Introduction
Nateglinide is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. It belongs to the meglitinide class of medications and functions as a rapid-acting insulin secretagogue. Approved by the FDA in 2000, nateglinide is specifically designed to control postprandial hyperglycemia by stimulating pancreatic insulin secretion in response to meals.
Mechanism of Action
Nateglinide exerts its glucose-lowering effects by binding to specific receptors on pancreatic beta cells, leading to the closure of ATP-sensitive potassium channels. This action results in membrane depolarization, opening of voltage-dependent calcium channels, and subsequent calcium influx, which triggers the exocytosis of insulin-containing secretory granules. Unlike sulfonylureas, nateglinide has a rapid onset and short duration of action, making it particularly effective for controlling postprandial glucose excursions.
Indications
Nateglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It may be used as monotherapy or in combination with other antihyperglycemic agents (such as metformin or thiazolidinediones) when glycemic control cannot be achieved with a single agent. Nateglinide is not indicated for type 1 diabetes mellitus or diabetic ketoacidosis.
Dosage and Administration
Standard dosing: 120 mg three times daily, taken 1-30 minutes before meals. For patients nearing glycemic goals, a starting dose of 60 mg three times daily may be used. Administration: Should be taken immediately before each main meal (breakfast, lunch, and dinner). If a meal is skipped, the corresponding dose should be omitted. Special populations:- Renal impairment: Use with caution in moderate to severe renal impairment; no specific dosage adjustment recommended
- Hepatic impairment: Use is contraindicated in patients with severe hepatic impairment
- Elderly: No dosage adjustment necessary based on age alone
- Pediatrics: Safety and effectiveness not established in pediatric patients
Pharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations occurring within 1 hour. Bioavailability is approximately 73%. Food intake shortly after administration increases absorption. Distribution: Extensive plasma protein binding (98%), primarily to albumin. Volume of distribution is approximately 10 liters. Metabolism: Primarily metabolized in the liver via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Major metabolites are less potent than the parent compound. Elimination: Approximately 75-85% excreted in urine and 10% in feces. Terminal elimination half-life is approximately 1.5 hours.Contraindications
- Hypersensitivity to nateglinide or any component of the formulation
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Severe hepatic impairment
- Concomitant use with gemfibrozil
Warnings and Precautions
Hypoglycemia: May cause hypoglycemia, particularly when meals are missed, inadequate calorie intake, or with increased physical activity. Risk is increased with renal or hepatic impairment, elderly patients, and those on concomitant glucose-lowering agents. Hepatic impairment: Use with caution in patients with moderate hepatic impairment; contraindicated in severe impairment. Cardiovascular effects: As with other insulin secretagogues, consider potential cardiovascular risks. Use cautiously in patients with cardiovascular disease. Macrovascular outcomes: No clinical studies have established conclusive evidence of macrovascular risk reduction with nateglinide or any other antidiabetic drug.Drug Interactions
Strong inhibitors of CYP2C9 (e.g., fluconazole): May increase nateglinide concentrations - consider dosage reduction Gemfibrozil: Contraindicated due to significant increase in nateglinide exposure CYP3A4 inhibitors (e.g., ketoconazole): May increase nateglinide concentrations CYP2C9 inducers (e.g., rifampin): May decrease nateglinide efficacy Beta-blockers, MAOIs, salicylates: May enhance hypoglycemic effects Thiazides, corticosteroids, sympathomimetics: May reduce hypoglycemic effectsAdverse Effects
Common (≥5%): Hypoglycemia, upper respiratory infection, flu-like symptoms, dizziness, weight gain, arthropathy Serious: Severe hypoglycemia (especially with renal impairment), hepatic dysfunction, hypersensitivity reactions Laboratory abnormalities: Elevated liver enzymes (usually transient)Monitoring Parameters
- Blood glucose levels (preprandial and postprandial)
- HbA1c every 3 months until stabilized, then every 6 months
- Liver function tests at baseline and periodically during treatment
- Renal function assessment
- Signs and symptoms of hypoglycemia
- Weight changes
- Therapeutic response and need for dosage adjustment
Patient Education
- Take medication 1-30 minutes before each main meal
- If a meal is skipped, skip the corresponding dose
- Recognize symptoms of hypoglycemia (sweating, trembling, dizziness, confusion)
- Carry a fast-acting source of glucose at all times
- Regular self-monitoring of blood glucose as directed by healthcare provider
- Maintain regular meal patterns and exercise schedule
- Inform all healthcare providers about nateglinide use
- Report any signs of hepatic dysfunction (jaundice, dark urine, abdominal pain)
- Do not use with gemfibrozil
- Adhere to dietary recommendations and exercise program
References
1. FDA Prescribing Information: Starlix (nateglinide) tablets 2. American Diabetes Association. Standards of Medical Care in Diabetes - 2023. Diabetes Care 2023;46(Suppl 1):S1-S291 3. Hanefeld M, et al. Rapid and short-acting meglitinide analogue nateglinide. Expert Opin Pharmacother 2001;2(7):1193-1203 4. Goldberg RB, et al. A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabetes Care 1998;21(11):1897-1903 5. McLeod JF. Clinical pharmacokinetics of nateglinide. Clin Pharmacokinet 2004;43(2):97-120 6. Lexicomp Online, Nateglinide Monograph. Wolters Kluwer Clinical Drug Information