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Liraglutide Phase 2 Study Shows Increased Insulin Secretion and Improved Blood Glucose Control in People With Type 2 Diabetes

Posted on: Tuesday, 13 June 2006, 12:00 CDT

WASHINGTON, June 13 /PRNewswire/ -- Liraglutide, an investigational treatment for type 2 diabetes under development by Novo Nordisk, improved the ability of pancreatic beta cells to secrete insulin in people with type 2 diabetes, according to findings from a late-breaking presentation today at the 66th annual meeting of the American Diabetes Association (ADA).(1)

The findings from the study, part of a larger, double-blind, placebo-controlled, randomized trial conducted over 14 weeks,(2) specifically showed that liraglutide increased the maximum capacity of beta cells to secrete insulin. In addition, insulin secretion was increased in the so-called "first phase" insulin response, which is typically diminished in patients with type 2 diabetes.

The larger trial showed that liraglutide reduced levels of A1C, the primary endpoint and a measure of a person's average blood glucose level over the past two to three months. Additionally, participants on the highest dose of liraglutide lost significantly more weight than did those on placebo by the end of the 14-week study.

"The prevalence of type 2 diabetes continues to increase, and we need to research and develop new therapies for the condition," said study investigator Sten Madsbad, M.D., DMSc., Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. "We are excited by these results as they demonstrate that liraglutide monotherapy significantly improves blood glucose control without risk of major or minor hypoglycemia, is well tolerated, lowers body weight and may help improve the body's ability to produce insulin."

Pancreatic beta cells are responsible for producing insulin, a hormone that helps transport glucose from the bloodstream into body cells, providing them an important source of energy and preventing blood glucose from becoming dangerously high. People with type 2 diabetes, the most common form of the condition, do not produce enough insulin or their body cells are less sensitive to it. While diet, exercise and weight loss may initially maintain control of blood glucose levels (glycemic control), beta cell function declines over time, necessitating therapy with one or more oral antidiabetic (OAD) agents that boost insulin secretion or heighten insulin sensitivity. As beta cell function further declines and OAD therapy eventually fails, insulin therapy is required.

One problem with insulin and some OAD therapies is that they can reduce blood glucose levels too low (hypoglycemia), which can also be dangerous. Liraglutide acts to lower blood glucose only when levels become too high,(3,4) and studies show it is associated with a low risk of hypoglycemia.(5,6) Furthermore, in animal models, liraglutide has been shown to decrease beta-cell apoptosis (programmed cell death) and increase beta-cell mass.(7,8,9,10,11)

Studies and findings

The larger study was a double-blind, placebo-controlled, randomized trial conducted over 14 weeks and included 165 patients with type 2 diabetes who were previously treated with diet or a single oral antidiabetic agent. After an initial four-week washout period, patients were randomized to one of three once-daily doses of liraglutide (0.65 mg, 1.25 mg and 1.9 mg) or placebo.

Improved blood glucose control was achieved with liraglutide monotherapy. Levels of A1C, the primary endpoint, were significantly reduced compared to placebo in all liraglutide treatment groups (p<0.0001). At the highest dose, the average reduction of A1C vs. placebo was 1.74 percent. Between 43 and 50 percent of patients who received liraglutide and 8 percent on placebo reached an A1C level of less than or equal to 7 percent. The improved glycemic control was achieved with no major or minor hypoglycemic episodes. In addition, patients on liraglutide had a reduction in bodyweight, with those on the highest dose losing approximately three kg (6.6 pounds) vs baseline and 1.2 kg (2.5 pounds) vs placebo after 14 weeks.

Liraglutide was well tolerated by participants in all groups, with the main adverse events being related to the gastrointestinal (GI) system. Nausea, which was experienced by 10 percent of participants in the high-dose group, and diarrhea, were the most common adverse events; however, the frequency of all GI events declined over time.

The late-breaking findings were from a subgroup of 39 participants who were also part of the larger trial. At baseline and after 14 weeks, these participants underwent standard tests to assess first-phase insulin secretion and maximal beta cell insulin secretory capacity. Of 39 participants who began the study, 28 completed the 14 weeks of treatment. The two higher doses of liraglutide (1.25 mg and 1.9 mg) significantly increased maximal beta cell insulin secretory capacity compared to placebo by 114 percent and 97 percent, respectively (p<0.05 for both doses), and first-phase insulin secretion by 124 percent and 107 percent, respectively (p<0.05).

