Type 2 Diabetes
Conditions
Keywords
Incretins, colesevelam, hepatobiliary circulation
Brief summary
The goal of this study was to determine the metabolic mechanism for a certain type medication's ability to lower blood sugar after a meal in Type 2 Diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.
Detailed description
Welchol (colesevelam hydrochloride) is a bile acid sequestrant (BAS) recently approved by the FDA for glucose lowering in patients with type 2 diabetes mellitus. Four randomized, controlled clinical studies in subjects with type 2 diabetes have demonstrated significant treatment difference in HbA1c (-0.5%). Study durations ranged from 12-26 weeks of therapy. In diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by reduction in A1c was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. Reductions in both fasting plasma glucose and postprandial concentrations have been demonstrated. Simple measures of insulin secretion and action have suggested that this is due to improved insulin action rather than improved insulin secretion. The mechanism by which bile acids interact with the key pathways regulating glucose concentrations is largely unknown. The investigators propose a randomized, double-blind, placebo controlled trial with a parallel-group design where subjects are randomized to receive colesevelam or matching placebo for a 12 week treatment period. A labeled mixed meal before and after treatment will be used to measure intestinal transit, postprandial and fasting glucose fluxes, insulin secretion and action as well as enteroendocrine secretion.
Interventions
DRUGColesevelam
Colesevelam hydrochloride; three 625mg tablets taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.
OTHERPlacebo
Three placebo tablets matching the active drug colesevelam in appearance, taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.
BEHAVIORALDiet
Subjects were instructed to follow a weight maintenance diet (\ 55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.
DRUGMetformin
Subjects continued to take their pre-study therapeutic doses of metformin (Metformin 500mg tablets taken by mouth twice daily for a total daily dose of 1000 to 2000 mg) through the 12 week study period.
Sponsors
Daiichi Sankyo
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 35-70 years old. * Body Mass Index greater than 19kg/m\^2 or less than 40kg/m\^2 or a total weight less than 130 kilograms. * Negative pregnancy test for women of childbearing potential. * Absence of gastrointestinal symptoms. * Signed informed consent. * Treatment with diet and/or metformin. Subjects must be on stable therapeutic doses of metformin and/or lipid-lowering agents for more than 3 months.
Exclusion criteria
* Structural or metabolic diseases/conditions that affect the gastrointestinal system, or functional gastrointestinal disorders. A screening Bowel Disease Questionnaire will be used to exclude subjects with irritable bowel syndrome. Patients with a history of dysphagia or intestinal motility disorders will be excluded. * Prior history of pancreatitis. * Prior history of hypertriglyceridemia (500mg/dL or greater). * Currently using a bile-acid binding resin such as colesevelam, colestipol, colestimide or cholestyramine. * To ensure homogeneity between treatment groups we will exclude subjects with insulin-treated type 2 diabetes mellitus, subjects who have received an inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors) or gliptins (a class of oral hypoglycemics), Byetta or sulfonylurea agent in the past three months. * HbA1c greater than 9.0%. * Patients who have not been stable on all medications for a period exceeding 3 months. * Use of drugs or agents within the past 2 weeks or planned use in the subsequent 4 weeks during the study period that: * Alter GI transit including laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants, Selective Serotonin Reuptake Inhibitors (SSRIs) and newer antidepressants. * Opiate-based analgesic drugs (Note: intermittent or chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAID) will be allowed). * Antihistamines * Anticholinergic agents * Female subjects who are pregnant or breast-feeding. Females must be either surgically sterilized, postmenopausal (\>12 months since last menses), or, if of childbearing potential, using reliable methods of contraception as determined by the physician. * Clinical evidence (including physical exam and Electrocardiogram) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study. Any candidate participants with such disorders mentioned will be referred to their general physician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Disposition Index | Baseline, 12 weeks | Total Disposition Index (DI) is a calculated value which represents the ability of a person's pancreas to lower blood glucose. A higher number means the pancreas is better able to lower blood glucose and a lower number means the pancreas is less able to lower blood glucose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose Concentration | Baseline, 12 Weeks | Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method. |
