Effect of Liraglutide or Exenatide Added to an Ongoing Treatment on Blood Glucose Control in Subjects With Type 2 Diabetes (LEAD-6)

• Change in Glycosylated A1c (HbA1c), Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Percentage point change in glycosylated A1c (HbA1c) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Change in Glycosylated A1c (HbA1c) at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Percentage point change in glycosylated A1c (HbA1c) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Percentage of subjects achieving treatment target of HbA1c less than 7.0% or less than or equal to 6.5% at Week 26 (end of randomisation)
• Percentage of Subjects Achieving Treatment Target of Either HbA1c < 7.0% or =< 6.5% at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Percentage of subjects achieving treatment target of HbA1c less than 7.0% or less than or equal to 6.5% at Week 78 (end of treatment)
• Change in Body Weight at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in body weight from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Body Weight, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in body weight from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Change in Body Weight at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in body weight from baseline (Week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Change in Fasting Plasma Glucose at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in fasting plasma glucose (FPG) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Fasting Plasma Glucose, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in fasting plasma glucose from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Change in Fasting Plasma Glucose at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in fasting plasma glucose from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group)
• Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after breakfast from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between glucose values measured before and after breakfast.
• Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after lunch from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after lunch.
• Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after dinner from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Mean Prandial Increment of Plasma Glucose After Breakfast, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after breakfast from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after breakfast.
• Change in Mean Prandial Increment of Plasma Glucose After Lunch, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after lunch from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after a lunch.
• Change in Mean Prandial Increment of Plasma Glucose After Dinner, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after dinner from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Mean Prandial Increment of Plasma Glucose After Breakfast at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after breakfast from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after breakfast.
• Change in Mean Prandial Increment of Plasma Glucose After Lunch at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after lunch from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after lunch.
• Change in Mean Prandial Increment of Plasma Glucose After Dinner at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean prandial increment of plasma glucose after dinner from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after breakfast from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after breakfast.
• Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 26 [ Time Frame: week 0. week 26 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after lunch from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after lunch.
• Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after dinner from baseline (week 0) to 26 weeks (end of randomisation). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Mean Postprandial Increment of Plasma Glucose After Breakfast, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after breakfast from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after breakfast.
• Change in Mean Postprandial Increment of Plasma Glucose After Lunch, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after lunch from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after lunch.
• Change in Mean Postprandial Increment of Plasma Glucose After Dinner, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after dinner from Week 26 (end of randomisation) to Week 78 (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Mean Postprandial Increment of Plasma Glucose After Breakfast at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after breakfast from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after breakfast.
• Change in Mean Postprandial Increment of Plasma Glucose After Lunch at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after lunch from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after lunch.
• Change in Mean Postprandial Increment of Plasma Glucose After Dinner at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in mean postprandial increment of plasma glucose after dinner from baseline (week 0) to 78 weeks (end of treatment). Prandial increments of plasma glucose were calculated as the difference between plasma glucose values measured before and after dinner.
• Change in Beta-cell Function at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]

  Change in Beta-cell function from baseline (week 0) to 26 weeks (end of randomisation). Beta-cell function was derived from fasting plasma glucose (FPG) and fasting insulin concentrations using the homeostasic model assessment (HOMA) method which uses the assumption that normal-weight normal subjects aged under 35 years have a 100% beta-cell function (HOMA-B).

  Beta-cell function: HOMA-B (%) = 20∙fasting insulin[uU/mL] divided by (FPG mmol/L]‑3.5).

• Change in Beta-cell Function, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]

  Change in Beta-cell function from Week 26 (end of randomisation) to Week 78 (end of treatment). Beta-cell function was derived from fasting plasma glucose (FPG) and fasting insulin concentrations using the homeostasic model assessment (HOMA) method which uses the assumption that normal-weight normal subjects aged under 35 years have a 100% beta-cell function (HOMA-B).

  Beta-cell function: HOMA-B (%) = 20∙fasting insulin[uU/mL] divided by (FPG mmol/L]‑3.5).

• Change in Beta-cell Function at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]

  Change in Beta-cell function from baseline (week 0) to 78 weeks (end of treatment). Beta-cell function was derived from fasting plasma glucose (FPG) and fasting insulin concentrations using the homeostasic model assessment (HOMA) method which uses the assumption that normal-weight normal subjects aged under 35 years have a 100% beta-cell function (HOMA-B).

  Beta-cell function: HOMA-B (%) = 20∙fasting insulin[uU/mL] divided by (FPG mmol/L]‑3.5).

