Nateglinide, a meglitinide derivative (glinide), is a short-acting, insulinotropic antidiabetic agent.1
Nateglinide is used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1, 3, 4, 6, 7, 8, 9 In clinical studies in adults, nateglinide was evaluated as monotherapy and in combination with other antidiabetic agents (e.g., metformin, thiazolidinedione).1, 4, 6, 7, 9
The manufacturer states that nateglinide should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1
When given as monotherapy for the management of type 2 diabetes mellitus, nateglinide improves glycemic control compared to placebo as evidenced by reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c) and mean fasting blood glucose.1
The efficacy of nateglinide as monotherapy for the management of type 2 diabetes mellitus was established in several randomized, double-blind studies of up to 24 weeks' duration.1, 4, 6 In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo.1 Patients previously treated with antidiabetic agents were required to discontinue the medication for at least 2 months prior to randomization.1 At baseline, the mean HbA1c was 7.9%, 8.1%, and 8.0% in the nateglinide 60 mg, nateglinide 120 mg, and placebo groups, respectively.1 Nateglinide improved glycemic control as measured by reductions in fasting blood glucose and HbA1c compared with placebo.1 Reductions in HbA1c were -0.3% and -0.5% in the nateglinide 60 mg and 120 mg groups, respectively, compared to an increase of 0.2% in the placebo group.1 The reductions in HbA1cand fasting blood glucose were similar for patients naïve to, and those previously exposed to, other antidiabetic agents.1
In a 24-week, double-blind, active-controlled study, patients with type 2 diabetes who had been on a sulfonylurea for ≥3 months and who had a baseline HbA1c≥6.5% were randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily.1 At baseline, the mean HbA1c was 8.0%, 7.9%, and 7.8% in the nateglinide 60 mg, nateglinide 120 mg, and glyburide groups, respectively.1 Patients randomized to nateglinide had increases in HbA1c and mean fasting blood glucose compared to glyburide.1 The mean increase in HbA1c was 1.3% and 1.1% in the nateglinide 60 mg and 120 mg groups, respectively, compared to 0.3% in the glyburide group.1
When given in combination with other oral antidiabetic agents, nateglinide improved glycemic control compared with monotherapy with either metformin or rosiglitazone as evidenced by reductions in HbA1c and fasting glucose.1
Efficacy of nateglinide in combination with metformin was established in several studies of 24 weeks' duration in which combined therapy resulted in improved glycemic control compared with monotherapy with nateglinide or metformin.1, 4, 7 In a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide (120 mg three times daily) monotherapy, metformin (500 mg three times daily) monotherapy, a combination of nateglinide and metformin, or placebo.1 At baseline, 57% of patients had not received prior treatment with oral antidiabetic agents; patients previously treated with antidiabetic agents were required to discontinue the medication for at least 2 months prior to randomization.1 At week 24, greater reductions in HbA1c were observed with metformin monotherapy (-0.8%) compared to nateglinide monotherapy (-0.4%); greater reductions were observed with the combination of nateglinide and metformin (-1.5%) compared to either monotherapy regimen and placebo (+0.4%).1 The reduction in mean fasting blood glucose compared to baseline was also greater with metformin monotherapy (-30 mg/dL) compared to nateglinide monotherapy (-13.1 mg/dL); greater reductions were observed with the combination of nateglinide and metformin (-44.9 mg/dL) compared to either monotherapy regimen and placebo (+8.0 mg/dL).1
In another 24-week, double-blind, placebo-controlled trial, patients with type 2 diabetes with HbA1c≥6.8% after treatment with metformin (≥1500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg total daily dosage) and were then randomized to receive either nateglinide (60 mg or 120 mg three times daily before meals) or placebo as an add-on to metformin.1 The combination of nateglinide and metformin resulted in greater reductions in HbA1c (-0.4% in the nateglinide 60 mg and metformin group and -0.6% in the nateglinide 120 mg and metformin group) compared to metformin and placebo (+0.01%).1
Efficacy of nateglinide in combination with rosiglitazone was established in a double-blind, placebo-controlled study of 24 weeks' duration in patients inadequately controlled with rosiglitazone (8 mg daily) monotherapy.1, 9 The addition of nateglinide (120 mg 3 times daily) to rosiglitazone monotherapy (8 mg once daily) resulted in improved glycemic control (as determined by reduction of HbA1c from baseline, the primary clinical end point) compared with continuation of rosiglitazone monotherapy.1, 9 The mean change in body weight from baseline was greater in patients receiving combination therapy than in those continuing to receive monotherapy.1, 9
