The Effect of Welchol on Glucose Metabolism in Type 2 Diabetics

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00951899
• Collaborator: Daiichi Sankyo, Inc. (Industry), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 40
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Colesevelam; Other: Placebo; Behavioral: Diet; Drug: Metformin	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: The Effect of Colesevelam Hydrochloride on Disposition Index and Incretin Concentrations in Subjects With Type 2 Diabetes Using a Double-blind, Placebo-controlled, Parallel-group Study Design
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Colesevelam Treatment with colesevelam hydrochloride in addition to Metformin and Diet	Drug: Colesevelam; Colesevelam hydrochloride; three 625mg tablets taken orally twice per day before breakfast and before the evening meal over a 12-week treatment period.; Other Names: Welchol ; Behavioral: Diet; Subjects were instructed to follow a weight maintenance diet (~55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.; Drug: Metformin; 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.; Other Names: Glucophage Glucophage XR Glumetza Fortamet
Placebo Comparator: Placebo Treatment with placebo in addition to Metformin and Diet	Other: Placebo; 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.; Behavioral: Diet; Subjects were instructed to follow a weight maintenance diet (~55% carbohydrate, 30% fat and 15% protein) for the 12 week study period.; Drug: Metformin; 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.; Other Names: Glucophage Glucophage XR Glumetza Fortamet

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Plasma Glucose Concentration [Baseline, 12 Weeks]

   Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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).

8. Lipid Values [Baseline, 12 weeks]

   Lipids are fat-like substances in the blood.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Daiichi Sankyo, Inc.
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Adrian Vella, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Adrian Vella, MD, Professor of Medicine, Endocrinology, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00951899
• Other Study ID Numbers: 08-008284; R01DK078646; R01DK082396; UL1RR024150
• First Posted: Aug 4, 2009
• Last Update Posted: Nov 11, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by Adrian Vella, MD, Professor of Medicine, Endocrinology, Mayo Clinic: Incretins; colesevelam; hepatobiliary circulation
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Metformin; Colesevelam Hydrochloride

Study Results

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 Detail	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.

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Period Title: Overall Study
STARTED	19	19
COMPLETED	19	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Colesevelam	Placebo	Total
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin	Total of all reporting groups
Overall Participants	19	19	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.6 (5.9)	60.2 (6.3)	61 (6.1)
Sex: Female, Male (Count of Participants)
Female	6 31.6%	6 31.6%	12 31.6%
Male	13 68.4%	13 68.4%	26 68.4%
Region of Enrollment (participants) [Number]
United States	19 100%	19 100%	38 100%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.8 (4.3)	30.4 (4.0)	30.6 (4.1)

Outcome Measures

1. Primary Outcome

Title	Total Disposition Index
Description	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

Outcome Measure Data

Analysis Population Description

Intent to treat analysis population.

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Disposition Index at Baseline	332 (41)	253 (40)
Disposition Index at 12 Weeks	519 (169)	310 (48)

2. Secondary Outcome

Title	Total Fasting Glucagon-Like Peptide-1 (GLP-1) Concentration
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Total GLP-1 at Baseline	18.3 (1.8)	18.6 (1.7)
Total GLP-1 at 12 Weeks	21.9 (2.1)	19.3 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Colesevelam
	Comments	Comparison of mean total GLP-1 concentration from baseline to 12 weeks in Colesevelam subjects
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	A P value < 0.05 was considered statistically significant
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Comparison of mean total GLP-1 concentration from baseline to 12 weeks in Placebo subjects
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Plasma Glucose Concentration
Description	Fasting glucose concentrations were measured at baseline and 2 hours post-meal using the glucose oxidase method.
Time Frame	Baseline, 12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Glucose at Baseline	7.0 (0.2)	7.4 (0.3)
Glucose at 12 Weeks	6.6 (0.2)	7.5 (0.5)
Postmeal Glucose Peak at Baseline	15.4 (0.6)	15.4 (0.6)
Postmeal Glucose Peak at 12 Weeks	14.4 (0.6)	15.8 (0.6)

4. Secondary Outcome

Title	Glycosylated Hemoglobin (HbA1c)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
HbA1c at Baseline	6.7 (0.1)	6.8 (0.1)
HbA1c at 12 Weeks	6.5 (0.2)	6.9 (0.2)

5. Secondary Outcome

Title	Insulin Concentration
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Insulin at Baseline	48 (6)	50 (6)
Insulin at 12 Weeks	45 (5)	51 (6)
Postmeal Insulin at Baseline	67.3 (7.9)	72.7 (8.3)
Postmeal Insulin at 12 Weeks	63.9 (6.1)	81.9 (11.6)

6. Secondary Outcome

Title	Fasting Endogenous Glucose Production (EGP)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
EGP at Baseline	17.6 (0.6)	17.7 (0.7)
EGP at 12 Weeks	17.2 (0.6)	17.6 (0.7)

7. Secondary Outcome

Title	Rate of Meal Glucose Appearance (Meal Ra)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Meal appearance glucose at Baseline	5941 (402)	5504 (354)
Meal appearance glucose at 12 Weeks	5413 (289)	5613 (354)

8. Secondary Outcome

Title	Rate of Meal Glucose Disappearance (Meal Rd)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Meal Rd at Baseline	8642 (414)	8784 (403)
Meal Rd at 12 Weeks	8155 (314)	8761 (382)

9. Secondary Outcome

Title	Lipid Values
Description	Lipids are fat-like substances in the blood.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Colesevelam	Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet	Placebo plus diet and metformin
Measure Participants	19	19
Total Cholesterol at Baseline	4.35 (0.19)	4.33 (0.14)
Total Cholesterol at 12 weeks	3.60 (0.16)	4.00 (0.14)
Triglycerides at Baseline	1.67 (0.15)	1.88 (0.27)
Triglycerides at 12 Weeks	2.19 (0.19)	1.55 (0.18)
High Density Lipoprotein (HDL) at Baseline	1.18 (0.06)	1.27 (0.08)
High Density Lipoprotein (HDL) at 12 Weeks	1.08 (0.10)	1.20 (0.07)
Low Density Lipoprotein (LDL) at Baseline	2.50 (0.17)	2.31 (0.13)
Low Density Lipoprotein (LDL) at 12 Weeks	1.59 (0.14)	2.09 (0.12)

Adverse Events

Time Frame	Baseline to 12 weeks.
Arm/Group Title	Colesevelam		Placebo
Arm/Group Description	Treatment with colesevelam in addition to metformin and diet		Placebo plus diet and metformin
All Cause Mortality
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/19 (0%)
Gastrointestinal disorders
GI ulcer and hemorrhage	1/19 (5.3%)	1	0/19 (0%)	0
Other (Not Including Serious) Adverse Events
	Colesevelam		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/19 (0%)
Blood and lymphatic system disorders
Low hemoglobin	1/19 (5.3%)	1	0/19 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.