About liraglutide

Currently in phase 3 clinical trials, liraglutide is a long-acting analog(12) 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. GLP-1 is released from the gastrointestinal tract upon ingestion of food. When glucose levels become too high, GLP-1 triggers the release of insulin from the pancreas(13) and decreases the secretion of glucagon,(14) a hormone that promotes glucose synthesis in the liver. GLP-1 releases insulin in a glucose-dependent manner, meaning that it only triggers insulin secretion if blood glucose is too high. This characteristic results in a low risk of hypoglycemia, which has been confirmed in a number of studies in which GLP-1 was infused intravenously or subcutaneously.(15,16,17,18,19,20)

Studies to date show that liraglutide significantly improves glycemic control in monotherapy and in combination therapy with metformin.(21,22,23,24) Clinical trials have shown liraglutide:

-- Acts in a glucose-dependent manner, meaning that it stimulates insulin secretion and inhibits glucagon secretion only when blood glucose levels are higher than normal.(25,26) -- Has a low risk of hypoglycemia.(27,28) -- Improves markers of beta cell function.(29,30) -- Is not associated with weight gain.(31) -- Is associated with mild to moderate and transient GI side effects. (32,33) -- Is suitable for once-daily administration.

Novo Nordisk is a healthcare company with an 80-year history of innovation and achievement in diabetes care. In addition to diabetes care, Novo Nordisk has a leading position within areas such as hemostasis management, growth hormone therapy, and hormone therapy for women. Novo Nordisk's business is driven by the Triple Bottom Line: a commitment to economic success, environmental soundness, and social responsibility to employees and customers. With headquarters in Denmark, Novo Nordisk employs more than 22,500 employees in 79 countries, and markets its products in 179 countries. Novo Nordisk's B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol 'NVO'. For global information, visit http://novonordisk.com/; for United States information, visit http://novonordisk-us.com/.

References: (1) Vilsboell T, Brock B, Perrild H, et al. 14 weeks of liraglutide therapy in subjects with T2DM significantly improves 1st phase insulin secretion and maximal beta-cell secretory capacity. Late- breaking oral presentation (abstract 750195) at: 66th annual meeting of the American Diabetes Association, Washington, DC, June 9-13, 2006. (2) Vilsboell T, Zdravkovic M, Le-Thi T, et al. Liraglutide significantly improves glycemic control, and lowers body weight without risk of either major or minor hypoglycemic episodes in subjects with type 2 diabetes. Oral presentation (abstract # 115-OR) at: 66th annual meeting of the American Diabetes Association, Washington, DC, June 9-13, 2006. (3) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. (4) 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. (5) 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. (6) 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. (7) 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. (8) 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. (9) 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. (10) Bregenholt S et al. The GLP-1 derivative NN2211 inhibits cytokine- induced apoptosis in primary rat b-cells. Diabetes 2001:50(S2):A31. (11) Bregenholt S, Moldrup A, Blume N, Karlsen AE, Nissen Friedrichsen B, Tornhave D, Knudsen LB, Petersen JS. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem Biophys Res Commun. 2005 May 6;330(2):577-84. (12) 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. (13) Vilsboell et al. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients Diabetologia 2002;45:1111-1119 (14) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long- acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. (15) Rachman J et al. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997 Feb;40(2):205-11. (16) Toft-Nielsen MB et al Determinants of the effectiveness of glucagon- like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001 Aug;86(8):3853-60. (17) Zander M et al Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes. Diabetes Care. 2004 Aug;27(8):1910-4. (18) Zander M et al Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002 Mar 9;359(9309): 824-30. (19) Zander M et al Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care. 2001 Apr;24(4):720-5. (20) Meneilly GS et al Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care. 2003 Oct;26(10):2835-41. (21) Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O; Liraglutide Dose-Response Study Group. Effects of liraglutide (NN2211), a long- acting GLP-1 analogue, on glycemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005 Aug;22(8):1016-23. (22) Harder H, Nielsen L, Tu DT, Astrup A. 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. Diabetes Care. 2004 Aug;27(8):1915-21. (23) Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; NN2211-1310 International Study Group. 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. (24) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long- acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. (25) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long- acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. (26) 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. (27) 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. (28) 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. (29) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long- acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004 May;53(5):1187-94. (30) 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. (31) Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR; NN2211-1310 International Study Group. 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. (32) Ibid (33) Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O; Liraglutide Dose-Response Study Group. Effects of liraglutide (NN2211), a long- acting GLP-1 analog, on glycemic control and bodyweight in subjects with Type 2 diabetes. Diabetes Med. 2005 Aug;22(8):1016-23.

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CONTACT: Media: An Phan, +1-609-987-4893, or Investors: Mads VeggerbyLausten, +1-609-919-7937, both for Novo Nordisk

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