EUNAT 60

Indications

• Type 2 diabetes mellitus
• Postprandial hyperglycemia

Dosage

Children: The safety and efficacy of nateglinide in children have not been established. Refer to the BNF for Children for further guidance.

Adults: The usual starting dose is 120 mg taken before each meal, with adjustments made based on glycemic control and individual tolerance, not exceeding a maximum daily dose of 360 mg.

Mechanism of action

Nateglinide enhances insulin secretion from pancreatic β cells in response to glucose levels. It acts by inhibiting ATP-sensitive potassium channels, leading to membrane depolarization and subsequent influx of calcium ions. This process stimulates the exocytosis of insulin granules. Importantly, nateglinide's action is glucose-dependent, meaning it does not promote insulin release in the absence of glucose, making it safer in hypoglycemic states compared to other secretagogues.

Pharmacodynamics

The pharmacodynamics of nateglinide revolves around its ability to enhance insulin release in a glucose-dependent manner. By inhibiting ATP-sensitive potassium channels on pancreatic β cells, nateglinide causes depolarization of the cell membrane, leading to calcium influx and increased insulin exocytosis. This effect is most pronounced at intermediate glucose levels, and nateglinide has little impact on insulin secretion when glucose levels are high, thereby preventing excessive insulin release.

Pharmacokinetics

Nateglinide is rapidly absorbed after oral administration, with peak plasma concentrations typically occurring within 1 hour. The drug is extensively metabolized in the liver, primarily via the cytochrome P450 system. The elimination half-life is approximately 1.5 hours, and renal excretion plays a minor role in its clearance. Due to its short duration of action, nateglinide is usually taken before meals to effectively control postprandial glucose levels.

Contra-indications

• Hypersensitivity to nateglinide or any of its components
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Severe renal impairment

Adverse effects

• Hypoglycemia
• Nausea
• Diarrhea
• Headache
• Dizziness
• Weight gain
• Abdominal pain

Interactions

• May enhance the hypoglycemic effect of other antidiabetic agents
• Caution with drugs that affect glucose metabolism
• May interact with CYP2C9 and CYP3A4 inducers or inhibitors

Precautions

• Monitor blood glucose levels regularly
• Use with caution in patients with hepatic impairment
• Risk of hypoglycemia, especially in elderly patients or those with inadequate caloric intake

Pregnancy

There are insufficient data on the use of nateglinide in pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Nateglinide is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 60 mg, 120 mg

Mechanism of action

Nateglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, nateglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, nateglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of nateglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Nateglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.

Pharmacodynamics

Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Nateglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.