Mechanisms of Glucose Lowering Effect of Colesevelam HCl

Effects of Colesevelam HCl on Hepatic Insulin Sensitivity, Gluconeogenesis, Glucose Absorption and Lipid Synthesis in Subjects With Type 2 Diabetes Mellitus

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00596427

Enrollment

Registered

2008-01-17

Start date

2007-11-30

Completion date

2009-04-30

Last updated

2012-10-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes

Keywords

type two diabetes, gluconeogenesis, glucose, lipid synthesis, hepatic insulin sensitivity, colesevelam HCl

Brief summary

The mechanism by which colesevelam HCl lowers glucose is not known. Knowledge of the potential mechanism of action is important for defining the role of the drug among oral antidiabetic agents available for use in subjects with diabetes. The objective of this study is to provide insight into the mechanisms of action of colesevelam HCl in T2DM. The mechanisms of interest include hepatic insulin sensitivity, rate of appearance of exogenous glucose and changes in incretin hormone concentrations.

Detailed description

Colesevelam HCl (marketed in the U.S. as WelChol®) is a non-absorbed polymer that binds bile acids in the intestine, impeding their reabsorption, and is indicated to lower low-density lipoprotein cholesterol (LDL-C) in subjects with hypercholesterolemia. As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-(alpha)-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase, and increasing the number of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects increase the clearance of LDL-C from the blood, decreasing serum LDL C levels (1; 2). Recently, it has been shown that colesevelam HCl also improves glycemic control in subjects with T2DM who are not controlled adequately on metformin, sulfonylurea or a combination of the two drugs (3). The mechanism of action for glucose lowering is not known. Improved glycemic control with colesevelam HCl treatment could be due to any of several mechanisms. Colesevelam HCl could reduce hepatic insulin resistance and lead to a decrease in hepatic glucose production (HGP). The observation by Schwartz et al (4) of significantly reduced fasting plasma glucose concentrations in colesevelam-treated T2DM patients suggests such a reduction in HGP, as fasting hyperglycemia is a direct function of HGP. Colesevelam HCl could also decrease post-prandial glucose absorption. Changes in glucose absorption with other bile acid sequestrants (BAS) (5) and bile acids (6) have been reported. With regard to molecular mediators of the colesevelam effect on glucose metabolism, there is considerable evidence emerging about the role of bile acids and nuclear transcription factors, such as the farnesyl X receptor (FXR), in the regulation of glucose and lipid metabolism (7) (8) (9-15). Changes in cellular lipids or nuclear hormone receptors might directly alter HGP although mechanisms leading to changes in hepatic lipid and glucose metabolism by colesevelam HCl have not previously been investigated. Significant changes in cholesterol and bile acid synthesis rates are expected with colesevelam treatment. BAS treatment can alter the transhepatic flux and compositional profile of the circulating bile acid pool (16), and thus its hydrophobicity, and this may effect the activation of nuclear receptors, including FXR (17; 18). Determination of the effect of colesevelam treatment on bile acid synthesis may provide evidence for its metabolic effects. The effects on hepatic fatty acid synthesis (de novo lipogenesis or DNL) have not been investigated and may provide further evidence for a metabolic effect of colesevelam. Specific hypotheses about its mode of action will be tested, focusing on hepatic glucose metabolism and intestinal glucose absorption.

Interventions

DRUGColesevelam HCL

Colesevelam HCL 625 mg: 3 tablets twice per day

DRUGPlacebo

Placebo tablets: 3 tablets twice per day

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

30 Years to 70 Years

Healthy volunteers

Inclusion criteria

Subjects meeting the following criteria at the Screening Visit will be eligible to participate in the trial: * Have given written informed consent * Male or Female 1. Females of childbearing potential who are on approved birth control method: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide or female condom plus spermicide 2. Females of non-childbearing potential: hysterectomy, tubal ligation 6 months prior screening or post-menopausal for at least 1 year * Previously diagnosed or newly diagnosed with T2DM * Age 30 to 70 years, inclusive * BMI ≥ 18.5 kg/m2 and ≤ 40 kg/m2 * HbA1C 7-10%, inclusive (exceptions between 6.7-7% may be enrolled with prior approval of SPONSOR) * Fasting plasma glucose \< 300 mg/dL * Diet controlled or on stable dose of a sulfonylurea and/or meglitinides and/or metformin for ≥ 90 days before screening * No history of liver, biliary or intestinal disease (AST/ALT \< 2X upper limit of normal value) * Normal TSH * Agrees to maintain their regular diet and exercise routine * Agrees to refrain from consumption of alcohol 48 hours prior to start of infusions (week 0 and week 12)

