Administration of the oral antidiabetic drug (OAD) repaglinide (called Prandin in the United States, NovoNorm in Europe, and 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. 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, Sansum 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.

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 per cent, the upper end of the desired level, and < 12 per cent). A1C is the per cent 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Upon entering the study, the participants' prior therapy was withdrawn for two weeks, and they were randomly assigned to either repaglinide + pioglitazone combination therapy, or repaglinide or pioglitazone monotherapy.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 per cent, 9.0 per cent and 9.1 per cent, 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 per cent vs. -0.18 per cent and +0.32 per cent, respectively (p < 0.001). 52 per cent of participants in the combination therapy group had final A1C levels at or below 7 per cent, and 76 per cent had levels at or below 8 per cent.

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 per cent, 41 per cent and 58 per cent, respectively. No participant experienced major episodes of hypoglycemia (requiring assistance). Minor episodes of hypoglycemia were experienced by 5 per cent, 8 per cent and 3 per cent 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.

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.

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 per cent), with Prandin alone (7 per cent), and with TZD alone (2 per cent). Peripheral edema was reported in patients on combination therapy (5 per cent) and TZDs alone (4 per cent) 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.

Prandin, NovoNorm and Gluconorm are registered trademarks of Novo Nordisk A/S and are protected by U.S. and foreign patents and patents pending.