In a 12-week study of patients with type 2 diabetes inadequately controlled on glyburide 10 mg daily, the addition of nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.1 Compared to baseline, the mean change in HbA1c was +0.2% and -0.02% in the nateglinide 60 mg/glyburide and nateglinide 120 mg/glyburide groups, respectively, compared to +0.3% in the glyburide and placebo group.1
The American Diabetes Association (ADA) publishes an annual guideline on diabetes management, which provides clinical practice recommendations for glucose-lowering therapies in patients with type 2 diabetes mellitus.709 The current 2025 ADA guideline states that in adults with type 2 diabetes mellitus, pharmacologic strategies that provide sufficient effectiveness to achieve and maintain the intended treatment goals should be used and guided by a person-centered shared decision-making approach.709 In general, higher-efficacy approaches have a greater likelihood of achieving glycemic goals.709 Weight management should be included as a distinct treatment goal, and other healthy lifestyle behaviors should also be considered.709 When selecting an appropriate treatment regimen, clinicians should be guided by factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.709 Meglitinides, including nateglinide, do not have additive beneficial effects on cardiovascular or kidney outcomes and are associated with an increased risk of hypoglycemia and weight gain.709 Therefore, their use should be limited or discontinued.709
The American Association of Clinical Endocrinology (AACE) also publishes guidelines for the management of type 2 diabetes.710 The principles of diabetes management outlined in the guidelines are similar to those recommended by the ADA.710 The AACE guidelines state that in adult patients with type 2 diabetes mellitus, meglitinides (including nateglinide) are associated with a higher risk of hypoglycemia and weight gain and therefore are not preferred; however, meglitinides may remain a treatment option in those patients with access or cost barriers to other antidiabetic agents.710
Nateglinide is administered orally 3 times daily 1-30 minutes before meals.1
If a meal is skipped, the dose of nateglinide corresponding to that meal should be skipped.1
Store nateglinide tablets at 25°C in a tight container; excursions permitted to 15—30°C.1
In adult patients, the recommended dosage of nateglinide is 120 mg orally three times daily before meals.1
In adult patients who are near glycemic goal when treatment is initiated, the recommended dosage of nateglinide is 60 mg orally three times daily before meals.1
No dosage adjustment is recommended in patients with mild hepatic impairment.1 Use of nateglinide in patients with moderate-to-severe hepatic impairment has not been studied; use with caution in these patients.1
No dosage adjustment is recommended in patients with mild to severe renal impairment (creatinine clearance 15—89 mL/minute).1
No dosage adjustment is necessary based on a greater sensitivity of some older individuals to nateglinide cannot be ruled out.1
As with other oral antidiabetic agents, there is a risk of developing hypoglycemia in patients receiving nateglinide.1, 3, 4 Severe hypoglycemia can cause seizures, may be life-threatening, or cause death.1 Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).1
Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient.1 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.1 Factors that may increase the 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 with other antidiabetic agents.1 Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.1
In clinical studies, hypoglycemia occurred in 2.4% of patients receiving monotherapy with the drug, and 0.3% of patients discontinued nateglinide because of hypoglycemia.1
To reduce the risk of hypoglycemia, the drug should be administered before meals, and if a meal is to be skipped, the dose of nateglinide should be omitted.1 Patients and caregivers must be educated to recognize and manage hypoglycemia.1 Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia.1 In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.1
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with nateglinide.1
There is insufficient evidence with nateglinide in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.1 In animal reproduction studies, there was no teratogenicity in rats and rabbits administered oral nateglinide during organogenesis at approximately 27 and 8 times the maximum recommended human dose, respectively, based on body surface area.1
