NATEGLINIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Nateglinide is a D-phenylalanine derivative that stimulates insulin secretion from pancreatic beta cells by binding to the sulfonylurea receptor (SUR1) on the ATP-sensitive potassium (K_ATP) channel, causing channel closure, membrane depolarization, calcium influx, and exocytosis of insulin.
| Metabolism | Primarily metabolized by cytochrome P450 isoenzymes CYP2C9 and CYP3A4 to hydroxylated metabolites; metabolites are further glucuronidated and excreted in urine and feces. |
| Excretion | Approximately 83% of a dose is excreted in urine as metabolites (primarily hydroxylated derivatives) and 10% in feces as unchanged drug and metabolites. Less than 1% is excreted unchanged in urine. |
| Half-life | 1.5 hours (range 1-2 hours). Short half-life supports preprandial dosing to control postprandial hyperglycemia without prolonged hypoglycemia risk. |
| Protein binding | 97-99% bound to plasma proteins, predominantly to albumin. |
| Volume of Distribution | Approximately 0.20 L/kg (range 0.15-0.30 L/kg). Clinical meaning: indicates distribution mainly in extracellular fluid with limited tissue binding. |
| Bioavailability | Absolute bioavailability is about 73% (range 50-90%) after oral administration. |
| Onset of Action | Oral: Onset of insulin secretion within 20-30 minutes after administration. |
| Duration of Action | Duration of insulinotropic effect is approximately 4-6 hours, corresponding to the postprandial period. Does not produce sustained hypoglycemia between meals. |
120 mg orally three times daily, 1 to 30 minutes before meals. Starting dose 60 mg three times daily in patients with HbA1c <8% or those at risk of hypoglycemia. Maximum dose 120 mg three times daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. For severe renal impairment (CrCl <30 mL/min) or ESRD, nateglinide is contraindicated due to reduced clearance. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Use is not recommended in severe hepatic impairment (Child-Pugh C) due to lack of data. |
| Pediatric use | Safety and efficacy not established in pediatric patients (<18 years). No recommended dosing available. |
| Geriatric use | No specific dose adjustment required; however, due to increased risk of hypoglycemia, initiate at 60 mg three times daily and monitor glucose closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Drugs that increase hypoglycemia risk (eg beta-blockers) Can cause hypoglycemia.
| Breastfeeding | No data on nateglinide excretion in human breast milk. M/P ratio unknown. Given potential for infant hypoglycemia, caution is advised; alternative therapies such as insulin or glyburide with more safety data are preferred during breastfeeding. |
| Teratogenic Risk | Nateglinide is classified as FDA Pregnancy Category C. Animal studies have shown fetal toxicity at high doses (cleft palate, skeletal anomalies) but no adequate human studies. In humans, nateglinide may cause hypoglycemia in the fetus/neonate if used near term. First trimester: theoretical risk of hypoglycemia affecting organogenesis. Second and third trimesters: risk of persistent neonatal hypoglycemia, macrosomia, or metabolic disturbances. Avoid use during pregnancy; insulin preferred. |
■ FDA Black Box Warning
None
| Common Effects | Hypoglycemia |
| Serious Effects |
["Type 1 diabetes mellitus","Diabetic ketoacidosis","Hypersensitivity to nateglinide or any excipients"]
| Precautions | ["Hypoglycemia: more frequent in elderly, malnourished, or patients with renal/hepatic impairment","Not indicated for type 1 diabetes or diabetic ketoacidosis","May cause hepatic enzyme elevations; rare cases of hepatitis","Potential for cross-reactivity with sulfonamides (nateglinide is not a sulfonylurea, but caution in sulfonamide allergy)"] |
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| Fetal Monitoring | Monitor maternal blood glucose frequently (preprandial and postprandial) to prevent hypoglycemia. Assess fetal growth and well-being via serial ultrasound and non-stress tests in the third trimester due to potential macrosomia or hypoglycemia. Monitor neonatal blood glucose for 24-48 hours post-delivery if nateglinide used near term. |
| Fertility Effects | No specific human studies on fertility. In animal studies, no adverse effects on fertility were observed at clinically relevant doses. However, uncontrolled diabetes can impair fertility; improved glycemic control may benefit reproductive function. |