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

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.

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.

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

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.

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

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

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.

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.

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.

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

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

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 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 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

Grundy SM, Ahrens EH Jr, Salen G. Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med. 1971 Jul;78(1):94-121. No abstract available.

Shepherd J, Packard CJ, Bicker S, Lawrie TD, Morgan HG. Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med. 1980 May 29;302(22):1219-22. doi: 10.1056/NEJM198005293022202.

Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther. 2007 Jan;29(1):74-83. doi: 10.1016/j.clinthera.2007.01.003.

Jenkins DJ, Wolever TM, Leeds AR, Gassull MA, Haisman P, Dilawari J, Goff DV, Metz GL, Alberti KG. Dietary fibres, fibre analogues, and glucose tolerance: importance of viscosity. Br Med J. 1978 May 27;1(6124):1392-4. doi: 10.1136/bmj.1.6124.1392.

Beysen C, Murphy EJ, Deines K, Chan M, Tsang E, Glass A, Turner SM, Protasio J, Riiff T, Hellerstein MK. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia. 2012 Feb;55(2):432-42. doi: 10.1007/s00125-011-2382-3. Epub 2011 Dec 2.