Exclusion criteria

Subjects are excluded from participation in the study if any of the following criteria apply: * Type 1 diabetes mellitus or history of diabetic ketoacidosis * Treatment with lipid lowering medication other than statins * Treatment with statins that have not been stable for 3 months before screening * Treatment with colesevelam HCl, cholestyramine or colestipol for hyperlipidemia within the last 3 months of screening * Treatment with a thiazolidinedione (TZD) at any time * Treatment with acarbose at any time * Treatment with insulin in the past 6 months * Treatment with antibiotics within the last 3 months * Treatment with any medication affecting liver or intestinal function within the last 3 months * Pregnant * Breastfeeding * Has had unstable weight within the last 3 months of screening (± 5 kg) * History of an allergic or toxic reaction to colesevelam HCl * History of dysphagia, swallowing disorders, or intestinal motility disorder * Serum triglycerides ≥ 350 mg/dL at screening visit (exceptions up to 500 mg/dl may be enrolled with prior approval of SPONSOR) * Serum LDL-C \<60 mg/dL at screening visit * Any condition or therapy which, in the opinion of the investigator, poses a risk to the subject or makes participation not in the subject's best interest * Use of any investigational drug within 3 months of screening * Chronic treatment with oral corticosteroids at any time or acute treatment within the last 3 months * History of drug or alcohol abuse, is currently a user (including recreational use) of any illicit drugs, or has a positive urine drug screen at screening * Donated a unit of blood within 30 days before screening

Design outcomes

Primary

Measure	Time frame	Description
Fasting Glycogenolysis	baseline and 12 weeks	Change from baseline of fasting glycogenolysis after 12 weeks of placebo or colesevelam treatment.
Rate of Appearance of Exogenous Glucose (Glucose Absorption)	baseline and 12 weeks	Change from baseline of the rate of appearance of oral glucose after 12 weeks of placebo or colesevelam treatment. Mean of values obtained between 0 and 300 min is reported.
Fasting Endogenous Glucose Production (EGP)	baseline and 12 weeks	Changes from baseline of fasting EGP after 12 weeks of placebo or colesevelam treatment.
Fasting Gluconeogenesis	baseline and 12 weeks	Change from baseline of fasting gluconeogenesis after 12 weeks of placebo or colesevelam treatment.

Secondary

Measure	Time frame	Description
Fasting Fractional Cholesterol Synthesis	baseline and 12 weeks	Changes from baseline in fasting fractional cholesterol synthesis after 12 weeks of colesevelam or placebo treatment. Fractional Cholesterol synthesis represents the fraction of free cholesterol in plasma that was newly synthesised.
Glucagon AUC	baseline and 12 weeks	Changes from baseline of glucagon AUC after 12 weeks of placebo or colesevelam treatment. AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes
Postprandial Fractional Cholic Acid Synthesis	baseline and 12 weeks	Changes from baseline in fractional cholic acid synthesis after 12 weeks of colesevelam or placebo treatment were evaluated. Fractional cholic acid synthesis represents the relative amount of cholic acid that is made from newly synthesised cholesterol.
Total Glucagon-like Peptide (GLP-1) Area Under the Curve (AUC)	baseline and 12 weeks	Changes from baseline of total GLP-1 AUC after 12 weeks of placebo or colesevelam treatment. AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes
Total Glucose-dependent Insulinotropic Polypeptide (GIP) AUC	baseline and 12 weeks	Changes from baseline of total GIP-1 AUC after 12 weeks of placebo or colesevelam treatment. AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes
Fasting Fractional De Novo Lipogenesis (DNL)	baseline and 12 weeks	Changes from baseline in fasting fractional DNL after 12 weeks of colesevelam or placebo treatment were calculated. Fractional DNL represents the fraction of palmitate in very-low density lipoproteins-triglycerides (VLDL-TG) that was newly synthesized.

