Repaglinide: A new oral antidiabetic agent
By William T. Elliot, MD
James Chan, PharmD, PhD
Danish drug giant Novo Nordisk Pharma-ceuticals has introduced its new oral antidiabetic agent, repaglinide (Prandin), to the U.S. market. Approved in December by the Food and Drug Administration (FDA), repaglinide is the newest drug available for the management of Type II diabetes mellitus. Repaglinide acts by stimulating insulin release from beta cells in the pancreas like sulfonylureas; however, the drug represents a new chemical class, the "meglitinides."
Repaglinide is different in chemical structure and pharmacokinetics/pharmacodynamics from currently available antidiabetic drugs, with the primary difference being that the drug is very fast-acting and is quickly eliminated - with the intention that the drug is to be taken with meals. Data from animal studies suggest that repaglinide has different binding characteristics on the beta cells compared to sulfonylureas and is more dependent on the presence of glucose for its action.1,2 Its insulinotropic action appears to involve both distinct and common mechanisms with sulfonylureas.2 Unlike sulfonylureas, repaglinide appears to preserve glucose-stimulated proinsulin biosynthesis in animal pancreatic islet cells.3
Indications
Repaglinide is indicated as an adjunct to diet and exercise to lower blood glucose concentration in patients with Type II diabetes who cannot achieve satisfactory control by diet and exercise alone. It is also indicated for combination therapy with metformin.
Potential advantages
Repaglinide has a rapid onset of action and a short duration of action. The rapid onset allows the patient to take the drug with meals, and the short duration may reduce the risk and/or severity of hypoglycemia. The preprandial dosing also allows patients to skip a dose if they miss a meal and add a dose if they eat extra meals. Repaglinide has been reported to by synergistic with metformin.4
While the risk and severity of hypoglycemia with repaglinide may be lower than that of sulfonylurea, hypoglycemia is still the most common side effect. In active control trials, mild or moderate hypoglycemia occurred in 16% of repaglinide-treated patients, compared to 20% of glyburide-trated patients and 19% of glipizide-trated patients.4 Drugs that inhibit cytochrome P450 isoenzyme 3A (e.g., erythromycin, ketoconazole) may inhibit the metabolism of repaglinide. Drugs that induce cytochrome P450 isoenzyme 3A (e.g. troglitazone, rifampin, carbamazepine, barbiturates) may increase repaglinide metabolism.4 Specific drug interaction studies involving these potentially interacting drugs and repaglinide have not been reported.
Dosing information
Repaglinide as Prandin is supplied in tablets of 0.5 mg, 1 mg, and 2 mg. For treatment-naïve patients whose HbA1c is less than 8%, the starting doze is 0.5 mg with each meal preprandially. For those previously treated and whose HbA1c is 8% or greater, the starting dose is 1 mg or 2 mg with each meal preprandially. Dosage adjustments should be determined by blood glucose response. The dose should be doubled if response is inadequate. Allow at least one week to assess response before further dose adjustments. The maximum recommended dose is 16 mg daily.4 The dose should be taken within 15 minutes of the meal but may vary from 30 minutes before to immediately preceding the meal.
Comments
Repaglinide is an oral hypoglycemic agent that has a rapid onset and short duration of action. Dosing in concert with meals may reduce the potential for hypoglycemia as plasma insulin levels return to baseline before the next meal. In a three-month maintenance placebo-controlled study involving both drug treatment-naïve and those previously treated with another antidiabetic agent, repaglinide was shown to reduce HbA1c by 1.7% units, fasting plasma glucose by an average of 61.3 mg/dl, and two-hour postprandial plasma glucose by 104 mg/dl compared to placebo. Sulfonylurea-naïve patients are more responsive to repaglinide (HbA1c decreased from 9.9% to 7.5%).
No comparative trials with other antidiabetic agents have been published. Information provided by the manufacturer suggests that repaglinide is at least as effective as glyburide and more effective that glipizide in maintaining overall glycemic control over one year. The combination of metformin and repaglinide has been reported to be more effective than either alone. The side effect profile of repaglinide is similar to that of the sulfonylureas but appears to have a lower risk of severe hypoglycemia.4
Clinical Implications
Diabetes has become one of the more common chronic disease in this country. Data from the Third National Health and Nutrition Examination Survey (NHANES III) that diabetes (both diagnosed and undiagnosed) affects 7% to 8% of adults and almost 20% (18.8%) of Americans aged 60 or older.5
The authors of NHANES III also suggest that the prevalence of obesity and sedentary lifestyles, along with high rates of impaired glucose tolerance detected in the survey, suggest that diabetes will continue to be a major health problem.5
Repaglinide provides another drug for the management of diabetes. This drug allows the patient to time the drug, and the resultant insulin increase, with meals and may reduce the risk of hypoglycemia. The drug may be of particular interest for patients who lead lifestyles associated with erratic meals; however, most diabetics are likely to prefer the convenience of a once- or twice-daily medication.
Other than what has been provided by Novo Nordisk, very little is known about this drug, as none of the clinical trials supporting its FDA approval have been published. It is not known whether repaglinide offers any significant clinical advantages over the sulfonylureas resulting from some apparent difference in their mechanism of action demonstrated in animal studies.
The wholesale cost of repaglinide is 57 cents, $75 cents, and $83 cents per tablet for the 0.5 mg, 1 mg, and 2 mg tablets, respectively.
William T. Elliot, MD, is Assistant Clinical Professor of Medicine at the University of California, San Francisco and Chairman of the Regional Pharmacy and Therapeutics Committee at Kaiser Permanente of Northern California.
James Chan, PharmD, PhD, is Head of Drug Information at Kaiser Permanente of Northern California.
References
1. Fuhlendorff J, et al. Diabetes 1998; 47(3):345-351.
2. Kofod H, et al. Diabetologia 1995; 38(suppl):Abstract 753.
3. Vinambres C, et al. Pharmacol Res 1996; 34:83-85.
4. Novo Nordisk Pharmaceuticals Inc. Prandin Product Monograph. Princeton, NJ; December 1997.
5. Harris MI, et al. Diabetes Care 1998; 21:518-524.
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