Arg(34)Lys(26)-(N- epsilon -(gamma-Glu(N-alpha-hexadecanoyl))-GLP-1(7-37)
Liraglutide,
a long-acting DPP-4-resistant GLP-1R
agonist, has been developed predominantly
for the treatment of type 2 diabetes, although exploratory studies of Liraglutide action in obese non-diabetic subjects are underway-see the November
20 2007 Press Release on Phase 2 study of Liraglutide in obese subjects.
The long-acting DPP-4-resistant GLP-1R agonist liraglutide was assessed in a randomized study of patients with T2DM for 5 weeks with metformin plus liraglutide, liraglutide alone, metformin alone, or metformin plus glimepiride (open label). The dose of liraglutide was increased weekly and ranged from from 0.5 to 2 mg daily. Liraglutide added to metformin monotherapy was significantly reduced fasting glucose (-3.9 mM -4.9; -2.9) and HbA1c (-0.8% -1.2; -0.4) together with a reduction in body weight (-2.9 kg in the metformin + liraglutide group). See Five Weeks of Treatment with the GLP-1 Analogue Liraglutide Improves Glycaemic Control and Lowers Body weight in Subjects with Type 2 Diabetes. Exp Clin Endocrinol Diabetes. 2006 Sep; 114 (8):417-23
Subsequent studies evaluated the use of liraglutide as monotherapy in patients with type 2 diabetes controlled on diet alone, or following discontinuation of oral agents. Fasting plasma glucose at the time of randomization was 7-13 mM. Three doses of liraglutide were examined; 0.625, 1.25 and 1.9 mg daily. Liraglutide was well tolerated and resulted in placebo-subtracted changes in HbA1c of up to 1.7% after 14 weeks of therapy, with 46% of patients reaching a HbA1c of less than 7% at the highest dose examined. Liraglutide therapy also reduced the proinsulin;insulin ratio, and a mean weight loss of almost 3 kk was observed in patients receiving 1.9 mg daily. See Liraglutide, a long-acting human GLP-1 Analog, given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight without Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus. Diabetes Care. 2007 Mar 19; [Epub ahead of print]
Th efficacy of liraglutide was assessed in Japanes subjects with type 2 diabetes, mean pre-treatment hbA1c of 8.3%, as monotherapy, in some patients after OAD washout, for 14 weeks. Liraglutide therapy was associated with substantial dose-dependent reductions in HbA1c, fasting and postprandial glucose, and beta cell function. Unexpectedly, no weight loss was observed in this study. See Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: A double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008 May 19. [Epub ahead of print]
Liraglutide has been compared in a head to head study with twice daily exenatide in subjects with type 2 diabetes taking metformin, a sulfonylurea, or both. Liraglutide produced supperior reductions in A1c relative to exenatide (1.1 vs 0.8%) and allowed more patients to achieve ADA glycemic targets, with similar reductions in body weight observed for both exenatide and liraglutide (about 3 kg). See the Liraglutide Lead 6 June 6 2008 Press Release.
Phase 3 Clinical Trial Data in Press Release form for Liraglutide
Phase 2B Clinical Trial results for Liraglutide were provided by Novo Nordisk in a November 25 2005 Press Release
A clinical trial of single dose subcutaneous of Liraglutide (NN2211) was carried out in healthy male subjects utilizing a randomized double blind design with a dose escalation ranging from 1.25-20 ug/kg. No serious adverse reactions were reported, and all subjects completed the study, however headaches, dizziness, nausea and vomiting were reported more frequently in drug-treated subjects. Nausea and vomiting were more prominent at the higher dosing levels. Only modest glucose lowering effects were seen in the normal subjects, with insulin levels trending lower. Insulin secretion was increased following IVGTT in Liraglutide-treated subjects. See Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects. Diabetes Care. 2002 Aug;25(8):1398-404 and The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002 Feb;45(2):195-202
Liraglutide was administered to 11 patients with mild Type 2 diabetes, mean age 59, HbA1c 6.5%, mean duration of diabetes 2.7 years (range 2 months to 12 years). Treatment with oral agents was stopped 2 days before the study period. Liraglutide 10 ug/kg was given by sc pen injection into the abdomen at 23:00. Blood sampling in the fasting and postprandial state was then used to assess the effect of liraglutide, and gastric emptying was assessed by co-administration of 3-OMG with a 2500 kJ meal at 11:30 am the next day.