| Glycosylated Hemoglobin (HbA1c) | Baseline, 12 weeks | HbA1c is the percent of red blood cell hemoglobin with glucose attached to it and an indicator of average blood glucose over the previous two to three months. |
| Insulin Concentration | Baseline, 12 Weeks | Fasting insulin levels were measured in the plasma using a chemiluminescence assay and is reported in nanomoles over 6 hours. |
| Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration | Baseline, 12 weeks | GLP-1 is thought to increase insulin secretion and was measured in the blood and reported in picomoles per liter. |
| Rate of Meal Glucose Appearance (Meal Ra) | Baseline, 12 Weeks | Meal Ra was measured using a triple-tracer mixed meal and reported in micromols in 6 hours. Meal derived glucose is a function of both gastric emptying and splanchnic meal extraction. Meal Ra was calculated by multiplying rate of appearance of \[1-\^13C\] glucose (obtained from the infusion rate of \[6-\^3H\] glucose and the clamped plasma ratio of \[6-\^3H\] glucose and \[1-\^13C\] glucose) by the meal enrichment. |
| Rate of Meal Glucose Disappearance (Meal Rd) | Baseline, 12 Weeks | Meal Rd is the rate at which glucose leaves the systemic circulation. It was measured using a triple-tracer mixed meal and reported in micromols over 6 hours. Meal Rd was calculated by subtracting the change in glucose mass from the overall rate of glucose appearance (i.e., meal Ra + EGP). |
| Lipid Values | Baseline, 12 weeks | Lipids are fat-like substances in the blood. |
| Fasting Endogenous Glucose Production (EGP) | Baseline, 12 Weeks | EGP was measured using a triple-tracer mixed meal and calculated using the Steele's model, reported in micromoles per kilogram per minute. |
Countries
United States
Participant flow
Recruitment details
Participants with type 2 diabetes on monotherapy with Metformin were recruited by advertisement from 2009 to 2010 at Mayo Clinic in Rochester, Minnesota.
Pre-assignment details
39 subjects provided written informed consent to participate. One subject lost intravenous access during the baseline study and withdrew consent. The remaining 38 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam Treatment with colesevelam in addition to metformin and diet | 19 |
| Placebo Placebo plus diet and metformin | 19 |
| Total | 38 |
Baseline characteristics
| Characteristic | Colesevelam | Placebo | Total |
|---|---|---|---|
| Age Continuous | 62.6 years STANDARD_DEVIATION 5.9 | 60.2 years STANDARD_DEVIATION 6.3 | 61 years STANDARD_DEVIATION 6.1 |
| Body Mass Index | 30.8 kg/m^2 STANDARD_DEVIATION 4.3 | 30.4 kg/m^2 STANDARD_DEVIATION 4 | 30.6 kg/m^2 STANDARD_DEVIATION 4.1 |
| Region of Enrollment United States | 19 participants | 19 participants | 38 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 19 | 0 / 19 |
| serious Total, serious adverse events | 1 / 19 | 0 / 19 |
Outcome results
Primary
Total Disposition Index
Total Disposition Index (DI) is a calculated value which represents the ability of a person's pancreas to lower blood glucose. A higher number means the pancreas is better able to lower blood glucose and a lower number means the pancreas is less able to lower blood glucose.
Time frame: Baseline, 12 weeks
Population: Intent to treat analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Total Disposition Index | Disposition Index at Baseline | 332 DItot (10^-14 dl/kg/min^2 per pmol/l) | Standard Error 41 |
| Colesevelam | Total Disposition Index | Disposition Index at 12 Weeks | 519 DItot (10^-14 dl/kg/min^2 per pmol/l) | Standard Error 169 |
| Placebo | Total Disposition Index | Disposition Index at Baseline | 253 DItot (10^-14 dl/kg/min^2 per pmol/l) | Standard Error 40 |
| Placebo | Total Disposition Index | Disposition Index at 12 Weeks | 310 DItot (10^-14 dl/kg/min^2 per pmol/l) | Standard Error 48 |
Secondary
Fasting Endogenous Glucose Production (EGP)
EGP was measured using a triple-tracer mixed meal and calculated using the Steele's model, reported in micromoles per kilogram per minute.
