Source: Kardiologiia  |  Posted 7 years ago

PRINCETON, NJ -- March 29, 2004 -- Administration of the oral antidiabetic drug (OAD) repaglinide (called Prandin? in the United States, NovoNorm? in Europe, and Gluconorm? in Canada) along with rosiglitazone, a differently acting OAD, improves glycemic control better than therapy with either agent alone, according to a study published in the current issue of Diabetic Medicine.(1) The study is the first full report of a clinical trial evaluating this combination OAD regimen. Another recent study demonstrated similar findings with a similar OAD, pioglitazone.(2)

"When type 2 diabetes progresses -- as it usually does -- maintaining adequate control of blood glucose often requires escalating from the usual, initial OAD monotherapy to combination OAD therapy," said lead investigator Philip Raskin, M.D., professor of medicine at the University of Texas Southwestern Medical Center in Dallas, Texas. He added, "Based on their different and complementary actions, a regimen combining repaglinide with rosiglitazone is a logical approach when OAD monotherapy does not adequately maintain glycemic control." He explained that repaglinide, which stimulates insulin secretion for a short period of time, is taken with meals to control the surge in blood glucose following food consumption (postprandial hyperglycemia); rosiglitazone acts differently, increasing the body's sensitivity to insulin.

Study and findings

The 24-week, open-label, randomized, multicenter trial enrolled 252 adult participants with type 2 diabetes who had inadequate glycemic control, as determined by A1C levels (>7 percent, the upper end of the desired level, and greater than or equal to 12 percent). A1C is the percent hemoglobin with glucose attached, and is an indicator of long-term glycemic control. The participants had been treated for at least three months before entering the study with either a sulfonylurea, which stimulates insulin production, or metformin, which increases the body's responsiveness to insulin.

Upon entering the study, the participants' prior therapy was withdrawn for two weeks, and they were randomly assigned to either repaglinide + rosiglitazone combination therapy, or repaglinide or rosiglitazone monotherapy in a 2:1:1 ratio. In the first 12 weeks of therapy, repaglinide and rosiglitazone doses were optimized for each participant, followed by 12 weeks of maintenance therapy.

Baseline A1C values were similar for the combination, repaglinide-only and rosiglitazone-only groups (9.1 percent, 9.3 percent and 9.0 percent, respectively). By the end of the study, average A1C values decreased much more compared to baseline in the combination group compared to the repaglinide or rosiglitazone monotherapy groups: -1.43 percent vs. -0.17 percent and -0.56 percent, respectively (p < 0.001). The reduction in A1C values for the combination group was significantly greater than the reduction in the two monotherapy groups combined (p < 0.01). In the combination group, 39 percent of participants had final A1C levels at or below 7 percent, compared to only 5 percent in the repaglinide-only group and 16 percent in the rosiglitazone-only group.

Average values of fasting plasma glucose also decreased compared to baseline much more in the combination group compared to repaglinide and rosiglitazone monotherapy groups: -94 mg/dl, -54 and -67 mg/dl, respectively (p < 0.001). Changes in blood lipid levels were generally similar in all three groups.

The rate of discontinuation, largely because of lack of efficacy, was lowest for the combination group compared to the repaglinide and rosiglitazone groups: 16.5 percent, 39.7 percent and 40.3 percent, respectively. Among all participants, one in the combination therapy group experienced a major episode of hypoglycemia (requiring assistance). Minor episodes of hypoglycemia were experienced by 9 percent, 6 percent and 2 percent of participants in the combination, repaglinide-only and rosiglitazone-only groups, respectively. Mean changes in weight from baseline were +4.4 kg, +1.6 kg, and +2.3 kg, respectively.

"Overall, these findings show that the combination of repaglinide and rosiglitazone is safe, well-tolerated and effective in improving glycemic control of patients with type 2 diabetes, and should be considered a promising treatment option in appropriate patients," said Dr. Raskin.

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.(3) 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 percent), with Prandin alone (7 percent), and with TZD alone (2 percent). Peripheral edema was reported in patients on combination therapy (5 percent) and TZDs alone (4 percent) 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 International Diabetes Federation, the number of people worldwide with the condition was estimated at 30 million in 1985, 135 million in 1995, and 194 million in 2003, and is expected to increase to at least 333 million by 2025.(4) 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.(5)

In the United States, 18.2 million people, or 6.3 percent of the population, have diabetes, though 5.2 million (or nearly one-third) are unaware they have the disease. In addition, it is estimated that at least 20.1 million Americans have pre-diabetes. Total costs of diabetes in the U.S. in 2002 are estimated at approximately $132 billion, including $92 billion in direct medical expenditures and $40 billion in indirect expenditures due to lost workdays, restricted activity days, mortality, and permanent disabilities due to diabetes.(6)

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 A/S and are protected by U.S. and foreign patents and patents pending.

References: (1) Raskin P, McGill J, Saad MF, Cappleman JM, Kaye W, Khutoryansky N, Hale, Hale PM, for the Repaglinide/Rosiglitazone Study Group. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabetic Medicine 2004; 21(4):329-335.

(2) Jovanovic L, Hassman DR, Gooch B, Jain R, Breco S, Khutoryansky N, Hale PM, for the Repaglinide/Pioglitazone Study Group. Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. Diab Res Clin Prac 2004; 63:127-134.

(3) Owens DR, 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.

(4) International Diabetes Federation. Diabetes prevalence. http://www.idf.org/home/index.cfm"node=264

(5) The World Health Organization. The Cost of Diabetes. Fact Sheet number 236, revised September 2002. http://www.who.int/mediacentre/factsheets/fs236/en/.

(6) American Diabetes Association. National Diabetes Fact Sheet. http://www.diabetes.org/diabetes-statistics/national-diabetes-fact- sheet.jsp. Accessed 02/19/2004

SOURCE: Novo Nordisk