Liraglutide H2H vs. Sitagliptin

An open label study assessed  the consequences of adding sitagliptin vs. liraglutide to patients not achieving adequate glycemic control on metformin (1.5 gm) (mean HbAc 7.5-10%). Both 1.8 (221 patients) and to a lesser extent, 1.2 mg of liraglutide (225 pts) were significantly more effective than sitagliptin (219 pts) in lowering HbA1c. Similarly, significantly more patients achieved HbA1c targets and lost weight on liraglutide compared to sitagliptin, however heart rate and reported nausea was higher in liraglutide-treated patients. Blood pressure reductions were not significant in this study. See Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial The Lancet 375:9724;1447-1456

Lead-1 Add oN To SU  Liraglutide vs rosiglitazone

Liraglutide (0.6-1.8 mg) or rosiglitazone 4 mg/day or placebo (n = 114) was added to patients receiving background therapy with glimepiride (2-4 mg/day) over 26 weeks. Liraglutide produced superior glucose lowering compared to placebo or rosiglitazone, with greater reductions in postprandial glucose, and less weight gain, relative to rosiglitazone. See Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009 Mar;26(3):268-78

Lead-2 Add oN Metformin

Data from the head to head clinical trial of liraglutide (0.6-1.8 mg) vs. glimepiride (4 mg)in patients already treated with metformin reveals liraglutide exerts comparable efficacy (about a 1% reduction in HbA1c from a mean starting HbA1c of 8.4%) compared to glimepiride over 26 weeks, with weight loss and less hypoglycemia but more nausea. Liraglutide was also associated with a small decrease in blood pressure and an increase in heart rate. See Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care. 009 Jan;32(1):84-90.

Lead-3 Monotherapy vs. Glimepiride

A 52 week head to head clinical trial of liraglutide (1.2-1.8 mg) vs. glimepiride (8 mg) in patients not taking other diabetes medications reveals liraglutide exerts superior efficacy (about a 1.14 % reduction in HbA1c from a mean starting HbA1c of 8.3-8.4%) compared to glimepiride over 52 weeks, with weight loss, reduced blood pressure and less hypoglycemia but more nausea. Changes in parameters of b-cell function were comparable in patients treated with liraglutide vs glimepiride. See Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009 Feb 7;373(9662):473-81

Lead-4 Combination therapy with metformin and TZDs (Rosiglitazone)

Zinman and colleagues reported the results of adding Liraglutide, 1.2 or 1.8 mg to patients treated concomitantly with metformin and rosiglitazone. Liraglutide produced a 1.5% reduction, with reduced fasting and postprandial glucose, and a reduction in body weight and systolic blood pressure. GI side effects and minor hypoglycemia were more common in liraglutide-treated subjects. The changes in blood pressure were most notable in this study, with a decrease in systolic blood pressure of 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively See Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care. 2009 Jul;32(7):1224-30.

LEAD 5 Liraglutide vs. insulin glargine

The effiacy of Liraglutide 1.8 mg once daily (n = 232), was compared to liraglutide placebo (n = 115) vs. open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Liraglutide reduced HbA(1c) significantly vs glargine (1.33% vs 1.09%; -0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (-1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference -3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide also reduced systolic BP (-4.0 mmHg) vs glargine (+0.5 mmHg; -4.5 mmHg difference) but not vs placebo (p = 0.0791). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009 Oct;52(10):2046-55

the Lead 6 study (liraglutide-Victoza) head to head vs Exenatide)

In a head to head 26 week study of Liraglutide vs. Exenatide, Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, on liraglutide, p=0.0015). Liraglutide also reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight loss (liraglutide -3.24 kg vs exenatide -2.87 kg) and nausea was less persistent and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode The duration of nausea and rates of minor hypoglycemia were also reduced in subjects treated with liraglutide Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009 Jul 4;374(9683):39-47

Data from a 14-week extension of the LEAD(TM) 6 phase 3b study assessed the impact of either continuing liraglutide or switching from exenatide to liraglutide. Patients who switched from exenatide to liraglutide experienced a reduction in HbA1c of 0.3 percentage points, a decrease in fasting plasma glucose of 0.9 mmol/L, weight loss of approximately 1 kg, and a reduction in systolic blood pressure of close to 4 mm Hg 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.

Immunogenicty in the Lead 6 trials

As GLP-1R agonists are injectable peptides/proteins, they all have the potential to generate antibodies, and other immune reactions. Indeed, clinical development of Taspoglutide, a human GLP-1R agonist, has been suspended pending clarification of immunogenicity issues arising in clinical trials. Buse and colleagues examined the immunogenicity of liraglutide in the LEAD clinical trial program.  Just less than 9% of patients developed anti-liraglutide antibodies, whereas 61% of patients on exenatide developed antibodies in LEAD-6. the proportion of patients developing immunoneutralizing antisera that impacted A1c reduction was low, but slightly higher in subjects treated with exenatide. About 5% of lliraglutide-treated patients had antibodies that cross-reacted with GLP-1, and 1% of liraglutide-treated patients developed immunoneutralizing antibodies. The presence of anti-exenatide antibodies did not affect the glycemic response to liraglutide when patients were switched from exenatide to liraglutide. Injection site reactions (~1%) were reported in patients treated with either exenatide or liraglutide 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 Mar 30 .

An overview an summary of the entire LEAD Phase 3 program for Liraglutide (Victoza) was presented at the NN Global Investor Day on September 26 2008