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Mechanisms of Glucose Lowering Effect of Colesvelam HCl

2014-08-27 03:33:40 | BioPortfolio

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.

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.

Study Design

Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Conditions

Diabetes

Intervention

Colesevelam HCL, Placebo

Location

Diablo Clinical Research, Inc
Walnut Creek
California
United States
94598

Status

Completed

Source

KineMed

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:33:40-0400

Clinical Trials [2241 Associated Clinical Trials listed on BioPortfolio]

Effects of Colesevelam on How the Body Responds to Insulin in Patients With Type 2 Diabetes

This study is designed to assess the potential mechanism of action by which WelChol® (colesevelam) may improve blood glucose control in patients with type 2 diabetes

Efficacy of Colesevelam in Subjects With Type 1 Diabetes Mellitus

This is a prospective, randomized, double blind, parallel, placebo controlled clinical trial evaluating the efficacy of colesevelam HCl in reducing LDL in subjects with type 1 diabetes mel...

Effects of Metformin Hydrochloride (HCl) in Combination With Colesevelam HCl, Compared to Metformin HCl Alone, in Patients With Type 2 Diabetes Mellitus and the Effects of Colesevelam HCl on Lipids and Glucose on Pre-diabetic Patients.

This is a 16-week double-blind, placebo-controlled (for colesevelam hydrochloride (HCl)) study in the type 2 diabetic subjects and pre-diabetic subjects. Diabetic participants will also b...

Effects on Colesevelam HC1 (WelChol®) on Insulin Sensitivity in Subjects With Type 2 Diabetes Mellitus

This study is designed to test whether WelChol (colesevelam HC1) improves blood sugar control in patients with type 2 diabetes by making their own insulin work more efficiently.

The Role of Metformin and Colesevelam in Human GLP-1 Secretion

Our primary hypothesis is that bile acid sequestrant colesevelam and the antidiabetic drug metformin potentiates the secretion of the gut hormone glucagon-like peptide 1 (GLP-1).

PubMed Articles [4618 Associated PubMed Articles listed on BioPortfolio]

Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients with Bile Acid Diarrhea in a Randomized Trial.

Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent wi...

Randomized 52-week Phase 2 Trial of Albiglutide Versus Placebo in Adult Patients With Newly Diagnosed Type 1 Diabetes.

GLP-1 receptor agonists are an established therapy in patients with type 2 diabetes; however, their role in type 1 diabetes remains to be determined.

Once-Weekly Dulaglutide with Insulin Therapy for Type 2 Diabetes: Efficacy and Safety Results from a Phase 4, Randomized, Placebo-Controlled Study.

Although global studies have investigated the combination of dulaglutide with insulin in patients with type 2 diabetes mellitus (T2DM), differences in lean body mass and dulaglutide dosing can complic...

Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.

In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their effic...

Placebo effects in the neuroendocrine system: conditioning of the oxytocin responses.

Evidence exists that placebo effects may influence hormone secretion. However, only few studies examined placebo effects in the endocrine system, including oxytocin placebo effects. We studied whether...

Medical and Biotech [MESH] Definitions

Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes (DIABETES MELLITUS; DIABETES INSIPIDUS).

An allylamine derivative that binds BILE ACIDS in the intestine and is used as an ANTICHOLESTEREMIC AGENT in the treatment of HYPERCHOLESTEROLEMIA and HYPERLIPIDEMIAS.

The time period before the development of symptomatic diabetes. For example, certain risk factors can be observed in subjects who subsequently develop INSULIN RESISTANCE as in type 2 diabetes (DIABETES MELLITUS, TYPE 2).

A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY.

The state of PREGNANCY in women with DIABETES MELLITUS. This does not include either symptomatic diabetes or GLUCOSE INTOLERANCE induced by pregnancy (DIABETES, GESTATIONAL) which resolves at the end of pregnancy.

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