Mealtime Glucose Regulation With Nateglinide in Healthy Volunteers
Comparison with repaglinide and placebo
- Jyoti B. Kalbag, MS,
- Yulia H. Walter, MS,
- Jerry R. Nedelman, PHD and
- James F. McLeod, MD
- From the Departments of Clinical Pharmacology (J.B.K., Y.H.W., J.F.M.) and Biostatistics (J.R.N.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
- Address correspondence and reprint requests to James F. McLeod, MD, Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936. E-mail: james.mcleod{at}pharma.novartis.com .
Abstract
OBJECTIVE— This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects.
RESEARCH DESIGN AND METHODS— Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose.
RESULTS— Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 μU · ml-1 · min-1, respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose.
CONCLUSIONS— In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.
Footnotes
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All authors are employed by and J.B.K., Y.H.W., and J.F.M. own stock in Novartis Pharmaceuticals.
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Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration; ECG, electrocardiogram; tmax, time to reach Cmax.
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted September 29, 2000.
- Received February 17, 2000.
- by the American Diabetes Association, Inc.
