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Studies Show Liraglutide Improves Glycemic Control in Monotherapy and Combination Therapy With Metformin

ORLANDO, Fla., June 8 /PRNewswire-FirstCall/ -- New studies presented today and last Sunday at the 64th annual meeting of the American Diabetes Association (ADA) highlight the potential of liraglutide, Novo Nordisk's investigational treatment for type 2 diabetes. One study in patients showed that liraglutide, used alone or in combination with metformin, improves glycemic control (fasting serum glucose) compared to using metformin alone. In combination with metformin, liraglutide improved both glycemic control (fasting serum glucose) and weight control when compared to glimepiride with metformin.(1) Another study in animals showed that liraglutide demonstrated decreased food intake and weight loss compared with another investigational drug (LAF237).(2)

"These new findings add to the growing body of data supporting the potential of liraglutide as a promising and valuable therapy for treating type 2 diabetes," said Professor Michael Nauck, Diabeteszentrum, Bad Lauterberg, Germany, who presented these latest clinical data on liraglutide. He explained that the treatment of type 2 diabetes is complicated by the need to treat frequent co-morbid conditions such as obesity, but that none of the currently available medications result in weight loss.

"Liraglutide represents a novel and entirely new approach to diabetes management and its multiple effects make it a promising therapy for this disorder," adds Professor Garber, Baylor College of Medicine, Houston, Texas.

Novel and broad action
Having completed Phase 2 clinical trials, liraglutide is a long-acting analog(3) of the naturally occurring hormone, Glucagon-Like Peptide-1 (GLP-1), which is rapidly broken down in the body and thus not practical as a therapy for type 2 diabetes. Studies to date show that liraglutide significantly improves glycemic control in monotherapy and in combination therapy with metformin. Liraglutide may present therapeutic benefits for type 2 diabetes because it:

* Acts in a glucose-dependent manner, meaning that it will stimulate insulin secretion and inhibit glucagon secretion only when blood glucose levels are higher than normal.(6,7)

* Has a low risk of hypoglycemia as observed in clinical studies to date.(4,5)

* Improves markers of beta cell function in patients. In a one-week trial in 13 patients, liraglutide treatment improved all parameters in standard beta cell function-tests (IVGTT, arginine stimulation, and hyperglycemic clamp) and, in a single-dose trial in 10 patients, beta-cell sensitivity to glucose was restored (ISR in response to graded glucose infusion).(6,7)

* Has the potential for beta cell regeneration as seen in animal studies.(8,9,10,11)

* Controls body weight. In a 12-week trial, liraglutide and glimepiride offered similar glycemic control but liraglutide was associated with a significant weight reduction compared with glimepiride treatment.(4)

* Is associated with mild to moderate and transient GI side effects as seen in two 12-week trials exposing more than 300 patients to liraglutide.(4,5)

* Is suitable for once-daily administration. A short-term trial demonstrated that once-daily dosing of liraglutide significantly improves the 24-hour BG profile(6) and all results in patients referenced above were obtained with once-daily dosing.

Studies and findings
A randomized, double-blind clinical trial in 144 subjects with type 2 diabetes,(1) examined the effects on glycemic control and body weight of liraglutide alone or in combination with metformin compared with metformin alone or in combination with glimepiride. Glimepiride belongs to the sulfonylurea class of OADs, and acts by stimulating the release of insulin from the pancreas; metformin is in a different class of OADs (biguanide), and acts by increasing the body's sensitivity to insulin, lowers glucose production by the liver and lowers gut absorption of glucose.

After five weeks, the treatment comparisons showed that liraglutide, used alone, resulted in a significant reduction in fasting serum glucose (-1.37mM) compared with metformin alone. In combination with metformin, liraglutide demonstrated improved glycemic and weight control compared with glimepiride. The liraglutide + metformin group had a 1.25 mM greater decrease in fasting serum glucose and lost 2.9 kg more body weight than did the glimepiride with metformin group.