• Change in Total Cholesterol at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in total cholesterol (TC) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Total Cholesterol, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in total cholesterol (TC) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Total Cholesterol at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in total cholesterol (TC) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Low-density Lipoprotein-cholesterol at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in Low-density Lipoprotein-cholesterol (LDL-C) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Low-density Lipoprotein-cholesterol, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in low-density lipoprotein-cholesterol (LDL-C) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Low-density Lipoprotein-cholesterol at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in Low-density Lipoprotein-cholesterol (LDL-C) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Very Low-density Lipoprotein-cholesterol at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in very low-density lipoprotein-cholesterol (VLDL-C) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Very Low-density Lipoprotein-cholesterol, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in Very Low-density Lipoprotein-cholesterol (VLDL-C) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Very Low-density Lipoprotein-cholesterol at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in Very Low-density Lipoprotein-cholesterol (VLDL-C) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in High-density Lipoprotein-cholesterol at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in High-density Lipoprotein-cholesterol (HDL-C) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in High-density Lipoprotein-cholesterol, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in High-density Lipoprotein-cholesterol (HDL-C) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in High-density Lipoprotein-cholesterol at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in High-density Lipoprotein-cholesterol (HDL-C) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Triglyceride at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in triglyceride (TG) from from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Triglyceride, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in Triglyceride (TG) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Triglyceride at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in triglyceride (TG) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Free Fatty Acid at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in Free Fatty Acid (FFA) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Free Fatty Acid, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in Free Fatty Acid (FFA) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Free Fatty Acid at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in Free Fatty Acid (FFA) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Apolipoprotein B at Week 26 [ Time Frame: week 0, week 26 ] [ Designated as safety issue: No ]
  Change in apolipoprotein B (ApoB) from baseline (week 0) to 26 weeks (end of randomisation)
• Change in Apolipoprotein B, Weeks 26-78 [ Time Frame: week 26, week 78 ] [ Designated as safety issue: No ]
  Change in apolipoprotein B (ApoB) from Week 26 (end of randomisation) to Week 78 (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Change in Apolipoprotein B at Week 78 [ Time Frame: week 0, week 78 ] [ Designated as safety issue: No ]
  Change in apolipoprotein B (ApoB) from baseline (week 0) to 78 weeks (end of treatment) within each treatment group (the liraglutide -> liraglutide group and the exenatide -> liraglutide group).
• Hypoglycaemic Episodes at Week 26 [ Time Frame: weeks 0-26 ] [ Designated as safety issue: Yes ]
  Total number of hypoglycaemic episodes occurring after baseline (week 0) and until week 26 (end of randomisation). Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.
• Hypoglyceamic Episodes, Weeks 26-78 [ Time Frame: weeks 26-78 ] [ Designated as safety issue: Yes ]
  Total number of hypoglycaemic episodes occurring after end of randomisation (week 26) and until week 78 (end of treatment). Hypoglycaemic episodes were defined as major, minor, or symptoms only. Major if the subject was unable to treat her/himself. Minor if subject was able to treat her/himself and plasma glucose was below 3.1 mmol/L. Symptoms only if subject was able to treat her/himself and with no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L.

• Body weight
• FPG
• 7-point plasma glucose profiles (self-measured)
• Fraction of subjects reaching HbA1c levels greater than or equal to 6.5% and lesser than 7.0%
• Beta-cell function and lipid profiles
• Hypoglycaemic episodes and adverse events

This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to compare the effect on glycaemic control of liraglutide or exenatide when added to subject's ongoing OAD (oral anti-diabetic drug) treatment of either metformin, sulphonylurea or a combination of both in subjects with type 2 diabetes. Two trial periods: A 26 week randomised, followed by a 52 week extension (14 + 38 weeks) where all subjects received liraglutide + OAD after previous randomisation to either liraglutide or exenatide, both combined with OAD treatment.

• Diabetes
• Diabetes Mellitus, Type 2

• Drug: liraglutide
  1.8 mg once daily for s.c. (under the skin) injection.
• Drug: exenatide
  10 mcg twice daily for s.c. (under the skin) injection.

• Experimental: Liraglutide
  Liraglutide 1.8 mg once daily + subject's own OAD treatment
  Intervention: Drug: liraglutide
• Active Comparator: Exenatide
  Exenatide 10 mcg twice daily + subject's own OAD treatment
  Intervention: Drug: exenatide

• Valentine WJ, Palmer AJ, Lammert M, Langer J, Brändle M. Evaluating the long-term cost-effectiveness of liraglutide versus exenatide BID in patients with type 2 diabetes who fail to improve with oral antidiabetic agents. Clin Ther. 2011 Nov;33(11):1698-712. Epub 2011 Oct 21.
• Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbæk N, Holst J, Nauck M. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011 Jun;96(6):1695-702. Epub 2011 Mar 30.
• Schmidt WE, Christiansen JS, Hammer M, Zychma MJ, Buse JB. Patient-reported outcomes are superior in patients with Type 2 diabetes treated with liraglutide as compared with exenatide, when added to metformin, sulphonylurea or both: results from a randomized, open-label study. Diabet Med. 2011 Jun;28(6):715-23.
• Buse JB, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J; Liraglutide Effect Action in Diabetes-6 Study Group. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010 Jun;33(6):1300-3. Epub 2010 Mar 23.
• Sullivan SD, Alfonso-Cristancho R, Conner C, Hammer M, Blonde L. Long-term outcomes in patients with type 2 diabetes receiving glimepiride combined with liraglutide or rosiglitazone. Cardiovasc Diabetol. 2009 Feb 26;8:12.

Inclusion Criteria:

• Type 2 diabetes
• Stable treatment with Oral Anti-Diabetic Drugs (metformin, sulphonylurea or a combination of both) for at least 3 months at the discretion of the Investigator
• HbA1C equal to or greater than 7.0% and equal to or lower than 11.0%
• Body Mass Index (BMI) equal to or lower than 45.0 kg/m2

Exclusion Criteria:

• Previous treatment with insulin
• Treatment with any anti-diabetic drug other than metformin and sulphonylurea
• Any previous exposure to exenatide or liraglutide
• Impaired liver or/and renal function
• History of any significant cardiac events
• Known retinopathy or maculopathy requiring acute treatment
• Recurrent major hypoglycaemia or hypoglycaemic unawareness