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Title: Combination Therapy With Insulin Sensitizers: Presented at Prandin (Repaglinide) Approved for New Indication

"Combination Therapy With Insulin Sensitizers: Presented at Prandin (Repaglinide) Approved for New Indication"

Studies Show Greater Glycemic Improvements With Prandin and Sensitizers Compared to Monotherapy in Treating Type 2 Diabetes PRINCETON, NJ -- October 22, 2002 -- Novo Nordisk announced today that the U.S. Food and Drug Administration (FDA) approved a new indication for use of the oral antidiabetic drug (OAD) Prandin® (repaglinide): combination therapy with rosiglitazone or pioglitazone, members of another class of OADs called insulin sensitizers, for the treatment of type 2 diabetes. Prandin, an "insulin secretagogue" because it stimulates insulin secretion, was previously approved for use as monotherapy or in combination with metformin, another type of insulin sensitizer. The new indication for Prandin is important because combination therapy may improve control of blood glucose levels for many people with type 2 diabetes whose condition has progressed and oral monotherapy together with diet and exercise cannot maintain adequate glycemic control. At that point, combination therapy with an additional OAD with a different mechanism of action may be appropriate. "Prandin is a highly effective agent to use with insulin sensitizers because of its ability to augment mealtime insulin secretion and proven efficacy in attaining glycemic control," said Alan J. Garber, M.D., Ph.D., professor of medicine, biochemistry and cell biology at Baylor College of Medicine in Houston. He explained that Prandin, which is taken with meals, in part to control postprandial glycemia, rapidly stimulates insulin secretion, whereas insulin sensitizers primarily improve the body's response to the hormone. He said that two recent studies support this combination approach, showing that, among patients previously poorly controlled with monotherapy with either a sulfonylurea or metformin, "the combination of Prandin with a sensitizer resulted in better blood glucose control than monotherapy with either of these agents alone." Supportive findings The FDA approval was based in large part on findings from two studies of Prandin in combination with either rosiglitazone (1, 2) or pioglitazone (3, 4) (preliminary data was presented at the American Diabetes Association annual meeting, 2001). Each study was a multicenter, open-label, randomized, 24-week trial in approximately 250 participants with type 2 diabetes inadequately controlled by previous oral therapy with sulfonylureas or metformin. The trials consisted of 12 weeks of dose-adjustment and 12 weeks of maintenance therapy. "Both studies showed significant improvement in glycemic control with Prandin in combination with the insulin sensitizer compared to monotherapy with these agents," said Dr. Garber. He added that, because the benefits were shown in patients who previously had unsatisfactory glycemic control with sulfonylurea or metformin monotherapy, the findings "are important for many people with type 2 diabetes who need to improve glycemic control, and provide new approaches to attaining control for patients as well as the physicians who treat them." In the Prandin-rosiglitazone trial, levels of glycated hemoglobin (A1c) -- the percent hemoglobin with glucose attached to it and an indicator of long-term blood glucose control -- decreased by 1.43% (from 9.1% at baseline to 7.7% at the end of the trial) for the Prandin/rosiglitazone group, but only by 0.17% and 0.56% for the Prandin-only and rosiglitazone-only groups, respectively. Fasting plasma glucose levels decreased by 94 mg/dL, 54 mg/dL, and 67 mg/dL in the Prandin/rosiglitazone, Prandin-only and rosiglitazone-only groups, respectively. Declines in A1c and fasting plasma glucose in the Prandin/rosiglitazone group were significantly greater than in the two monotherapy groups (p < 0.001). The results in the Prandin-pioglitazone trial were very similar. A1c levels decreased by 1.76% (from 9.3% to 7.5%) in the combination group, compared to changes of -0.18% and +0.32% in the Prandin-only and pioglitazone-only groups, respectively. Fasting plasma glucose levels decreased by 82 mg/dL, 34 mg/dL, and 19 mg/dL in the three groups, respectively. Declines