage of glucose/min | Standard Error 0.1 |
| Colesevelam | Glucose Disappearance Rate | Baseline | 1.26 percentage of glucose/min | Standard Error 0.08 |
Secondary
Insulin Sensitivity
Tissue response to circulating insulin in the blood. Insulin sensitivity is measured using a mathematical model that quantifies the fractional rate of change in glucose concentrations per unit of insulin. Low values are insulin resistant and high values are insulin sensitive. \*Please note: the -1 in the Unit of Measure should be a superscripted value.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Insulin Sensitivity | 8 weeks | 4.6 min-1 per pmol/L | Standard Error 0.6 |
| Colesevelam | Insulin Sensitivity | Baseline | 4.8 min-1 per pmol/L | Standard Error 0.5 |