Effects of Exenatide and Insulin Glargine in Subjects With Type 2 Diabetes

• Beta-cell Function 4 Weeks After Cessation of Therapy [ Time Frame: Baseline (week -2) and 56 weeks ] [ Designated as safety issue: No ]
  Treatment effect on beta-cell function as measured by the ratio of Week 56 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period [i.e., clamp time 290 min to 300 min]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 56 divided by arginine-stimulated insulin secretion at baseline [week -2]).
• Change in First Phase C-peptide Release [ Time Frame: baseline (week -2), 52 weeks, and 56 weeks ] [ Designated as safety issue: No ]
  Ratio of first phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to first phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline [week -2]). C-peptide is measured as a surrogate marker of insulin secretion. First phase C-peptide/insulin release is measured during the first ten minutes of glucose infusion during a hyperglycemic clamp procedure.
• Change in Second Phase C-peptide Release [ Time Frame: baseline (-2 weeks), 52 weeks, and 56 weeks ] [ Designated as safety issue: No ]
  Ratio of second phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to second phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline [week -2]). C-peptide is measured as a surrogate marker of insulin secretion. Second phase C-peptide/insulin release is measured from time=10 minutes to time=80 minutes of glucose infusion during a hyperglycemic clamp procedure.
• Change in Glycosylated Hemoglobin (HbA1c) [ Time Frame: Week 0 and week 52 ] [ Designated as safety issue: No ]
  Change in HbA1c from week 0 to week 52 (i.e., HbA1c at week 52 minus HbA1c at week 0).
• Change in Fasting Plasma Glucose [ Time Frame: 0 weeks and 52 weeks ] [ Designated as safety issue: No ]
  Change in fasting plasma glucose from week 0 to week 52 (i.e., fasting plasma glucose at week 52 minus fasting plasma glucose at week 0).
• Seven Point Self Monitored Blood Glucose (SMBG) Measurements [ Time Frame: 0 weeks and 52 weeks ] [ Designated as safety issue: No ]
  SMBG measured at 7 time points (before and after breakfast, before and after lunch, before and after dinner, at bedtime).
• Change in Body Weight [ Time Frame: 0 weeks and 52 weeks ] [ Designated as safety issue: No ]
  Change in body weight from week 0 to week 52 (i.e., body weight at week 52 minus body weight at week 0).
• M-value at Baseline, Week 52 and Week 56 [ Time Frame: baseline (week -2), 52 weeks, and 56 weeks ] [ Designated as safety issue: No ]
  M-value at baseline (week -2), week 52 (end of on-drug period), and week 56 (during off-drug period). Insulin sensitivity was assessed during the euglycemic/hyperglycemic clamp test at baseline (week -2), week 52, and week 56. Insulin-mediated glucose uptake (M-value) was calculated as the mean glucose requirement during the 90-120 minute interval of the clamp.

This Phase 3, open-label, multicenter study is designed to compare the effects of exenatide and insulin glargine (Lantus® injection) on beta-cell function in patients with type 2 diabetes mellitus using metformin.

• Drug: exenatide
  subcutaneous injection, titrated up to a maximum of 20mcg three times a day in order to meet defined blood glucose targets
  Other Name: Byetta
• Drug: Insulin glargine
  subcutaneous injection, once a day, titrated as necessary in order to meet defined blood glucose targets
  Other Name: Lantus
• Drug: Metformin
  Patients usual dosage

• Experimental: Exenatide Arm
  Exenatide and Metformin
  Interventions:

  • Drug: exenatide
  • Drug: Metformin
• Active Comparator: Insulin Glargine Arm
  Insulin Glargine and Metformin
  Interventions:

  • Drug: Insulin glargine
  • Drug: Metformin

• Bunck MC, Cornér A, Eliasson B, Heine RJ, Shaginian RM, Taskinen MR, Smith U, Yki-Järvinen H, Diamant M. Effects of exenatide on measures of ?-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care. 2011 Sep;34(9):2041-7.
• Bunck MC, Cornér A, Eliasson B, Heine RJ, Shaginian RM, Wu Y, Yan P, Smith U, Yki-Järvinen H, Diamant M, Taskinen MR. One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress. Atherosclerosis. 2010 Sep;212(1):223-9. Epub 2010 Apr 29.

Inclusion Criteria:

• Diagnosis of type 2 diabetes, but otherwise healthy
• HbA1c between 6.6% and 9.5%, inclusive.
• Body mass index (BMI) of 25 kg/m2 to 40 kg/m2, inclusive.
• Treated with a stable dose of metformin for at least 2 months prior to screening.

Exclusion Criteria:

• Patients previously in a study using exenatide.
• Treated with oral anti-diabetic medications other than metformin within 2 months of screening (thiazolidinediones within 5 months of screening).
• Treated with insulin within 3 months of screening.