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.1 Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related mortality.1 Nateglinide should be used during pregnancy only if the benefit justifies the potential risk to the fetus.1
There is no information on the presence of nateglinide in human milk, the effects on the breast-fed infant, or the effects on milk production.1 Nateglinide is distributed into milk in rats.1 Because of the potential for hypoglycemia in nursing infants, nateglinide is not recommended for use while breastfeeding.1
Safety and efficacy not established in pediatric patients less than 18 years of age.1
No substantial differences in safety and efficacy nor in the pharmacokinetics relative to younger adults, but increased sensitivity cannot be ruled out.1
In patients with mild hepatic impairment, the mean increase in peak plasma concentration (Cmax) and AUC of nateglinide were 37% and 30% respectively, as compared to healthy matched control subjects.1 There are no data on the pharmacokinetics of nateglinide in patients with moderate-to-severe hepatic impairment.1
Use with caution in patients with moderate-to-severe hepatic impairment.1 No dosage adjustment is necessary in patients with mild hepatic impairment.1
There are no pharmacokinetic data in patients with mild (creatinine clearance 60—89 mL/minute) renal impairment.1 Compared to healthy matched subjects, patients with type 2 diabetes mellitus with moderate and severe (creatinine clearance 15—50 mL/minute) renal impairment not on dialysis displayed similar apparent clearance, AUC, and Cmax.1 Patients with type 2 diabetes mellitus and renal failure on dialysis exhibited reduced overall drug exposure and reductions in plasma protein binding compared to matched healthy subjects.1 In a cohort of 8 patients with type 2 diabetes mellitus and end-stage renal disease (estimated glomerular filtration rate <15 mL/minute per 1.73 m2), M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months.1 In another cohort of 8 patients with type 2 diabetes mellitus on hemodialysis, M1 concentration decreased after a single session of hemodialysis.1 Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose.1
No dosage adjustment is necessary in patients with mild to severe renal impairment, but those with severe impairment may be at increased risk of hypoglycemia.1
The most common adverse effects of nateglinide (≥3% of patients) are upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, and diarrhea.1
The major metabolic pathway for nateglinide is hydroxylation followed by glucuronide conjugation; metabolism occurs primarily by cytochrome P-450 (CYP) 2C9 (70%) and to a lesser extent by CYP3A4 (30%).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Nateglinide is a potential inhibitor of CYP2C9.1 Inhibition of CYP3A4 was not detected in in vitro experiments.1
As nateglinide is metabolized by CYP2C9 and CYP3A4, there is potential for pharmacokinetic interactions (altered metabolism) when used concomitantly with inhibitors and inducers of these isoenyzmes.1
Inhibitors of CYP2C9 (e.g., amiodarone, fluconazole, voriconazole) may increase the blood glucose lowering effect of nateglinide and increase the risk of hypoglycemia.1 Dosage reductions and increased frequency of glucose monitoring may be required when nateglinide is used concomitantly with these drugs.1
Inducers of CYP2C9 and 3A4 (e.g., rifampin, phenytoin, St. John's wort [ Hypericum perforatum ]) may reduce the blood glucose lowering effect of nateglinide and increase susceptibility to hyperglycemia.1 Dosage increases of nateglinide and increased frequency of glucose monitoring may be required when nateglinide is used concomitantly with these drugs.1
Drugs that May Potentiate Hypoglycemic Effects
Alcohol, anabolic hormones, (e.g., methandrostenolone), monoamine oxidase (MAO) inhibitors, nonselective β-adrenergic blocking agents, nonsteroidal anti-inflammatory agents (NSAIAs), and salicylates may increase the blood glucose lowering effect of nateglinide and susceptibility to hypoglycemia.1 Dosage reductions of nateglinide and increased frequency of glucose monitoring may be required when nateglinide is used concomitantly with these drugs.1
Drugs that May Antagonize Hypoglycemic Effects
Corticosteroids, somatropin, somatostatin analogs, (e.g., lanreotide, octreotide), sympathomimetic agents, thiazide diuretics, and thyroid hormones may reduce the blood glucose lowering effect of nateglinide and increase susceptibility to hyperglycemia.1 Dosage increases of nateglinide and increased frequency of glucose monitoring may be required when nateglinide is used concomitantly with these drugs.1
Drugs that May Blunt Hypoglycemic Manifestations
β-adrenergic blocking agents, clonidine, and reserpine may blunt the signs and symptoms of hypoglycemia.1 Increased frequency of glucose monitoring may be required when nateglinide is used concomitantly with these drugs.1
