Usage
- This triple combination medication is prescribed for type 2 diabetes mellitus in adults when diet, exercise, and single or dual therapy with Metformin or Nateglinide are insufficient to achieve adequate glycemic control.
- Pharmacological Classification: Antidiabetic combination (Biguanide + Meglitinide + Alpha-glucosidase inhibitor).
- Mechanism of Action: This combination lowers blood glucose levels through three different pathways: Metformin decreases hepatic glucose production and enhances insulin sensitivity; Nateglinide stimulates postprandial insulin release from the pancreas; Voglibose delays intestinal carbohydrate absorption by inhibiting alpha-glucosidase.
Alternate Names
- While this specific combination doesn’t have an international nonproprietary name (INN), the individual components do: Metformin, Nateglinide, and Voglibose.
- Brand Names: Trubose Forte, Trubose Trio, Nateglide Trio, Nateglide-MV Forte, Volix-M.
How It Works
- Pharmacodynamics: Metformin reduces hepatic glucose production, increases insulin sensitivity in peripheral tissues, and may decrease intestinal glucose absorption. Nateglinide stimulates insulin secretion from pancreatic beta-cells, primarily in response to a meal. Voglibose inhibits alpha-glucosidase enzymes in the small intestine, delaying the digestion and absorption of carbohydrates, which reduces postprandial hyperglycemia.
- Pharmacokinetics:
- Metformin: Not metabolized by the liver. Primarily excreted unchanged in the urine. Renal function significantly impacts its clearance.
- Nateglinide: Rapidly absorbed after oral administration, reaching peak plasma concentrations within an hour. Metabolized primarily by CYP2C9 and CYP3A4 enzymes in the liver. Excreted mainly in bile and feces.
- Voglibose: Minimally absorbed from the gut, with only a small fraction reaching systemic circulation. Primarily excreted unchanged in feces.
- Mode of Action:
- Metformin: Exact mechanism is unclear but involves activation of AMP-activated protein kinase (AMPK), leading to a cascade of events that modulate glucose metabolism.
- Nateglinide: Binds to and closes ATP-dependent potassium channels on pancreatic beta-cell membranes, depolarizing the cells and leading to insulin release.
- Voglibose: Competitively inhibits alpha-glucosidase enzymes in the brush border of the small intestine, preventing the breakdown of complex carbohydrates into absorbable monosaccharides.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation:
- Metformin: AMPK activator.
- Nateglinide: ATP-dependent potassium channel blocker on pancreatic beta-cells.
- Voglibose: Alpha-glucosidase inhibitor.
- Elimination Pathways:
- Metformin: Renal excretion.
- Nateglinide: Hepatic metabolism (CYP2C9 and CYP3A4), biliary and fecal excretion.
- Voglibose: Primarily fecal excretion.
Dosage
Standard Dosage
Adults:
- Dosage is individualized based on blood glucose targets and patient tolerance. Start with Nateglinide 60 mg, Metformin 500 mg, and Voglibose 0.2 mg thrice daily immediately before meals. Adjust doses based on blood glucose response and tolerance. Maximum dose for Voglibose is 0.6mg/day, divided into three doses. Nateglinide can be titrated up to 120 mg thrice daily before meals. Metformin can be increased according to standard recommendations.
Children:
- This combination is not recommended for use in children under 18 years of age. Safety and efficacy have not been established in this population.
Special Cases:
- Elderly Patients: Initiate therapy cautiously and monitor renal function closely due to potential age-related decline in kidney function. Consider lower starting doses of Metformin.
- Patients with Renal Impairment: Metformin is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Dose adjustments or avoidance may be necessary in moderate renal impairment. Voglibose and Nateglinide may require dose adjustment as well.
- Patients with Hepatic Dysfunction: Metformin should be used cautiously in patients with hepatic dysfunction due to the risk of lactic acidosis, though the drug itself is not extensively metabolized by the liver. Nateglinide is primarily metabolized by the liver, requiring careful dose adjustment in hepatic impairment. Voglibose is minimally absorbed, so significant hepatic dysfunction may not necessitate dose changes.
- Patients with Comorbid Conditions: Use cautiously in patients with heart failure, history of myocardial infarction, or conditions predisposing to hypoglycemia.
Clinical Use Cases
The combination of Metformin, Nateglinide, and Voglibose is not specifically indicated for use in the settings of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Dosage adjustments may be needed based on patient status and metabolic demands in these settings. Consult with an endocrinologist for tailored recommendations.
Dosage Adjustments
Dose adjustments should be made based on renal function, hepatic function, concomitant medications, and individual glycemic response. Regular monitoring of blood glucose, HbA1c, renal function, and hepatic function tests is essential.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea, abdominal pain, flatulence, loss of appetite, taste disturbance (metallic taste), hypoglycemia.
Rare but Serious Side Effects
- Lactic acidosis (Metformin), severe hypoglycemia (Nateglinide), hepatic dysfunction, Vitamin B12 deficiency (Metformin).
Long-Term Effects
- Potential for vitamin B12 deficiency with long-term Metformin use. Regular monitoring recommended.
