A Study to Compare the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly to Those of Sitagliptin and Pioglitazone,in Subjects With Type 2 Diabetes Treated With Metformin (DURATION - 2)

• Percentage of Subjects Achieving HbA1c Target of <7% at Week 26 [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
  Percentages of subjects achieving HbA1c target values of <7% at Week 26.
• Percentage of Subjects Achieving HbA1c Target of <=6.5% at Week 26 [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
  Percentages of subjects achieving HbA1c target values of <=6.5% at Week 26.
• Percentage of Subjects Achieving HbA1c Target of <=6.0% at Week 26 [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
  Percentages of subjects achieving HbA1c target values of <=6.0% at Week 26.
• Change in Body Weight From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in body weight from baseline (Day 1) to Week 26.
• Change in Fasting Plasma Glucose From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in fasting plasma glucose from baseline (Day 1) to Week 26.
• Change in Systolic Blood Pressure From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in systolic blood pressure from baseline (Day 1) to Week 26.
• Change in Diastolic Blood Pressure From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in diastolic blood pressure from baseline (Day 1) to Week 26.
• Change in Fasting Total Cholesterol From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in fasting total cholesterol from baseline (Day 1) to Week 26.
• Change in Fasting High-density Lipoprotein (HDL) From Baseline to Week 26 [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Change in fasting HDL from baseline (Day 1) to Week 26.
• Ratio of Fasting Triglycerides at Week 26 to Baseline [ Time Frame: Day 1, Week 26 ] [ Designated as safety issue: No ]
  Ratio of triglycerides (measured in mg/dL) at Week 26 to baseline (Day 1). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
• Assessment on Event Rate of Treatment-emergent Hypoglycemic Events [ Time Frame: Day 1 to Week 26 ] [ Designated as safety issue: Yes ]
  Major hypoglycemia: events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration < 54 mg/dL prior to treatment. Minor hypoglycemia: symptoms consistent with hypoglycemia and blood glucose concentration < 54 mg/dL prior to treatment and not classified as major hypoglycemia.

• To examine the safety and tolerability of exenatide once weekly compared to sitagliptin and thiazolidinedione in subjects with type 2 diabetes mellitus. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
• To compare the effects of exenatide once weekly to those achieved by sitagliptin and thiazolidinedione in subjects with type 2 diabetes mellitus on the following: *Body weight; *Parameters related to glycemic control [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
• To compare the effects of exenatide once weekly to those achieved by sitagliptin and thiazolidinedione in subjects with type 2 diabetes mellitus on the following: *Parameters related to cardiovascular health; *Patient reported outcomes [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]

This study will compare the benefits of exenatide once weekly treatment to those achieved by the approved antidiabetic therapies sitagliptin and pioglitazone in subjects whose type 2 diabetes is managed with metformin therapy alone. The safety and tolerability of the three treatment regimens will also be compared.

• Drug: exenatide once weekly
  subcutaneous injection, 2.0mg, once a week
• Drug: sitagliptin
  oral tablet, 100mg, once a day
  Other Name: Januvia
• Drug: pioglitazone
  oral tablet, 45mg, once a day
• Drug: placebo tablet
  oral tablet, once a day
• Drug: placebo once weekly
  subcutaneous injection, once a week

• Experimental: 1
  Interventions:

  • Drug: exenatide once weekly
  • Drug: placebo tablet
• Active Comparator: 2
  Interventions:

  • Drug: sitagliptin
  • Drug: placebo once weekly
• Active Comparator: 3
  Interventions:

  • Drug: pioglitazone
  • Drug: placebo once weekly

• Meloni AR, DeYoung MB, Han J, Best JH, Grimm M. Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals. Cardiovasc Diabetol. 2013 Mar 23;12:48. doi: 10.1186/1475-2840-12-48.
• Peyrot M, Bushnell DM, Best JH, Martin ML, Cameron A, Patrick DL. Development and validation of the self-management profile for type 2 diabetes (SMP-T2D). Health Qual Life Outcomes. 2012 Oct 5;10:125. doi: 10.1186/1477-7525-10-125.
• Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012 Jun;14(6):546-54. doi: 10.1111/j.1463-1326.2012.01561.x. Epub 2012 Feb 10.
• Wysham C, Bergenstal R, Malloy J, Yan P, Walsh B, Malone J, Taylor K. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med. 2011 Jun;28(6):705-14.
• Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE; DURATION-2 Study Group. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010 Aug 7;376(9739):431-9. Epub 2010 Jun 26.

Inclusion Criteria:

• Has been diagnosed with type 2 diabetes mellitus
• Has a hemoglobin-specific A1c fraction (HbA1c) of 7.1% to 11.0%, inclusive, at study start
• Has a body mass index (BMI)of 25 kg/m2 to 45 kg/m2, inclusive, at study start
• Has been on a stable treatment regimen of metformin for a minimum of 2 months prior to study start

• Either is not treated with or has been on a stable treatment regimen with any of the following medications for a minimum of 2 months prior to study start:

  1. Hormone replacement therapy (female subjects)
  2. Oral contraceptives (female subjects)
  3. Antihypertensive agents
  4. Lipid-lowering agents
  5. Thyroid replacement therapy
  6. Antidepressant agents
  7. Drugs known to affect body weight, including prescription medications (e.g. orlistat [XENICAL®], sibutramine [MERIDIA®], topiramate [TOPAMAX®]) and over-the-counter antiobesity agents

Exclusion Criteria:

• Has been previously exposed to exenatide once weekly
• Has donated blood within 60 days of study start or is planning to donate blood during the study

• Currently being treated, or is expected to require or undergo treatment with any of the following treatment-excluded medications:

  1. Exenatide (BYETTA®) or any Dipeptidyl peptidase-4 DPP-4)inhibitor, sulfonylurea (SU), thiazolidinedione (TZD), or glucagon-like peptide (GLP)-1 analog within 3 months prior to study start
  2. Alpha-glucosidase inhibitor, meglitinide, nateglinide, or pramlintide (SYMLIN®) within 30 days of study start
  3. Insulin within 2 weeks of study start or for more than 1 week within 3 months of study start
  4. Systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR®) steroids known to have a high rate of systemic absorption
  5. Drugs interacting with the CYP2C8 enzyme system, including gemfibrozil (LOPID®) and rifampin
• Has received any investigational drug within 1 month (or five half-lives of investigational drug, whichever is greater) of study start
• Has previously experienced a clinically significant adverse event (e.g., significant edema) related to TZD or DPP-4 inhibitor use