Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control

• Change From Baseline to Individual Time Points in HbA1c, Insulin Doses, and Total Insulin Dosage [ Time Frame: 60 weeks from Baseline ] [ Designated as safety issue: No ]
• Percentage of Subjects Achieving an HbA1C Less Than (<) 7.0% and Less Than (<) 6.5% [ Time Frame: 60 weeks from Baseline ] [ Designated as safety issue: No ]
• Change From Baseline to Study Time Points in 7-point Blood Glucose (BG) Profile (Before Meals, 2 Hours After Meals, at Bedtime) [ Time Frame: 60 weeks from Baseline ] [ Designated as safety issue: No ]
• Change From Baseline to End of Study and to Individual Time Points in Components of Lipid Profile (Total Cholesterol, High-density Lipoprotein Cholesterol [HDL], Low-density Lipoprotein Cholesterol [LDL], Triglycerides, LDL Subfractions) [ Time Frame: 60 weeks from Baseline ] [ Designated as safety issue: No ]
• Occurrences of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia, and Serious Hypoglycemia [ Time Frame: 60 weeks from Baseline ] [ Designated as safety issue: Yes ]
  • Symptomatic hypoglycemia (BG<70 mg/dL, BG<50 mg/dL): including 1 or more symptoms: headache, dizziness, general feeling of weakness, drowsiness, confusion, pallor, irritability, trembling, sweating, rapid heartbeat & a cold, clammy feeling.
  • Mild-to-moderate hypoglycemia: SMBG ≥ 36 mg/dL but <70 mg/dL

  • Severe hypoglycemia: assistance of another party is required & either:

    • SMBG of <36 mg/dL, or
    • with prompt response to treatment with oral carbohydrates, IV glucose or glucagon.

  • Serious hypoglycemia:

    • Hypoglycemia with coma/loss of consciousness Or Hypoglycemia seizure/convulsion.
• Rate of Hypoglycemia, Symptomatic Hypoglycemia, Severe Hypoglycemia and Serious Hypoglycemia [ Time Frame: 60 Weeks from Baseline ] [ Designated as safety issue: Yes ]
  • Symptomatic hypoglycemia (BG<70 mg/dL, BG<50 mg/dL): including 1 or more symptoms: headache, dizziness, general feeling of weakness, drowsiness, confusion, pallor, irritability, trembling, sweating, rapid heartbeat & a cold, clammy feeling.
  • Mild-to-moderate hypoglycemia: SMBG ≥ 36 mg/dL but <70 mg/dL

  • Severe hypoglycemia: assistance of another party is required & either:

    • SMBG of <36 mg/dL, or
    • with prompt response to treatment with oral carbohydrates, IV glucose or glucagon.

  • Serious hypoglycemia:

    • Hypoglycemia with coma/loss of consciousness Or Hypoglycemia seizure/convulsion.

The purpose of this study is to compare the change in hemoglobin A1c (HbA1c) from baseline to Week 12 between the 3 treatment arms.

• Drug: Insulin Glargine
  Insulin glargine administered subcutaneously once daily.
• Drug: Insulin Glulisine
  Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)

• Experimental: Insulins + Sulfonylurea (SU) + Thiazolidinedione (TZD)
  Arm 1: Insulin glargine administered subcutaneously once daily plus a sulfonylurea and a TZD. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
  Interventions:

  • Drug: Insulin Glargine
  • Drug: Insulin Glulisine
• Experimental: Insulins + Metformin (MET) + Thiazolidinedione (TZD)
  Arm 2: Insulin glargine administered subcutaneously once daily plus metformin and a TZD. Insulin glulisine will be added after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
  Interventions:

  • Drug: Insulin Glargine
  • Drug: Insulin Glulisine
• Experimental: Insulins + Metformin (MET) + Sulfonylurea (SU)
  Arm 3: Insulin glargine administered subcutaneously once daily plus metformin and a sulfonylurea. Insulin glulisine will be added arms after Week 12 or later for those subjects needing prandial insulin therapy (HbA1c >6.5%)
  Interventions:

  • Drug: Insulin Glargine
  • Drug: Insulin Glulisine

Inclusion Criteria:

Subjects meeting all of the following criteria will be considered for enrollment into the study:

1. 18 to 79 years of age, inclusive
2. Diagnosis of type 2 diabetes mellitus
3. Continuous treatment with therapeutic dosages of a thiazolidinedione (rosiglitazone or pioglitazone), metformin, and a sulfonylurea daily prior to entering the study
4. Screening HbA1c ≥ 7.0%
5. Fasting C-peptide concentration ≥ 0.27 ng/ml
6. Negative glutamic acid decarboxylase (GAD) antibodies
7. Demonstrated ability and willingness to perform self-monitoring blood glucose (SMBG) using a plasma-referenced glucose meter and to maintain an electronic diary
8. Demonstrated ability and willingness to use an electronic diary to record SMBG results, insulin doses, and hypoglycemic events.
9. Signed, informed consent and Health Insurance Portability and Accountability Act (HIPAA) documentation

Exclusion Criteria:

1. Stroke, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or angina pectoris, within the last 12 months
2. Cardiac status New York Heart Association (NYHA) III-IV
3. Impaired renal function as shown by, but not limited to, serum creatinine ≥ 1.5 mg/dL for males, or ≥ 1.4 mg/dL for females
4. Chronic use of insulin: (more than 3 weeks of continuous use) in the past 12 months
5. Acute infection
6. Clinically significant peripheral edema
7. Acute or chronic history of metabolic acidosis, including diabetic ketoacidosis
8. Clinical evidence of active liver disease, or serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 2.5 times the upper limit of the normal range
9. History of hypoglycemia unawareness
10. Pregnancy or lactation
11. Known hypersensitivity to insulin glargine or any of the components of Lantus®
12. Known hypersensitivity to insulin glulisine or any of the components of Apidra®
13. Any malignancy within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or adequately treated cervical carcinoma in situ
14. Current addiction or current alcohol abuse, or history of substance or alcohol abuse within the last 2 years
15. Diagnosis of dementia
16. Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
17. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
18. subject is currently taking or was treated with the following medications 3 months prior to screening: Byetta(exenatide), Starlix(nateglinide),Prandin (repaglinide), Januvia(sitagliptin), Janumet(metformin + sitagliptin)
19. Any disease or condition that in the opinion of the investigator and/or sponsor may interfere with the completion of the study