in A1c and fasting plasma glucose in the Prandin/pioglitazone group were significantly greater than in the two monotherapy groups (p < 0.001). In these studies, hypogycemia occurred in 7% of combination therapy patients in comparison to 7% for Prandin monotherapy and 2% for sensitizer monotherapy patients. Peripheral edema was reported in 12 out of 250 patients who received combination therapy and 3 out of 124 who received only sensitizers, with no cases reported for those who received Prandin. There were reports in 2 patients, both of whom had a prior history of coronary artery disease, of episodes of edema with congestive heart failure. Both recovered after diuretic treatment. No such cases were reported in the monotherapy groups. Mean weight change was +4.9 kg for the combination therapy groups from the 2 studies. About Prandin (Repaglinide) Tablets Prandin (repaglinide), the first product of a unique class (the meglitinides), rapidly stimulates insulin secretion, and its action profile coincides with mealtime dosing to control postprandial glycemia (5). Prandin is indicated as monotherapy or in combination with metformin, rosiglitazone or pioglitazone for individuals with type 2 diabetes whose hyperglycemia (abnormally high blood glucose) cannot be controlled by diet and exercise alone plus monotherapy with metformin, sulfonylureas, repaglinide or thiazolidinediones (rosiglitazone / pioglitazone). While it improves overall glycemic control, including fasting blood glucose levels, (6) Prandin was developed specifically for dosing at mealtime, to control postprandial hyperglycemia as well. In addition, Prandin may allow greater flexibility in eating patterns. In one-year clinical trials, the most common adverse events leading to discontinuation of Prandin therapy were hyperglycemia, hypoglycemia and related symptoms. The most common other side effects reported were cold- and flu-like symptoms, headache, diarrhea, joint ache and back pain. About Diabetes The prevalence of diabetes is skyrocketing in many countries around the world. According to the World Health Organization (WHO), the number of people worldwide with the condition was estimated at 30 million in 1985, 135 million in 1995, and 177 million in 2000, and is expected to increase to at least 300 million by 2025. Overall, direct health care costs of diabetes range from 2.5% to 15% of annual national health care budgets, depending on diabetes prevalence and the sophistication of the treatment available (7). Full prescribing information for Prandin is available by contacting Novo Nordisk Pharmaceuticals, Inc. Prandin is a registered trademark of Novo Nordisk A/S and is protected by patents and patents pending. Novo Nordisk is a focused healthcare company and the world leader in diabetes care. In addition, Novo Nordisk has a leading position within areas such as hemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society. With headquarters in Denmark, Novo Nordisk employs approximately 17,500 people in 68 countries and markets its products in 179 countries. For further company information visit http://www.novonordisk.com. References (1) Raskin P, McGill J, Hale P, Khutoryansky N, Santiago O. Repaglinide/Rosiglitazone combination therapy of type 2 diabetes. Presented at: American Diabetes Association annual meeting, Philadelphia, PA, June, 2001. Abstract 516-P. Diabetes 2002; 50(Suppl. 2): A128. (2) Data on file, Novo Nordisk. (3) Jovanovic L, Jain R, Greco S, Hale P, Khutoryansky N, Santiago O. Repaglinide/Pioglitazone combination therapy of type 2 diabetes. Presented at: American Diabetes Association annual meeting, Philadelphia, PA, June, 2001. Abstract 1830-P. Diabetes 2002; 50(Suppl.2): A439. (4) Data on file, Novo Nordisk. (5) Owens S, Luzio SD, Ismail I, Bayer T. Increased prandial insulin secretion following a single preprandial oral dose of repaglinide in patients with type 2 diabetes. Diabetes Care 2000; 23:513-523. (6) Goldberg RB, Einhorn D, Lucas CP, Rendell MS, Damsbo P, Huang WC, Strange P, Brodows RG. A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabetes Care 1998; 21(11):1897-1903. (7) The World Health Organization. The Cost of Diabetes. Fact Sheet N 236, revised September 2002. http://www.who.int/mediacentre/factsheets/fs236/en/ SOURCE: Novo Nordisk

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