FDA Approves Nateglinide for Treatment of Type 2 Diabetes
A derivative of the amino acid D-phenylalanine, nateglinide stimulates insulin secretion from pancreatic beta cells by interacting with their ATP-sensitive potassium channels. This interaction causes depolarization of the beta cells and the opening of calcium channels, resulting in calcium influx and insulin secretion. The extent of insulin release is glucose dependent. Because the drugs effectiveness depends on the presence of functioning pancreatic beta cells, patients whose hyperglycemia does not adequately come under control through treatment with glyburide or another agent that stimulates insulin secretion should not use nateglinide.
In randomized clinical trials in diabetic patients previously treated with diet alone, nateglinide significantly lowered mean hemoglobin A1C (HbA1C) and fasting plasma glucose (FPG) levels compared with placebo. Nateglinide was shown in other studies to be less effective than glyburide or metformin at lowering diabetic patients HbA1C and FPG levels. Among therapy-naive patients, however, reductions in mean HbA1C and FPG levels in the nateglinide group were similar to those in the metformin group.
Patients treated with nateglinide and metformin had greater reductions in HbA1C and FPG than patients who received monotherapy with either agent. Among patients whose diabetes was inadequately controlled by glyburide, the addition of nateglinide yielded no benefit.
In several of the clinical trials, nateglinide monotherapy was associated with weight gain in comparison with placebo or metformin monotherapy. No significant weight change was noted for patients who received nateglinide in combination with metformin. Although adverse-event profiles for nateglinide and placebo were similar, there was an overall 2.4% frequency of hypoglycemia in patients treated with nateglinide monotherapy during the trials. Hypoglycemia led to discontinuation of therapy in only 0.3% of nateglinide-treated patients.
Nateglinide is 98% bound to serum proteins, primarily albumin. Before elimination in the urine, the drug undergoes extensive metabolism by cytochrome P-450 (CYP) isoenzymes 2C9 (70%) and 3A4 (30%). No change in nateglinides pharmacokinetic properties was observed in elderly subjects or patients with renal impairment. However, total exposure to nateglinide was increased by 30% in subjects with mild hepatic insufficiency; the drug was not studied in people with moderate or severe hepatic impairment. Therefore, nateglinide should be used with caution in patients with chronic liver disease.
Nateglinide has been shown in vitro to inhibit the metabolism of tolbutamide, a marker for CYP2C9 activity; the new antidiabetic agent is therefore considered a potential inhibitor of this isoenzyme. No inhibition of CYP3A4 metabolism was detected during experiments in vitro. Studies of nateglinide with glyburide, metformin, digoxin, warfarin, or diclofenac showed no clinically relevant change in the pharmacokinetics of either agent in a pair. Protein-displacement studies with nateglinide and several highly protein-bound drugs, including propranolol, warfarin, and phenytoin, found no alterations in the extent of binding by either agent. Caution is advised when nateglinide is used with drugs known to potentiate or reduce the hypoglycemic action of oral antidiabetic agents.
The recommended dosage of nateglinide, alone or in combination with metformin, is 120 mg three times daily, 130 minutes before meals. Patients should be advised to skip a scheduled dose of nateglinide when skipping a meal. A 60-mg three-times-daily dosage of nateglinide may be used in patients who are near their target HbA1C level at the start of treatment.
Starlix tablets, in 60- and 120-mg strengths, are available in bottles of 100 and 500.