Other

Measure	Time frame	Description
Glycosylated Hemoglobin (HbAlc)	baseline and 12 weeks	Changes from baseline of HbA1c after 12 weeks of placebo or colesevelam treatment.
Glucose AUC	baseline and 12 weeks	Changes from baseline of glucose AUC after 12 weeks of placebo or colesevelam treatment. AUC values were calculated by the trapezoid method using all results between 0 and 300 minutes

Countries

United States

Participant flow

Recruitment details

Participants with type 2 diabetes. All pre-existing drug treatments were stable for at least 3 months prior.

Pre-assignment details

Participants excluded based on fasting plasma glucose levels, fasting serum triglyceride levels, LDL-cholesterol levels, pregnancy or a history of liver, biliary, or intestinal diseases. Participants treated with insulin or lipid agent less than six months prior were excluded as well.

Participants by arm

Arm	Count
Type-2 Diabetes Mellitus Patients Treated With Colesevelam Subjects received six tablets a day of colesevelam (3.75g/day) for 12 weeks; three tablets with lunch and three tablets with dinner.	30
Type-2 Diabetes Mellitus Patients Treated With Placebo Subjects received six tablets a day of matched placebo(3.75g/day) for 12 weeks; three tablets with lunch and three tablets with dinner.	30
Total	60

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Increased Fasting Triacylglycerol level	1	0
Overall Study	Protocol Violation	1	0
Overall Study	Withdrawal by Subject	2	2

Baseline characteristics

Characteristic	Type-2 Diabetes Mellitus Patients Treated With Colesevelam	Type-2 Diabetes Mellitus Patients Treated With Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	6 Participants	5 Participants	11 Participants
Age, Categorical Between 18 and 65 years	24 Participants	25 Participants	49 Participants
Age Continuous	59 years STANDARD_DEVIATION 9	56 years STANDARD_DEVIATION 9	57.5 years STANDARD_DEVIATION 9
BMI	30 kg/m2 STANDARD_DEVIATION 5	31 kg/m2 STANDARD_DEVIATION 5	30.5 kg/m2 STANDARD_DEVIATION 5
Glucose	9.2 mmol/l STANDARD_DEVIATION 2.3	8.4 mmol/l STANDARD_DEVIATION 2.4	8.8 mmol/l STANDARD_DEVIATION 2.3
HbA 1c	8.5 percentage STANDARD_DEVIATION 1.2	8.0 percentage STANDARD_DEVIATION 0.9	8.25 percentage STANDARD_DEVIATION 1.05
HDL-cholesterol	0.9 mmol/l STANDARD_DEVIATION 0.2	1.0 mmol/l STANDARD_DEVIATION 0.2	1.0 mmol/l STANDARD_DEVIATION 0.2
Insulin	76 pmol/l STANDARD_DEVIATION 42	97 pmol/l STANDARD_DEVIATION 42	87 pmol/l STANDARD_DEVIATION 42
LDL-cholesterol	2.8 mmol/l STANDARD_DEVIATION 0.8	2.8 mmol/l STANDARD_DEVIATION 1	2.8 mmol/l STANDARD_DEVIATION 0.9
Region of Enrollment United States	30 participants	30 participants	60 participants
Sex: Female, Male Female	12 Participants	14 Participants	26 Participants
Sex: Female, Male Male	18 Participants	16 Participants	34 Participants
Total cholesterol	4.6 mmol/l STANDARD_DEVIATION 1.2	4.6 mmol/l STANDARD_DEVIATION 1.3	4.6 mmol/l STANDARD_DEVIATION 1.3
Triacylglycerol	2.2 mmol/l STANDARD_DEVIATION 0.8	2.0 mmol/l STANDARD_DEVIATION 0.9	2.1 mmol/l STANDARD_DEVIATION 0.9
Weight	84 kg STANDARD_DEVIATION 16	88 kg STANDARD_DEVIATION 19	86 kg STANDARD_DEVIATION 18

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	19 / 26	23 / 28
serious Total, serious adverse events	0 / 30	0 / 30