Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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
Brief Summary: 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.


Options:
A: Inclusion Criteria:

* Age 18-75 years, inclusive
* Diagnosed with type 2 diabetes
* Hemoglobin (HbA1c) between 7.5% to 9.5%
* Prescribed an ADA accepted diet
* Receiving stable dose of metformin alone or in combination with other oral anti-diabetic medications for 90 days before Visit 1

Exclusion Criteria:

* History of type 1 diabetes or ketoacidosis
* History of chronic (more than 2 months) insulin therapy or the initiation of insulin for chronic treatment
* History of pancreatitis
* Uncontrolled hypertension
* Recent severe cardiovascular disease
* Allergy or toxic response to colesevelam or any of its components
* Body mass index (BMI) \>45 kg/m2
B: 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 .
C: Inclusion Criteria:

1. A diagnosis of type 2 diabetes mellitus first made at age 30 years or older
2. Age 55 years or older at entry
3. Ability to provide informed consent
4. A substantially elevated risk of cardiovascular disease, indicated by:

   * A history of major macrovascular disease defined as any one of: stroke, myocardial infarction, hospital admission for transient ischaemic attack, hospital admission for unstable angina, coronary artery bypass graft, percutaneous transluminal coronary angioplasty (with or without stenting), peripheral revascularisation (angioplasty or surgery) or amputation secondary to vascular disease or
   * A history of major microvascular disease defined as any one of nephropathy (albumin:creatinine ratio \>300ug/mg), retinal photocoagulation therapy, proliferative retinopathy (new blood vessels on the disc or elsewhere, vitreous haemorrhage, pre-retinal haemorrhage, or fibrous proliferations on the disc or elsewhere), macular oedema (retinal thickening within one disc diameter of the macular centre) or blindness in either eye (corrected visual acuity 6/60 or worse, persisting for three months or more) not known to be due to non-diabetic causes or
   * A first diagnosis of type 2 diabetes made 10 or more years prior to entry or
   * Another major risk factor for vascular disease defined as any one of: current daily cigarette smoking, total cholesterol greater than 6.0 mmol/l (with or without cholesterol lowering treatment), HDL cholesterol \<1.0 mmol/l, microalbuminuria (albumin:creatinine ratio 30-300ug/mg) or
   * Age 65 years or over

Exclusion Criteria:

1. A definite contraindication to treatment with an ACE inhibitor or a thiazide-like diuretic
2. A specific indication for treatment with an ACE inhibitor other than perindopril 2-4 mg daily (see also section 5.2.3) or a thiazide-like diuretic
3. A definite and specific indication for treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
4. A definite contra-indication to treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
5. A definite indication for long-term full-dose or bed-time insulin therapy
6. Participation in a trial within the month prior to the Registration Visit or current participation in another trial

Other potential reasons for ineligibility include:

* High probability of non-adherence to study treatment or follow-up
* Current clinical instability (e.g. a major cerebral or coronary event or sight-threatening retinopathy or macular oedema within the previous few weeks)
* Life threatening non-vascular disease other than diabetes and its complications
* Moderate or severe dementia
* Major disability that is likely to prevent regular attendance at study clinics

Final decisions about eligibility were made at the discretion of the study investigator and the potential study participant, in the light of any requirements or guidance from local ethics committees and other regulatory bodies.
D: Inclusion Criteria:

* Ages 18 - 75 years, inclusive
* Diagnosed with type 2 diabetes
* Stable insulin therapy for 6 weeks
* Stable dose of any other antidiabetic medications for 90 days
* Hemoglobin A1c value between 7.5% to 9.5%
* C peptide greater than 0.5 ng/mL
* Prescribed ADA diet

Exclusion Criteria:

* History of type 1 diabetes or ketoacidosis
* History of pancreatitis
* Uncontrolled hypertension
* Allergy or toxic response to colesevelam or any of its components
* Serum LDL-C less than 60 mg/dL
* Serum TG greater than 500 mg/dL
* Body mass index (BMI) greater than 45 kg/m2-

Answer: B