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Repaglinide Plus Pioglitazone Improves Blood Glucose Control in Type 2 Diabetes Better Than Either Agent Alone

PRINCETON, NJ -- February 23, 2004 -- Administration of the oral antidiabetic drug (OAD) repaglinide (called Prandin® in the United States, NovoNorm® in Europe, and Gluconorm® in Canada) along with pioglitazone, a differently acting OAD, improves glycemic control better than therapy with either agent alone, according to a study published in the current issue of Diabetes Research and Clinical Practice.(1) The study is the first full report of a clinical trial evaluating this combination OAD regimen.

"The often inevitable progression of type 2 diabetes usually requires altering therapy from the usual, initial OAD monotherapy to combination OAD therapy," said lead investigator Lois Jovanovic, M.D., director and chief scientific officer, Sansui Medical Research Institute in Santa Barbara, California. She added, "Based on their different and complementary actions, a regimen combining repaglinide with pioglitazone is a logical approach when OAD monotherapy does not adequately maintain glycemic control." She 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); pioglitazone acts differently, increasing the body's sensitivity to insulin.

Study and findings

The 24-week, open-label, randomized, multicenter trial enrolled 246 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 < 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Upon entering the study, the participants' prior therapy was withdrawn for two weeks, and they were randomly assigned to either repaglinide + pioglitazone combination therapy, or repaglinide or pioglitazone monotherapy. In the first 12 weeks of therapy, repaglinide doses were optimized for each participant, followed by 12 weeks of maintenance therapy. Pioglitazone dosages were fixed at 30 mg/day.

Baseline A1C values were similar for the three groups (9.3 percent, 9.0 percent and 9.1 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 pioglitazone monotherapy groups: -1.76 percent vs. -0.18 percent and +0.32 percent, respectively (p < 0.001). 52 percent of participants in the combination therapy group had final A1C levels at or below 7 percent, and 76 percent had levels at or below 8 percent.

Average values of fasting plasma glucose also decreased compared to baseline much more in the combination group compared to repaglinide and pioglitazone monotherapy groups: -82 mg/dl, -33.9 and -18.5 mg/dl, respectively (p < 0.05). 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 pioglitazone groups: 15 percent, 41 percent and 58 percent, respectively. No participant experienced major episodes of hypoglycemia (requiring assistance). Minor episodes of hypoglycemia were experienced by 5 percent, 8 percent and 3 percent of participants in the combination, repaglinide and pioglitazone groups, respectively. Mean changes in weight from baseline were +5.5 kg, +0.3 kg, and +2.0 kg, respectively.

"Overall, these findings show that the combination of repaglinide and pioglitazone is safe, well-tolerated and effective in improving glycemic control of patients with type 2 diabetes," said Dr. Jovanovic. She recommended further, long-term studies to determine if the effects are sustained.

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 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 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.(4)

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.(5) In addition, at least 16 million Americans have pre-diabetes.(6) Diabetes is the fifth leading cause of death by disease in the U.S., and increases the risk of complications such as cardiovascular disease, blindness, kidney failure, extremity amputations, neurological disorders, and other chronic conditions. Total costs of diabetes in the U.S. in 2002 are estimated at approximately $132 billion, including $91.8 billion in direct medical expenditures and $39.8 billion in indirect expenditures due to lost workdays, restricted activity days, mortality, and permanent disabilities due to diabetes.(7) Major studies have confirmed that tighter blood glucose control can reduce the risks of long-term complications in both type 1 and type 2 diabetes.(8),(9)

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) 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.

(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/.

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

(5) American Diabetes Association. Basic diabetes information. http://www.diabetes.org/info/facts/facts.jsp Accessed 01/19/2004.

(6) American Diabetes Association. Basic diabetes information. http://www.diabetes.org/main/application/commercewf"origin=*.jsp&event=link(B) Accessed 08/19/2003.

(7) American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2002. Diabetes Care 2003; 26:917-932.

(8) Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-986.

(9) UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-853.


SOURCE: Novo Nordisk

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