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Prandin (Repaglinide) Approved for Combination Therapy With Ins

May 6, 2002

Studies Show Greater Glycemic Improvements With Prandin and Sensitizers Compared to Monotherapy in Treating Type 2 Diabetes Novo Nordisk announced last week 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."

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) 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. 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.
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.