The key findings from this study include a decrease in both fasting and meal-related glycemic excursion, and an increase in insulin secretory capacity as assessed by HOMA. Pharmacokinetic profiling revealed a drug t1/2 of ~10+ 4 hours. Two patients experienced treatment-associated nausea, one mild, and one moderate, and these patients had the highest peak levels of liraglutide (over 11 nM). These findings illustrate the therapeutic properties of this analog, and highlight some of the challenges for therapeutic delivery of a GLP-1 analog, namely balancing maximum efficacy with tolerability across a broad spectrum of patients. To review the data, see Bedtime Administration of NN2211, a Long-Acting GLP-1 Derivative, Substantially Reduces Fasting and Postprandial Glycemia in Type 2 Diabetes. Diabetes. 2002 Feb;51(2):424-429
Subjects treated with varying doses of once daily liraglutide (193) with a mean initial HbA1c of 7.6% were randomly assigned to fixed-dosage groups ranging from 0.045, 0.225, 0.45, 0.60, or 0.75 mg), placebo, or open-label sulfonylurea (glimepiride, 1-4 mg). In the 0.75-mg liraglutide group, HbA(1c) decreased by 0.75, body weight decreased by 1.2 kg in the 0.45-mg liraglutide group and the proinsulin-to-insulin ratio was also improved (decreased). See Improved Glycemic Control With No Weight Increase in Patients With Type 2 Diabetes After Once-Daily Treatment With the Long-Acting Glucagon-Like Peptide 1 Analog Liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004 Jun;27(6):1335-42
Liraglutide also improves selected parameters of β-cell function in human subjects with type 2 diabetes. A 14 week study of patients with T2DM treated with different doses of liraglutide revealed improved glucose-and arginine-stimulated insulin secretion, as outlined in Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic β-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus. Diabet Med. 2008 Jan 14; [Epub ahead of print]
An 8 week study of liraglutide in 33 obese subjects with Type 2 diabetes with a mean entry HbA1c examined glycemic control, body weight and energy expenditure in subjects treated with a single daily dose of 0.6 mg per day. Liraglutide reduce HbA1c (0.33%), decreased plasma glucose, prevented weight gain, with no effect on energy expenditure. See The Effect of Liraglutide, a Long-Acting Glucagon-Like Peptide 1 Derivative, on Glycemic Control, Body Composition, and 24-h Energy Expenditure in Patients With Type 2 Diabetes
A 12 week study of Liraglutide in assessed the efficacy of once daily liraglutide compared to metformin in type 2 diabetes. Liraglutide produced comparable HbA1c reduction with prevention of weight gain, as described in Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005 Aug;22(8):1016-23
Liraglutide - Preclinical Data
Liraglutide has been studied in a number of different of preclinical models. Liraglutide at a comparatively large doses of 200 ug/kg twice daily for 10 days inhibited food intake and decreased body weight in MSG-treated obese rats. A 7-day Liraglutide treatment of normal rats produced a decrease in energy expenditure, however normalizing the effect for the degree of weight loss revealed no change in EE per weight unit of lean body mass. See Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes. 2001 Nov;50(11):2530-9
The properties of Liraglutide have also been examined in mice and pigs. Liraglutide dose-dependently reduced blood glucose in ob/ob mice, with evidence for antihyperglycemic activity still evident 24 h after Liraglutide administration. Although an initial reduction in food intake was observed, body weight was not affected during the 2 week study period. Consistent with the effects of other GLP-1R agonists, Liraglutide increased β cell proliferation and β cell mass. See The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E745-52
The acute and chronic effects of Liraglutide have been examined in minipigs. Liraglutide acutely increased insulin and inhibited glucagon secretion, and decreased gastric emptying, similar to findings with other GLP-1R agonists. Liraglutide also acutely increased glucose utilization during a hyperglycaemic glucose clamp. See NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs. Eur J Pharmacol. 2002 Sep 13;451(2):217-25
A head to head study of the DPP-4 inhibitor Vildagliptin vs. Vildagliptin, however there were no major differences in glucose or HbA1c, whereas plasma insulin levels were significantly higher in rats treated with Vildagliptin. Both Vildagliptin and β-cell mass compared to vehicle-treated candy-fed rats. Hence, both drugs appear to be reasonably potent controlling blood glucose, whereas GLP-1R agonists may be associated with reduced food intake and weight loss. See Liraglutide, a Long-Acting Glucagon-Like Peptide-1 Analog, Reduces Body Weight and Food Intake in Obese Candy-Fed Rats, Whereas a Dipeptidyl Peptidase-IV Inhibitor, Vildagliptin, Does Not. Diabetes. 2007 Jan;56(1):8-15