Usage
- Medical Conditions: This combination therapy is prescribed for type 2 diabetes mellitus in adults when metformin alone does not adequately control blood glucose levels. It is particularly useful in managing postprandial hyperglycemia (high blood sugar after meals).
- Pharmacological Classification: Antidiabetic agents. Metformin is a biguanide, and nateglinide is a meglitinide.
- Mechanism of Action: Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Nateglinide stimulates insulin release from the pancreas by binding to and closing ATP-sensitive potassium channels on the pancreatic beta-cell membrane, leading to depolarization and calcium influx, which triggers insulin secretion.
Alternate Names
Nateglinide is also known by its International Nonproprietary Name (INN) - nateglinide. A common brand name for nateglinide is Starlix. Metformin is commonly sold under the brand name Glucophage. Metformin + Nateglinide is not marketed under a combined brand name.
How It Works
- Pharmacodynamics: Metformin primarily reduces hepatic glucose production and improves insulin sensitivity. Nateglinide increases insulin secretion, predominantly postprandially.
- Pharmacokinetics:
- Metformin: Absorbed from the gastrointestinal tract, not metabolized by the liver, and excreted primarily unchanged in the urine. Half-life is approximately 4–8.7 hours.
- Nateglinide: Rapidly absorbed after oral administration, extensively metabolized by the liver primarily by CYP2C9 and CYP3A4 enzymes, and excreted in the urine and feces. Half-life is about 1.5 hours.
- Mode of Action: Metformin acts by activating AMP-activated protein kinase (AMPK), which leads to a decrease in hepatic gluconeogenesis. Nateglinide binds to a specific site on pancreatic beta-cell ATP-sensitive potassium channels, distinct from the sulfonylurea binding site. This binding closes the channels, resulting in membrane depolarization, calcium influx, and ultimately, insulin secretion.
- Elimination Pathways: Metformin is primarily excreted unchanged in the urine. Nateglinide is extensively metabolized by the liver with less than 1% of the parent drug excreted unchanged.
Dosage
Standard Dosage
Adults:
Nateglinide: 60-120 mg three times daily, taken 1-30 minutes before main meals (breakfast, lunch, and dinner). If a meal is skipped, the corresponding dose should be skipped. The starting dose is usually 60 mg three times daily for patients near their HbA1c goal.
Metformin: 500 mg twice daily or 850 mg once daily with meals, titrated as needed up to a maximum of 2550 mg/day divided into 2-3 doses.
Children:
Nateglinide is not recommended for use in children under 18 years of age due to a lack of data on safety and efficacy.
Metformin is commonly used in pediatric patients with type 2 diabetes, starting with 500 mg twice a day or 850 mg once daily, with titration based on efficacy and tolerability, up to a maximum dose of 2000 mg/day.
Special Cases:
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Elderly Patients: Start with lower doses and titrate cautiously to avoid hypoglycemia. Renal function should be assessed before starting metformin.
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Patients with Renal Impairment: Metformin should be avoided in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) due to an increased risk of lactic acidosis. Dosage adjustments for metformin are needed for patients with moderate renal impairment, as per guidelines. No dose adjustment is typically necessary for nateglinide in mild to moderate renal impairment.
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Patients with Hepatic Dysfunction: Nateglinide should be used with caution in moderate to severe hepatic impairment. Metformin should be used with caution in moderate liver disease and is contraindicated in severe hepatic dysfunction.
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Patients with Comorbid Conditions: Individualized dosage adjustments may be necessary depending on coexisting conditions.
Clinical Use Cases
Nateglinide and metformin combination therapy isn’t typically adjusted for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. In such cases, blood glucose management might necessitate switching to intravenous insulin.
Dosage Adjustments
Dose adjustments should be based on blood glucose monitoring, including fasting blood glucose and HbA1c levels. Patients with renal or hepatic impairment require careful consideration and potential dose modifications.
Side Effects
Common Side Effects:
- Nateglinide: Hypoglycemia, upper respiratory tract infection, headache, dizziness.
- Metformin: Diarrhea, nausea, vomiting, flatulence, abdominal discomfort, metallic taste.
Rare but Serious Side Effects:
- Nateglinide: Severe hypoglycemia, allergic reactions.
- Metformin: Lactic acidosis (rare but serious).
Long-Term Effects:
- Metformin: Vitamin B12 deficiency (monitor levels periodically).
