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Title: Repaglinide Shows Greater Improvement in Blood Glucose Control Than Nateglinide in Type 2 Diabetes

"Repaglinide Shows Greater Improvement in Blood Glucose Control Than Nateglinide in Type 2 Diabetes"

PRINCETON, NJ -- June 26, 2003 -- Administration of the oral antidiabetic drug (OAD) repaglinide (called Prandin® in the United States, NovoNorm® in Europe, and Gluconorm® in Canada) in people with type 2 diabetes resulted in significantly greater reductions in blood glucose markers than nateglinide when taken in combination with metformin, according to a study published in the current issue of Diabetes Care. Although both agents are designed for people with type 2 diabetes to take with meals to control the rise in blood glucose following food consumption, the new report shows that repaglinide therapy results in greater improvement in levels of A1C (the percentage of hemoglobin with glucose attached and an indicator of long-term blood glucose control) and fasting plasma glucose (FPG). The study is the first head-to-head comparison of repaglinide and nateglinide in combination with metformin. "Improving glycemic control is one of the main goals in diabetes therapy," said lead investigator Philip Raskin, M.D., professor of medicine and Clifton and Betsy Robinson Chair in Biomedical Research at the University of Texas Southwestern Medical Center in Dallas, Texas. "Our findings suggest that repaglinide, when compared with nateglinide, in combination with metformin, offers healthcare professionals greater control over both A1C, and FPG in type 2 diabetes -- and controlling both of these parameters is necessary for optimal glycemic control," he said. Study and findings The open-label, randomized, multicenter trial enrolled 192 participants with type 2 diabetes who had inadequate glycemic control, as determined by A1C levels (>7% < 12%). Prior to the study, the participants had been treated with other OADs: a sulfonylurea, which stimulates insulin production; metformin, which increases the body's responsiveness to insulin; or low-dose combination therapy with metformin and the sulfonylurea glyburide. At the beginning of the study, participants discontinued their previous therapy and, during a four-week run-in period, started dose escalation with metformin (to 1000 mg twice daily). Participants were then randomly assigned to additional therapy with either repaglinide (1-4 mg/meal, n=96) or nateglinide (120 mg/meal [dose could be reduced to 60 mg/meal if hypoglycemic events made it necessary], n=96) for 16 weeks. During the study, participants self-monitored blood glucose (SMBG) levels before and two hours after each meal, and at bedtime and 2 am. Blood levels of glucose, insulin and glucagon were assessed after participants consumed a standard liquid test meal at the beginning and end of the study. Findings showed participants taking repaglinide achieved better glycemic control than did those taking nateglinide. From the fourth week of the study on, the repaglinide group had significantly lower A1C values than the nateglinide group. By the end of the study, the change in A1C from baseline was significantly greater for the repaglinide group (-1.28% vs. -0.67%, respectively, p < 0.001). From the first week of the study on, the repaglinide group also had significantly lower FPG levels than the nateglinide group. By the end of the study, the change in FPG from baseline was significantly greater for the repaglinide group (-39 vs. -21 mg/dL, respectively, p=0.002). Mean SMBG values were consistently lower for repaglinide vs. nateglinide, and were significantly lower for measurements taken before breakfast, before lunch, and at 2:00 am. Baseline-adjusted blood levels of glucose, insulin and glucagon following the liquid test meal were not significantly different for the two treatment groups at the end of the study.(1) "Reductions in A1C and FPG with repaglinide were significantly greater than with nateglinide," said Dr. Raskin. He added that the larger effect of repaglinide was not due to dosing differences, since the median final dosage of repaglinide was only 31 percent of the recommended maximum vs. 100 percent of the recommended maximum for nateglinide. Safety assessments were generally comparable for the two treatment regimens. There were no major episodes of major hypoglycemia in either treatment group. Minor hypoglycemic episodes occurred in 7 percent of the patients in the repaglinide/metformin group vs. 2 percent of patients in the nateglinide/metformin group. Both repaglinide and nateglinide were associated with small weight changes (+0.6 kg vs -0.5 kg, respectively).(1) About Prandin (Repaglinide) Tablets Repaglinide (Prandin), 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.(2) Prandin is indicated for monotherapy use as an adjunct to diet and exercise in patients with type 2 diabetes; it is also indicated for combination use with metformin or thiazolidinediones (pioglitazone or rosiglitazone) in patients who cannot be controlled by diet and exercise plus monotherapy with metformin, thiazolidinediones, sulfonylureas or repaglinide. In the thiazolidinedione (TZD) combination studies, hypoglycemia occurred in patients on combination therapy (7%), with Prandin alone (7%), and with TZD alone (2%). Peripheral edema was reported in patients on combination therapy (5%) and TZDs alone (4%) per 24 weeks treatment (adjusted for dropout rates), with none for Prandin alone. Two combination therapy patients with coronary artery disease history reported edema with congestive heart failure. Mean weight change was +4.9 kg for combination therapy. In one-year monotherapy clinical trials, the most common adverse events leading to discontinuation of Prandin therapy were hyperglycemia, hypoglycemia and related symptoms. 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.(3) For individual countries, the direct health care costs of diabetes are from 2.5 percent to 15 percent of annual national health care budgets, depending on the prevalence of diabetes in the country and the sophistication of the treatment available. (3) Full prescribing information for Prandin® is available by contacting Novo Nordisk Pharmaceuticals, Inc. or visiting http://www.novonordisk-us.com. Prandin, NovoNorm and Gluconorm are registered trademarks of Novo Nordisk. References: (1) Raskin P, Klaff L, McGill J, South SA, Hollander P, Khutoryansky N, Hale PM, for the repaglinide vs. nateglinide metformin combination study group. Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin. Diabetes Care 2003 July; 26(2):2063-2068. (2) 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(4):518-523. (3) The World Health Organization. The Cost of Diabetes. Fact Sheet number 236, revised September 2002. http://www.who.int/mediacentre/factsheets/fs236/en/. SOURCE: Novo Nordisk

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