Drug class: Meglitinides

Medically reviewed by Drugs.com on Apr 10, 2025. Written by ASHP.

Introduction

Nateglinide, a meglitinide (glinide) derivative, is a short-acting, insulinotropic antidiabetic agent.

Uses for Nateglinide

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.

Used as monotherapy or in combination with other antidiabetic agents (e.g., metformin, thiazolidinedione).

Guidelines from the American Diabetes Association (ADA) and other experts recommend consideration of factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences when selecting a treatment regimen. Weight management should be included as a distinct treatment goal and other healthy lifestyle behaviors should also be considered. Meglitinides do not have additive beneficial effects on cardiovascular or kidney outcomes and are associated with increased risk of hypoglycemia and weight gain; use should be limited (e.g., in those with access or cost barriers to other agents) or discontinued.

Not for the treatment of type 1 diabetes mellitus or ketoacidosis.

Nateglinide Dosage and Administration

General

Pretreatment Screening

• Blood glucose determinations (e.g., HbA_1c) should be performed to determine recommended starting dosage relative to the patient's glycemic goal.

Patient Monitoring

• Patients should perform self-monitoring of blood glucose. In patients at higher risk of or with reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Administration

Oral Administration

Administer 3 times daily 1–30 minutes before meals to reduce the risk of hypoglycemia.

If a meal is skipped, the dose of nateglinide should be omitted.

Dosage

Adults

Type 2 Diabetes Mellitus

Oral

120 mg 3 times daily before meals.

For patients near glycemic goal when nateglinide initiated, 60 mg 3 times daily before meals.

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild impairment. Use with caution in patients with moderate or severe impairment.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary. Greater sensitivity of some older individuals cannot be ruled out.

Cautions for Nateglinide

Contraindications

• Known hypersensitivity to nateglinide or any ingredient in the formulation.

Warnings/Precautions

Hypoglycemia

Potential for hypoglycemia. Hypoglycemia may impair concentration ability and reaction time; severe hypoglycemia can cause seizures, may be life-threatening, or cause death.

Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., β-adrenergic blocking agents), or in patients who experience recurrent hypoglycemia.

Factors that may increase risk of hypoglycemia include changes in meal patterns (e.g., macronutrient changes), changes in level of physical activity, changes to coadministered medication, and concomitant use of antidiabetic agents. Patients with renal or hepatic impairment may be at higher risk for hypoglycemia.

To reduce risk, administer nateglinide before meals; if a meal is skipped, dose should be omitted. Educate patients and caregivers to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays essential role in prevention and management of hypoglycemia. In patients at higher risk of hypoglycemia and patients with reduced symptomatic awareness, increased frequency of blood glucose monitoring is recommended.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide.

Specific Populations

Pregnancy

Insufficient data to evaluate drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Poorly controlled diabetes during pregnancy carries risk to mother and fetus; nateglinide should be used during pregnancy only if benefit justifies the potential risk to fetus.

Lactation

No data on presence of nateglinide in human milk, effects on breast-fed infant, or effects on milk production. Distributed into milk in rats. Because of risk of hypoglycemia in nursing infants, nateglinide not recommended for use while breast-feeding.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety, efficacy, or pharmacokinetics relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Use with caution in patients with moderate to severe hepatic impairment.

Renal Impairment

No data in mild (Cl_cr 60—80 mL/minute) renal impairment. No significant difference in pharmacokinetics in moderate to severe (Cl_cr 15—50 mL/minute) renal impairment not on dialysis. Reduced drug exposure and protein binding in end-stage renal disease requiring dialysis. Severe renal impairment may be at increased risk of hypoglycemia.

Common Adverse Effects

Most common adverse effects (≥3%): Upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea.

Drug Interactions

Extensively metabolized by CYP2C9 and, to a lesser extent, CYP3A4.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Based on in vitro data, nateglinide is a potential inhibitor of CYP2C9; inhibition of CYP3A4 not detected in vitro. Potential pharmacokinetic interaction (altered metabolism of nateglinide) when administered concomitantly with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole, voriconazole) resulting in increased susceptibility to hypoglycemia or inducers of CYP2C9 or CYP3A4 (e.g., rifampin, phenytoin, St. John's wort [Hypericum perforatum]) resulting in increased susceptibility to hyperglycemia. Dosage adjustments of nateglinide and increased frequency of glucose monitoring may be required when used concomitantly with these drugs.