Adverse Drug Reactions (ADR):
- Nateglinide: Severe hypoglycemia, angioedema, hypersensitivity reactions.
- Metformin: Lactic acidosis (rare but life-threatening).
Contraindications
- Nateglinide: Type 1 diabetes, diabetic ketoacidosis, severe hepatic impairment, hypersensitivity to nateglinide.
- Metformin: Severe renal impairment (eGFR <30 mL/min/1.73 m2), metabolic acidosis, hepatic impairment, hypersensitivity to metformin.
Drug Interactions
- Nateglinide: CYP2C9 and 3A4 inhibitors and inducers can alter nateglinide levels. Concomitant use with other antidiabetic agents can increase the risk of hypoglycemia. Beta-blockers can mask the symptoms of hypoglycemia.
- Metformin: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, ranitidine, triamterene, trimethoprim, vancomycin) can compete with metformin for renal tubular transport systems, increasing the risk of metformin accumulation. Alcohol can increase the risk of lactic acidosis. Iodinated contrast media can transiently impair renal function, increasing the risk of lactic acidosis.
Pregnancy and Breastfeeding
- Nateglinide: Contraindicated during pregnancy and breastfeeding.
- Metformin: Use during pregnancy should be individualized based on the balance of risks and benefits. Consider alternatives during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Metformin decreases hepatic glucose production and improves insulin sensitivity; nateglinide stimulates insulin release.
- Side Effects: Hypoglycemia, gastrointestinal issues (with metformin), lactic acidosis (rare but serious with metformin).
- Contraindications: Type 1 diabetes, diabetic ketoacidosis, renal impairment (metformin), hepatic impairment (nateglinide), hypersensitivity.
- Drug Interactions: CYP450 interactions (nateglinide), cationic drugs (metformin), other antidiabetic agents.
- Pregnancy & Breastfeeding: Contraindicated for nateglinide. Metformin use should be carefully considered.
- Dosage: Nateglinide: 60-120 mg TID before meals. Metformin: 500-2550 mg/day.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (for metformin use), liver function tests (for nateglinide use).
Popular Combinations
Metformin + Nateglinide is itself a common combination aiming to target both basal and postprandial hyperglycemia.
Precautions
- General Precautions: Monitor blood glucose, renal function, and liver function. Patients should be educated about the signs and symptoms of hypoglycemia.
- Specific Populations: See “Special Cases” under Dosage.
- Lifestyle Considerations: Encourage diet and exercise. Alcohol should be used with caution while taking metformin due to the increased risk of lactic acidosis.
FAQs (Frequently Asked Questions)
A: Metformin: 500-2550 mg daily, divided into 2-3 doses; nateglinide: 60-120 mg three times daily before meals.
Q2: How does nateglinide differ from sulfonylureas?
A: Nateglinide has a more rapid onset and shorter duration of action, minimizing the risk of late postprandial and nocturnal hypoglycemia. It binds to a different site on the ATP-sensitive potassium channels of pancreatic beta cells.
Q3: Can nateglinide be used in patients with renal impairment?
A: It can generally be used without dosage adjustment in mild to moderate renal impairment, but caution is advised.
Q4: What are the signs and symptoms of hypoglycemia that patients should be aware of?
A: Sweating, trembling, dizziness, confusion, hunger, headache, blurred vision, weakness, and palpitations.
A: Blood glucose levels (fasting and postprandial), HbA1c levels, renal function (especially for metformin), liver function tests (especially for nateglinide), and vitamin B12 levels (for long-term metformin use).
Q6: Can this combination be used in patients with type 1 diabetes?
A: No. Nateglinide, like other insulin secretagogues, requires functioning beta cells, which are absent or dysfunctional in type 1 diabetes.
Q7: What should be done if a patient on nateglinide skips a meal?
A: The patient should skip the dose of nateglinide associated with that meal to prevent hypoglycemia.
Q8: What is the role of hepatic function in dosing nateglinide?
A: Nateglinide is extensively metabolized by the liver. Dose adjustment is not required in mild hepatic impairment, but caution and close monitoring are necessary in moderate to severe hepatic impairment. It is contraindicated in severe hepatic dysfunction.
A: Lactic acidosis is a rare but serious side effect of metformin, particularly in patients with renal impairment. Its occurrence is quite uncommon but requires immediate medical attention.
