Pharmacology Update
Nateglinide Tablets—Starlix (Novartis)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Nateglinide is the newest oral agent for the management of type 2 diabetes. Nateglinide is a D-phenylalanine derivative, nonsulfonylurea that has a short duration of action similar to repaglinide (Prandin). These agents are taken at mealtime to stimulate the release of insulin—thus reducing mealtime blood glucose excursions. Nateglinide is marketed as Starlix by Novartis.
Indications
Nateglinide is indicated as monotherapy in patients with type 2 diabetes who have not achieved adequate glycemic control by diet and physical exercise and who have not been chronically treated with other antidiabetic agents. It is also indicated for use in combination with metformin. Nateglinide should not be initiated in patients who have been inadequately controlled on other agents that act by stimulating insulin secretion.1
Dosage
The recommended starting dose for monotherapy or in combination is 120 mg three times a day, 1-30 minutes before meals. A lower 60 mg dose may be used in patients who are near HbA1c goal when therapy is initiated.1
No dosage adjustment is required in patients with mild to severe renal impairment or mild hepatic impairment.1 The drug is available in 60, 120, and 180 mg tablets.
Potential Advantages
Compared to repaglinide, the other marketed shortacting insulin secretagogue, nateglinide appears to have a lower incidence of hypoglycemia. In placebo-controlled trials, the frequency of hypoglycemia was 2.4% for nateglinide vs. 0.4% for placebo and 31% vs. 7% for repaglinide vs. placebo.1,2 Short-acting secretagogues permit mealtime flexibility and reduce between meal and nocturnal hypoglycemia. The patient can skip a tablet if a meal is missed thus avoiding hypoglycemia, which could be problematic with a long-acting secretagogue such as glyburide. Insulin profiles after repaglinide or nateglinide reflect more closely those of nondiabetic patients.3,4
Nateglinide appears to be tissue specific. At concentrations that stimulate insulin secretion, nateglinide is least likely to inhibit cardiovascular potassium-dependent adenosine triphosphate (K [ATP]) channels in animal models compared to glyburide or repaglinide.5
Potential Disadvantages
Nateglinide appears to be less potent than repaglinide and glyburide for inhibition of K (ATP) channels.6 Results from clinical trials reported by the manufacturer indicated a 1% point reduction in HbA1c compared to placebo in treatment-naive patients (mean baseline 8.1%) and 0.6% reduction nonnaive patients (baseline 8.5%).1 There are no published comparative trials between nateglinide and repaglinide.
In general, sulfonylureas or repaglinide as monotherapy generally decrease HbA1c by 1.5-2%.7 Nateglinide is only recommended for use in sulfonylurea-naive patients while repaglinide is not restricted to use in treatment-naive patients.1,2 Nateglinide is a potential inhibitor of cytochrome P450 2C9 and may inhibit drugs metabolized by this isoenzyme. Nateglinide requires three times a day dosing, with each meal.
Comments
Nateglinide is a rapid and short-acting phenylalanine derivative that releases insulin from pancreatic beta cells by inhibiting the K (ATP) channels. It is a less potent inhibitor and the inhibition may be of shorter duration.6 It restores early insulin secretion phase and post-prandial glucose excursion in type 2 diabetics.3,8 As monotherapy, nateglinide is more effective in treatment-naive patients compared to previously treated patients.1 The addition of metformin to nateglinide improves glycemic control compared to monotherapy in treatment-naive patients and is more effective than metformin alone in patients previously treated with glyburide.1,9,10 Glycosylated hemoglobin reductions compared to placebo of up to 2 percentage points have been reported with the combination.1,8
Clinical Implication
Nateglinide offers an alternative to repaglinide as a rapid short-acting insulin secretagogue. Its lower potency may limit its use to treatment-naive mild diabetics or in combination with other drugs with a different mechanism of action such as metformin. Its primary advantage is a low incidence of hypoglycemia. The wholesale cost for nateglinide is about $2.50 per day (120 mg 3 times a day) and is more expensive than repaglinide, about $2 (1 mg 3 times a day).
References
1. Starlix Product Information. Novartis. January 2001.
2. Prandin Product Information.
3. Hanefeld M, et al. Diabetes Care 2000;23:202-207.
4. Massi-Benedetti M, Damsbo P. Expert Opin Investig Drugs 2000;9(4):885-898.
5. Hu S, et al. J Pharmacol Exp Ther 1999;291(3):
1372-1379.
6. Hu S, et al. J Pharmacol Exp Ther 2000;293(2):
444-452.
7. DeFrono RA. Ann Intern Med 1999;131:281-303.
8. Dunn CJ, Faulds D. Drugs 2000;60(3):607-615.
9. Horton ES, et al. Diabetes Care 2000;23:1660-1665.
10. Hirchberg Y, et al. Diabetes Care 2000;23:349-353.
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