Thus, despite better glycemic control, weight loss was observed in the liraglutide and metformin group (2.4 percent) but not in the glimepiride and metformin group where weight gain was seen (+0.9 percent) compared to baseline. There were no biochemically confirmed episodes of hypoglycemia with liraglutide treatment (alone or in combination with metformin). Gastrointestinal side effects, although reported frequently, were mild to moderate and transient in nature. The most common gastrointestinal side effect was nausea, resulting in the withdrawal of 3 out of 72 subjects exposed to liraglutide or liraglutide in combination with metformin.

A preclinical study(2) compared the effects of liraglutide with the investigational drug LAF237 in diet induced obese rats fed with chow and candy to mimic the excessive food intake associated with human obesity. The presented data suggest that there are significant pharmacodynamic differences between the two drugs; whereas liraglutide is a long-acting analog of native GLP-1, LAF237 is a DPP-IV inhibitor. DPP-IV inhibitors work by rescuing endogenous peptides normally metabolized by DPP-IV, including but not limited to GLP-1. Thus, liraglutide gives rise to chronically elevated GLP-1 levels, whereas LAF237 gives rise to increased postprandial levels of endogenous GLP-1 and other peptide hormones. By the end of the 12-week study, liraglutide- treated rats significantly decreased their intake of candy and their body weight to the level of the lean control group. In contrast, LAF237-treated rats did not decrease their calorie intake, gained weight, and were significantly heavier than the lean control group.

Novo Nordisk expects to initiate Phase 3 clinical trials in the second half of 2004.

(1) Nauck MA et al. Liraglutide significantly improves glycemic control and reduces body weight compared with glimepiride as add-on to metformin in type 2 diabetes. Oral presentation / publication number 356-OR, presented at: 64th annual meeting of the American Diabetes Association, Orlando, Florida, June 4-8, 2004.
(2) Knudsen LB et al. Liraglutide, a long-acting GLP-1 derivative, reduces body weight and food intake in obese candy fed rats while the DPP-IV inhibitor LAF237 does not. Presentation number: 1408-P. Presentation Category: 18 C - Integrated Physiology - GLP-1, GIP, and other Gut Hormones, presented at: 64th annual meeting of the American Diabetes Association, Orlando, Florida, June 4-8, 2004.
(3) Knudsen LB, et al. GLP-1 derivatives as novel compounds for the treatment of type 2 diabetes: selection of NN2211 for clinical development. Drugs of the Future 2001, 26(7): 677-685.
(4) Matthews S et al. A long-acting GLP-1 derivative, NN2211: its use in the treatment of type 2 diabetes. Poster 678. Presented at: European Association for the Study of Diabetes annual meeting, Budapest, Hungary, September, 2002.
(5) Saad et al. The effect of NN2211, a long-acting GLP-1 derivative, on glycemic control and body weight in obese patients with Type 2 diabetes Diabetologia 2002;45(Suppl 2)A44. Presented at: European Association for the Study of Diabetes annual meeting, Budapest, Hungary, September, 2002
(6) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, et al. One week's treatment with the long-acting GLP-1 derivative, liraglutide (NN2211), markedly improves 24-h glycaemia, a- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53:1187-1194.
(7) Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, Galecki A, Halter JB. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003; 52:1786-1791.
(8) Sturis J, Gotfredsen CF, Romer J, Rolin B, Ribel U, Brand CL, et al. GLP-1 derivative liraglutide in rats with beta-cell deficiencies influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol 2003; 140:123-132.
(9) Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB. The long-acting GLP-1 derivative, NN2211, ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrin Metab 2002; 283:E745-E752.
(10) Bregenholt S et al. The GLP-1 analogue, NN2211, inhibits free fatty acid-induced apoptosis in primary rat b-cells. Diabetologia 2001; 44(S1):A19.
(11) Bregenholt S et al. The GLP-1 derivative NN2211 inhibits cytokine- induced apoptosis in primary rat b-cells. Diabetes 2001:50(S2):A31

Source: Novo Nordisk

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