Repaglinide More Effective than Nateglinide in Type 2 Diabetes

Laurie Barclay, MD

May 16, 2003

May 16, 2003 — In two separate randomized trials presented at the American Academy of Clinical Endocrinology annual meeting, repaglinide was more effective than nateglinide in type 2 diabetes. Reductions in HbA 1c and fasting plasma glucose were greater with repaglinide regardless of whether it was used as monotherapy or in combination with metformin.

The first trial was a parallel-group, open-label, multicenter trial in 150 patients with type 2 diabetes previously treated with diet and exercise. During the three months preceding enrollment, HbA 1c values were greater than 7% but not greater than 12%.

"This clinical trial was the first direct comparison of repaglinide monotherapy and nateglinide monotherapy," lead author Mohammed F. Saad, MD, FRCP, a professor of medicine at the University of California at Los Angeles, told Medscape. "This study demonstrated that these two mealtime oral treatments for type 2 diabetes differ in their efficacy, with patients having approximately 0.5% lower HbA 1c values at the end of 16 weeks of treatment if they were using repaglinide rather than nateglinide."

Patients were randomized to treatment with repaglinide (0.5 mg/meal; maximum of 4 mg/meal) or nateglinide (60 mg/meal increased to 120 mg/meal if needed) to reach preprandial glycemic targets of 90 to 140 mg/dL. During the first three weeks of therapy, secretagogue doses were adjusted.

After 16 weeks of treatment, mean reductions of HbA 1c were -1.6% for the repaglinide group and -1.0% for the nateglinide group ( P = .002). The repaglinide group also fared better in terms of final HbA 1c values (7.3% vs. 7.9%) and mean reductions of fasting plasma glucose (-57 mg/dL vs. -18 mg/dL; P < .001).

Postprandial glycemic effects were similar in both groups, and no episodes of major hypoglycemia requiring assistance from another person were reported in either group.

"The risk of minor hypoglycemia was 7% [for] repaglinide vs. 0% [for] nateglinide patients," said Dr. Saad. "This study provides information to healthcare providers directly comparing these two agents."

Novo Nordisk Pharmaceuticals, Inc., the manufacturer of repaglinide, supported this trial, employs two of its authors (Naum Khutoryansky and Paula Hale), and provided grant support for the trial to the other two authors, Dr. Saad and Julio Rosenstock, MD, FACE.

The second study, an open-label, parallel-group, multicenter trial, designed to compare the two drugs in combination with metformin, enrolled 192 patients with HbA 1c values between 7% and 12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide/metformin).

During four weeks of metformin run-in therapy, doses were escalated to 1,000 mg twice daily. Patients were randomized to the addition of repaglinide (1 mg/meal; maximum of 4 mg/meal) or nateglinide (120 mg/meal; reduced to 60 mg if needed) for 16 weeks. During the first two weeks of therapy, repaglinide doses were adjusted to achieve preprandial blood glucose of 80 to 140 mg/dL. Median final doses were 5 mg/day for repaglinide and 360 mg/day for nateglinide.

"In this study, the efficacy and safety of repaglinide and nateglinide were directly compared under conditions where patients also received metformin," lead author Philip Raskin, MD, FACE, from the University of Texas Southwestern Medical Center in Dallas, told Medscape. "Repaglinide plus metformin showed significantly greater efficacy than nateglinide plus metformin after 16 weeks of therapy. Reductions of HbA 1c were roughly 0.5% greater for repaglinide."

Compared with the nateglinide group, the repaglinide group did better in terms of mean end-of-study reductions of HbA 1c (-1.28% vs. -0.67%; P < .001); final mean HbA 1c (7.1% vs. 7.5%); and mean reductions in fasting plasma glucose (-39 mg/dL vs. -21 mg/dL; P = .002).

Changes in area under the curve of glucose or insulin were similar in both groups. Minor hypoglycemic episodes (blood glucose < 50 mg/dL) occurred in 7% of the repaglinide group and in 2% of the nateglinide group.

"These results closely mirror the findings of the monotherapy study," Dr. Raskin said. "These two studies provide information to the healthcare professional comparing repaglinide and nateglinide, both in monotherapy and in combination with metformin."

Novo Nordisk Pharmaceuticals, Inc., the manufacturer of repaglinide, also supported this trial Dr. Raskin received grant support from Novo Nordisk for this clinical trial, and he is a member of its medical scientific advisory board. Drs. Hale and Khutoryansky coauthored this study.

AACE 12th Annual Meeting: Abstracts 44, 46. 2003.

Reviewed by Gary D. Vogin, MD

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