There is a potential pharmacokinetic interaction with highly protein-bound drugs resulting in drug displacement.1 No influence on the extent of nateglinide protein binding was found in in vitro experiments with furosemide, propanolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, aspirin, and metformin.1 Similarly, nateglinide had no influence on the protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, and aspirin in vitro.1 Prudent evaluation of individual cases is warranted in the clinical setting when nateglinide is used concomitantly with other highly protein-bound drugs.1
No clinically important change in the pharmacokinetics of either drug observed.1
No clinically important change in the pharmacokinetics of either drug observed.1
No clinically important change in the pharmacokinetics of either drug observed.1
No clinically important change in the pharmacokinetics of either drug observed.1
No clinically important change in the pharmacokinetics of either drug observed.1
Nateglinide, a d-phenylalanine derivative, is an insulinotropic antidiabetic agent.1, 2, 3, 4, 8 Like repaglinide, nateglinide is a meglitinide-derivative (glinide) antidiabetic agent that is structurally unrelated to oral sulfonylurea antidiabetic agents and repaglinide.2, 8 Functioning pancreatic β-cells are required for nateglinide's hypoglycemic activity since the drug lowers blood glucose concentrations principally by augmenting endogenous insulin secretion from the pancreas in response to a meal.1, 2, 3, 4, 8 The extent of insulin release is glucose dependent and diminishes at low blood glucose levels.1 Nateglinide interacts with the ATP-sensitive potassium channel on pancreatic β-cells; nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.1
Following oral administration of nateglinide immediately prior to a meal, peak plasma concentration occurs within 1 hour; the absolute bioavailability is 73%.1 Nateglinide stimulates pancreatic insulin secretion within 20 minutes of oral administration.1 The pharmacokinetics of nateglinide are not affected by the composition of a meal (e.g., high protein, fat, or carbohydrate); when given with or after meals, AUC is unaffected but there is a delay in the rate of absorption characterized by a decrease in peak plasma concentrations and a delay in time to peak plasma concentration.1 Peak plasma levels are significantly reduced when nateglinide is administered 10 minutes prior to a liquid meal as compared to a solid meal.1 Nateglinide is extensively (98%) bound to plasma proteins, primarily serum albumin and to α1-acid glycoprotein to a lesser extent.1 Nateglinide is extensively metabolized by cytochrome P-450 (CYP) 2C9 and, to a lesser extent, CYP3A4 isoenzymes.1, 3 The major metabolites are less potent antidiabetic agents than the parent drug with the exception of the isoprene minor metabolite, which possesses potency similar to that of the parent compound.1 Based on nateglinide's ability to inhibit the metabolism of tolbutamide in vitro, the drug may be an inhibitor of CYP2C9 in vivo.1 The average elimination half-life of nateglinide is 1.5 hours.1 Nateglinide and its metabolites are rapidly and completely eliminated following oral administration; 83% of radiolabeled nateglinide was recovered in the urine (16% as parent drug) and 10% was eliminated in the feces.1 No pharmacokinetic data are available in patients with mild (creatinine clearance 60—89 mL/minute) renal impairment.1 Patients with moderate and severe (creatinine clearance 15—50 mL/minute) renal impairment not on dialysis display similar apparent clearance, AUC, and peak plasma concentrations.1 Patients with renal failure requiring dialysis exhibit reduced overall drug exposure and reduced plasma protein binding.1 In patients with mild hepatic impairment, an increase in peak plasma concentration and AUC of 37% and 30%, respectively, were observed compared to healthy matched control subjects.1 There are no data on the pharmacokinetics of nateglinide in patients with moderate-to-severe hepatic impairment.1 Age, race, and sex do not influence the pharmacokinetics of nateglinide.1
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 60 mg* | Nateglinide Tablets | |
120 mg* | Nateglinide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Rising Pharma Holdings, LLC. Nateglinide tablets prescribing information. East Brunswick, NJ; 2024 Dec.
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709. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2025. Diabetes Care. 2025; 48(Suppl 1):S181-S206.
710. Samson SL, Vellanki P, Blonde L et al. American Association of Clinical Endocrinology Consensus Statement: comprehensive type 2 diabetes management algorithm-2023 update. Endocr Pract. 2023; 29:305-340.