Time frame: Baseline, 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Fasting Endogenous Glucose Production (EGP) | EGP at 12 Weeks | 17.2 micromol/kg/min | Standard Error 0.6 |
| Colesevelam | Fasting Endogenous Glucose Production (EGP) | EGP at Baseline | 17.6 micromol/kg/min | Standard Error 0.6 |
| Placebo | Fasting Endogenous Glucose Production (EGP) | EGP at Baseline | 17.7 micromol/kg/min | Standard Error 0.7 |
| Placebo | Fasting Endogenous Glucose Production (EGP) | EGP at 12 Weeks | 17.6 micromol/kg/min | Standard Error 0.7 |
Secondary
Glycosylated Hemoglobin (HbA1c)
HbA1c is the percent of red blood cell hemoglobin with glucose attached to it and an indicator of average blood glucose over the previous two to three months.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Glycosylated Hemoglobin (HbA1c) | HbA1c at Baseline | 6.7 Percentage of hemoglobin | Standard Error 0.1 |
| Colesevelam | Glycosylated Hemoglobin (HbA1c) | HbA1c at 12 Weeks | 6.5 Percentage of hemoglobin | Standard Error 0.2 |
| Placebo | Glycosylated Hemoglobin (HbA1c) | HbA1c at Baseline | 6.8 Percentage of hemoglobin | Standard Error 0.1 |
| Placebo | Glycosylated Hemoglobin (HbA1c) | HbA1c at 12 Weeks | 6.9 Percentage of hemoglobin | Standard Error 0.2 |
Secondary
Insulin Concentration
Fasting insulin levels were measured in the plasma using a chemiluminescence assay and is reported in nanomoles over 6 hours.
Time frame: Baseline, 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Insulin Concentration | Postmeal Insulin at Baseline | 67.3 nmols/6 hrs | Standard Error 7.9 |
| Colesevelam | Insulin Concentration | Insulin at 12 Weeks | 45 nmols/6 hrs | Standard Error 5 |
| Colesevelam | Insulin Concentration | Postmeal Insulin at 12 Weeks | 63.9 nmols/6 hrs | Standard Error 6.1 |
| Colesevelam | Insulin Concentration | Insulin at Baseline | 48 nmols/6 hrs | Standard Error 6 |
| Placebo | Insulin Concentration | Postmeal Insulin at 12 Weeks | 81.9 nmols/6 hrs | Standard Error 11.6 |
| Placebo | Insulin Concentration | Insulin at 12 Weeks | 51 nmols/6 hrs | Standard Error 6 |
| Placebo | Insulin Concentration | Postmeal Insulin at Baseline | 72.7 nmols/6 hrs | Standard Error 8.3 |
| Placebo | Insulin Concentration | Insulin at Baseline | 50 nmols/6 hrs | Standard Error 6 |
Secondary
Lipid Values
Lipids are fat-like substances in the blood.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Lipid Values | Total Cholesterol at Baseline | 4.35 mmol/l | Standard Error 0.19 |
| Colesevelam | Lipid Values | Total Cholesterol at 12 weeks | 3.60 mmol/l | Standard Error 0.16 |
| Colesevelam | Lipid Values | Triglycerides at Baseline | 1.67 mmol/l | Standard Error 0.15 |
| Colesevelam | Lipid Values | Triglycerides at 12 Weeks | 2.19 mmol/l | Standard Error 0.19 |
| Colesevelam | Lipid Values | High Density Lipoprotein (HDL) at Baseline | 1.18 mmol/l | Standard Error 0.06 |
| Colesevelam | Lipid Values | High Density Lipoprotein (HDL) at 12 Weeks | 1.08 mmol/l | Standard Error 0.1 |
| Colesevelam | Lipid Values | Low Density Lipoprotein (LDL) at Baseline | 2.50 mmol/l | Standard Error 0.17 |
| Colesevelam | Lipid Values | Low Density Lipoprotein (LDL) at 12 Weeks | 1.59 mmol/l | Standard Error 0.14 |
| Placebo | Lipid Values | Low Density Lipoprotein (LDL) at 12 Weeks | 2.09 mmol/l | Standard Error 0.12 |
| Placebo | Lipid Values | Total Cholesterol at Baseline | 4.33 mmol/l | Standard Error 0.14 |
| Placebo | Lipid Values | High Density Lipoprotein (HDL) at Baseline | 1.27 mmol/l | Standard Error 0.08 |
| Placebo | Lipid Values | Total Cholesterol at 12 weeks | 4.00 mmol/l | Standard Error 0.14 |
| Placebo | Lipid Values | Low Density Lipoprotein (LDL) at Baseline | 2.31 mmol/l | Standard Error 0.13 |
| Placebo | Lipid Values | Triglycerides at Baseline | 1.88 mmol/l | Standard Error 0.27 |
| Placebo | Lipid Values | High Density Lipoprotein (HDL) at 12 Weeks | 1.20 mmol/l | Standard Error 0.07 |
| Placebo | Lipid Values | Triglycerides at 12 Weeks | 1.55 mmol/l | Standard Error 0.18 |
Secondary
Plasma Glucose Concentration
Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.