Adverse Drug Reactions (ADR)
- Lactic acidosis, severe hypoglycemia requiring hospitalization, angioedema, Stevens-Johnson syndrome.
Contraindications
- Hypersensitivity to any component of the combination.
- Type 1 diabetes mellitus.
- Diabetic ketoacidosis.
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²).
- Acute or chronic metabolic acidosis.
- Severe hepatic impairment.
- Congestive heart failure requiring drug therapy.
- Recent myocardial infarction.
- Conditions predisposing to intestinal obstruction.
- Chronic intestinal diseases with malabsorption.
Drug Interactions
- CYP450 Interactions: Nateglinide is metabolized by CYP2C9 and CYP3A4. Concomitant use with inhibitors (e.g., azole antifungals, some macrolides) or inducers (e.g., rifampin, phenytoin) of these enzymes can alter nateglinide levels.
- Other Drug Interactions:
- Corticosteroids, thiazide diuretics, thyroid products, sympathomimetics can reduce the hypoglycemic effect.
- Beta-blockers can mask symptoms of hypoglycemia.
- Alcohol can increase the risk of hypoglycemia and lactic acidosis (Metformin).
- Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, ranitidine, triamterene, vancomycin) that are eliminated by renal tubular secretion can interact with Metformin.
Pregnancy and Breastfeeding
- The safety of this combination during pregnancy and breastfeeding has not been established. It is generally not recommended. If antidiabetic medication is absolutely necessary during pregnancy, insulin is typically preferred.
Drug Profile Summary
- Mechanism of Action: Multifactorial: Metformin (reduces hepatic glucose production, increases insulin sensitivity), Nateglinide (stimulates postprandial insulin release), Voglibose (delays carbohydrate absorption).
- Side Effects: Nausea, vomiting, diarrhea, abdominal pain, flatulence, hypoglycemia, lactic acidosis (rare).
- Contraindications: Type 1 diabetes, severe renal/hepatic impairment, diabetic ketoacidosis.
- Drug Interactions: CYP2C9 and CYP3A4 inhibitors/inducers, alcohol, cationic drugs.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Individualized based on glycemic control.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (eGFR), hepatic function tests, Vitamin B12 levels.
Popular Combinations
- This fixed-dose combination is itself a popular combination aimed at targeting different aspects of blood glucose regulation in type 2 diabetes.
Precautions
- Monitor renal function, especially in the elderly.
- Closely monitor for and promptly manage hypoglycemia.
- Counsel patients on appropriate diet, exercise, and lifestyle modifications.
- Advise patients to avoid or limit alcohol intake.
- Educate patients about the signs and symptoms of hypoglycemia and lactic acidosis.
FAQs (Frequently Asked Questions)
A: Dosage is individualized based on blood glucose targets and patient tolerance. A common starting point is Nateglinide 60mg, Metformin 500mg, and Voglibose 0.2mg thrice daily immediately before meals.
Q2: What are the common side effects?
A: Common side effects include gastrointestinal issues like nausea, vomiting, diarrhea, abdominal pain, and flatulence, as well as hypoglycemia.
Q3: Is this combination safe in pregnancy?
A: The safety during pregnancy and breastfeeding hasn’t been established. It’s generally not recommended. Insulin is typically preferred if antidiabetic medication is required during pregnancy.
Q4: Are there any specific monitoring requirements for patients on this combination?
A: Regular monitoring of blood glucose, HbA1c, renal function (eGFR), and hepatic function is crucial. Periodic monitoring of Vitamin B12 levels is recommended for patients on long-term metformin therapy.
Q5: What are the signs and symptoms of lactic acidosis?
A: Lactic acidosis is a rare but serious side effect of Metformin. Symptoms can include malaise, myalgias, respiratory distress, somnolence, hypotension, and resistant hypoglycemia.
Q6: What should be done if a patient experiences hypoglycemia?
A: If a patient experiences mild hypoglycemia, advise them to consume 15-20 grams of fast-acting carbohydrate, such as glucose tablets or fruit juice. If hypoglycemia is severe or the patient is unconscious, glucagon or intravenous glucose may be required.
Q7: What are the key drug interactions to be aware of?
A: Nateglinide interacts with CYP2C9 and CYP3A4 inhibitors and inducers. Metformin interacts with cationic drugs eliminated by renal tubular secretion and alcohol. Alcohol can also potentiate the hypoglycemic effects of nateglinide.
Q8: Can this combination be used in patients with renal impairment?
A: Metformin is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Dose adjustments or avoidance may be necessary in moderate renal impairment. Nateglinide and Voglibose should also be used cautiously in patients with renal impairment, and dose modifications may be required.
Q9: What patient education is essential for this medication?
A: Patients should be educated on the importance of adherence to the prescribed regimen, lifestyle modifications (diet and exercise), how to recognize and manage hypoglycemia, avoidance of excessive alcohol intake, and regular monitoring of blood glucose and other parameters as advised. They should also be instructed to immediately report any signs or symptoms of lactic acidosis.