Drugs That May Increase Hypoglycemic Effects

Pharmacodynamic interaction with such drugs as alcohol, anabolic hormones (e.g., methandrostenolone), MAO inhibitors, nonselective β-adrenergic-blocking agents, NSAIAs, and salicylates. Dosage reductions of nateglinide and increased frequency of glucose monitoring may be required when used concomitantly with these drugs.

Drugs That May Antagonize Hypoglycemic Effects

Pharmacodynamic interaction with such drugs as corticosteroids, somatropin, somatostatin analogues (e.g., lanreotide, octreotide), sympathomimetic agents, thiazide diuretics, and thyroid hormones. Dosage increases of nateglinide and increased frequency of blood glucose monitoring may be required when used concomitantly with these drugs.

Drugs That May Blunt Hypoglycemic Manifestations

β-adrenergic blocking agents, clonidine, and reserpine may blunt the signs and symptoms of hypoglycemia. Increased frequency of glucose monitoring may be required when nateglinide used concomitantly with these drugs.

Protein-bound Drugs

Potential pharmacokinetic interaction, but no important effects on nateglinide protein binding observed in vitro with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, aspirin, and metformin. In addition, nateglinide had no influence in vitro on protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, or aspirin. Prudent evaluation of individual cases warranted when nateglinide used concomitantly with other highly protein-bound drugs.

Specific Drugs

Nateglinide Pharmacokinetics

Absorption

Bioavailability

Approximately 73% (absolute), indicating a modest first-pass effect.

Onset

Stimulates pancreatic insulin secretion within 20 minutes following oral administration.

Duration

Peak insulin concentrations occur approximately 1 hour after dose and return to baseline by 4 hours.

Food

When administered with or after meals, food delays absorption, as evidenced by a decrease in peak plasma concentration and prolongation of the time to peak plasma concentration; however, extent of absorption is not affected. When nateglinide is administered 10 minutes prior to a liquid meal, peak plasma drug concentrations are reduced appreciably. Pharmacokinetics are not affected by the composition of a meal (e.g., high protein, fat, carbohydrate).

Distribution

Extent

Distributed into milk in animals; not known whether the drug distributes into human milk.

Plasma Protein Binding

98%.

Special Populations

Reduced plasma protein binding in end-stage renal disease requiring dialysis.

Elimination

Metabolism

Predominantly metabolized by CYP2C9 (70%) and CYP3A4 (30%). Major metabolites are less potent than parent drug. Isoprene minor metabolite is as potent as parent compound.

Elimination Route

In urine (83%), as unchanged drug (16%), and feces (10%).

Half-life

Approximately 1.5 hours.

Special Populations

Mild hepatic insufficiency increases the peak and total exposure of nateglinide by 30%.

No impact on clearance, AUC, or peak plasma concentration in patients with moderate to severe (Cl_cr 15—50 mL/minute) renal impairment not requiring dialysis. End-stage renal disease requiring dialysis reduces overall drug exposure.

Pharmacokinetics not affected by age, race, and sex.

Stability

Storage

Oral

Tablets

Tight containers at 25°C; may be exposed to 15–30°C.

Actions

• Insulinotropic antidiabetic agent (a d-phenylalanine derivative).

• Requires functioning pancreatic β-cells for hypoglycemic activity. Lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal.

• Interacts with ATP-sensitive potassium channel on pancreatic β-cells; highly tissue selective with low affinity for heart and skeletal muscle.

• Extent of insulin release is glucose dependent and diminishes at low blood glucose levels.

Advice to Patients

• Inform patients of the potential risks and advantages of nateglinide.

• Advise patients of the importance of taking nateglinide 1–30 minutes before each meal and of skipping a scheduled dose of nateglinide if a meal is skipped to decrease the risk of hypoglycemia.

• Inform patients and caregivers on how to recognize and manage hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Inform patients and caregivers that self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia.

• Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c) testing, and assessment of diabetes complications.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise patients that breast-feeding is not recommended while taking nateglinide.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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