Time frame: Baseline, 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Plasma Glucose Concentration | Glucose at 12 Weeks | 6.6 mmol/L | Standard Error 0.2 |
| Colesevelam | Plasma Glucose Concentration | Postmeal Glucose Peak at 12 Weeks | 14.4 mmol/L | Standard Error 0.6 |
| Colesevelam | Plasma Glucose Concentration | Postmeal Glucose Peak at Baseline | 15.4 mmol/L | Standard Error 0.6 |
| Colesevelam | Plasma Glucose Concentration | Glucose at Baseline | 7.0 mmol/L | Standard Error 0.2 |
| Placebo | Plasma Glucose Concentration | Glucose at 12 Weeks | 7.5 mmol/L | Standard Error 0.5 |
| Placebo | Plasma Glucose Concentration | Glucose at Baseline | 7.4 mmol/L | Standard Error 0.3 |
| Placebo | Plasma Glucose Concentration | Postmeal Glucose Peak at Baseline | 15.4 mmol/L | Standard Error 0.6 |
| Placebo | Plasma Glucose Concentration | Postmeal Glucose Peak at 12 Weeks | 15.8 mmol/L | Standard Error 0.6 |
Secondary
Rate of Meal Glucose Appearance (Meal Ra)
Meal Ra was measured using a triple-tracer mixed meal and reported in micromols in 6 hours. Meal derived glucose is a function of both gastric emptying and splanchnic meal extraction. Meal Ra was calculated by multiplying rate of appearance of \[1-\^13C\] glucose (obtained from the infusion rate of \[6-\^3H\] glucose and the clamped plasma ratio of \[6-\^3H\] glucose and \[1-\^13C\] glucose) by the meal enrichment.
Time frame: Baseline, 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Rate of Meal Glucose Appearance (Meal Ra) | Meal appearance glucose at Baseline | 5941 micromol/6h | Standard Error 402 |
| Colesevelam | Rate of Meal Glucose Appearance (Meal Ra) | Meal appearance glucose at 12 Weeks | 5413 micromol/6h | Standard Error 289 |
| Placebo | Rate of Meal Glucose Appearance (Meal Ra) | Meal appearance glucose at Baseline | 5504 micromol/6h | Standard Error 354 |
| Placebo | Rate of Meal Glucose Appearance (Meal Ra) | Meal appearance glucose at 12 Weeks | 5613 micromol/6h | Standard Error 354 |
Secondary
Rate of Meal Glucose Disappearance (Meal Rd)
Meal Rd is the rate at which glucose leaves the systemic circulation. It was measured using a triple-tracer mixed meal and reported in micromols over 6 hours. Meal Rd was calculated by subtracting the change in glucose mass from the overall rate of glucose appearance (i.e., meal Ra + EGP).
Time frame: Baseline, 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Rate of Meal Glucose Disappearance (Meal Rd) | Meal Rd at Baseline | 8642 micromol/6h | Standard Error 414 |
| Colesevelam | Rate of Meal Glucose Disappearance (Meal Rd) | Meal Rd at 12 Weeks | 8155 micromol/6h | Standard Error 314 |
| Placebo | Rate of Meal Glucose Disappearance (Meal Rd) | Meal Rd at Baseline | 8784 micromol/6h | Standard Error 403 |
| Placebo | Rate of Meal Glucose Disappearance (Meal Rd) | Meal Rd at 12 Weeks | 8761 micromol/6h | Standard Error 382 |
Secondary
Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration
GLP-1 is thought to increase insulin secretion and was measured in the blood and reported in picomoles per liter.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Colesevelam | Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration | Total GLP-1 at Baseline | 18.3 pmol/L | Standard Error 1.8 |
| Colesevelam | Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration | Total GLP-1 at 12 Weeks | 21.9 pmol/L | Standard Error 2.1 |
| Placebo | Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration | Total GLP-1 at Baseline | 18.6 pmol/L | Standard Error 1.7 |
| Placebo | Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration | Total GLP-1 at 12 Weeks | 19.3 pmol/L | Standard Error 2.4 |
Comparison: Comparison of mean total GLP-1 concentration from baseline to 12 weeks in Colesevelam subjectsp-value: 0.0006t-test, 2 sided
Comparison: Comparison of mean total GLP-1 concentration from baseline to 12 weeks in Placebo subjectsp-value: 0.3t-test, 2 sided