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.

Effects of Metformin HCl in Combination With Colesevelam HCl, Compared to Metformin HCl Alone, as Initial Therapy in Drug naïve Subjects With Type 2 Diabetes Mellitus, and the Effects of Colesevelam HCl on the Lipid Profile in Subjects With Pre Diabetes

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 be treated with open label, background,metformin HCl. Two-hundred sixty subjects with type 2 diabetes (T2DM) and 200 pre-diabetic subjects are planned to be be enrolled. Qualified subjects with T2DM will be randomized 1:1 to receive metformin HCl plus colesevelam HCl or metformin HCl plus placebo matching colesevelam HCl. Qualified pre-diabetic subjects will be randomized 1:1 to receive colesevelam HCl or matching placebo.

Inclusion Criteria:

• Age 18 to 79 years, inclusive.

• HbA1C in the range of greater than or equal to 6.5 percent to small than or equal to 10.0 percent, to be enrolled in the T2DM cohort.

• 2-hour post 75 g OGTT glucose levels in the range of:

  • greater than or equal to 200 mg/dL to be enrolled in the T2DM cohort, or
  • greater than or equal to 140 to 200 mg/dL to be enrolled in the pre-diabetes cohort.

• FPG levels in the range of:

  • greater than or equal to 126 mg/dL to be enrolled in the T2DM cohort, or
  • greater than or equal to 110 to smaller than or equal to 125 mg/dL to be enrolled in the pre-diabetes cohort.

• LDL-C levels greater than or equal to 100 mg/dL.

• Drug-naïve, defined as having never received treatment for T2DM or not having received antidiabetic drug therapy during the 3 months prior to screening visit.

• Previous diagnosis of:

  • T2DM or prediabetes, to be enrolled in the respective cohorts, or
  • CHD, CVD, and/or primary hypercholesterolemia + BMI greater than or equal to 25 mg/kg2 to be screened for T2DM or pre-diabetes.

• Understanding of the study procedures and agreement to participate in the study by giving written informed consent at screening visit.

• Women may be enrolled if all 3 of the following criteria (in addition to the above criteria)are met:

  • They are not pregnant (women of childbearing potential must have a negative serum pregnancy test [serum beta human chorionic gonadotropin )] at screening visit);
  • They are not breast-feeding; and
  • They do not plan to become pregnant during the study.

• In addition to all of the above criteria, women must also meet 1 of the following 3 criteria to be enrolled:

  • They have been post-menopausal for at least 1 year; or
  • They are of childbearing potential and will practice 1 of the following methods of birth control throughout the study: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Methods of contraception that are not acceptable are partner's use of condoms or partner's vasectomy.

Exclusion Criteria:

• History of type 1 diabetes and/or history of acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• History of chronic (requiring daily for greater than 2 months) use of insulin therapy, except for the treatment of gestational diabetes.
• Current or prior (within the past 3 months) treatment with an oral antidiabetic drug.
• Current or prior (within the past 3 months) treatment with colesevelam HCl (WelChol), colestipol, colestimide, or cholestyramine.
• History of dysphagia, swallowing disorders, or intestinal motility disorder.
• Any serious disorder, including pulmonary, hepatic, gastrointestinal (including clinically significant malabsorption), uncontrolled endocrine/metabolic, hematologic/oncologic (within the last 5 years), neurologic, and psychiatric diseases, that would interfere with the conduct of the study or interpretation of the data.
• Acute coronary syndrome (eg, myocardial infarction or unstable angina), coronary intervention (coronary artery bypass graft or percutaneous transluminal coronary angioplasty or similar procedure), congestive heart failure (requiring pharmacological treatment), or transient ischemic attack within 3 months of screening visit.
• History of pancreatitis.
• History of acquired immune deficiency syndrome or human immunodeficiency virus.
• History of drug or alcohol abuse within the past 2 years.
• Hospitalization for any cause within 14 days prior to screening visit.
• History of an allergic or toxic response to colesevelam HCl or any of its components.
• Known hypersensitivity to metformin HCl.
• Serum TG greater than or equal to 500 mg/dL.
• Body mass index (BMI) greater than 40 kg/m2 .