Glibenclamide + Metformin + Rosiglitazone

Usage

This triple combination therapy is prescribed for the management of type 2 diabetes mellitus in patients whose blood sugar levels are not adequately controlled by diet, exercise, or other oral antidiabetic medications. It combines three different classes of drugs that work synergistically to improve glycemic control.

• Pharmacological Classification: This combination includes a sulfonylurea (glibenclamide), a biguanide (metformin), and a thiazolidinedione (rosiglitazone).

• Mechanism of Action:

  • Glibenclamide: Stimulates insulin release from the pancreas.
  • Metformin: Decreases hepatic glucose production and improves insulin sensitivity.
  • Rosiglitazone: Enhances insulin sensitivity in peripheral tissues (muscle and fat).

Alternate Names

• This specific combination doesn’t have a widely recognized international non-proprietary name (INN). It’s commonly referred to by the generic names of its components.
• Brand Names: This particular triple combination is not commonly marketed under a single brand name. Instead, the individual components are available under various brand names (e.g., Glucophage for metformin, Avandia for rosiglitazone, Daonil or Glynase for glibenclamide, among others), and they might be prescribed separately.

How It Works

• Pharmacodynamics: The combined effect of these drugs lowers blood glucose levels by increasing insulin secretion, reducing hepatic glucose output, and improving peripheral insulin sensitivity.

• Pharmacokinetics:

  • Glibenclamide: Well-absorbed orally, metabolized by the liver, and excreted primarily in bile and urine.
  • Metformin: Absorbed from the gastrointestinal tract, not metabolized significantly, and excreted unchanged by the kidneys.
  • Rosiglitazone: Extensively metabolized by the liver (primarily CYP2C8 and CYP2C9) and excreted in feces and urine.

• Mode of Action:

  • Glibenclamide: Binds to sulfonylurea receptors on pancreatic beta-cells, closing ATP-sensitive potassium channels, leading to membrane depolarization and calcium influx, which triggers insulin release.
  • Metformin: Exact mechanism is unclear, but it’s thought to activate AMP-activated protein kinase (AMPK), leading to decreased hepatic gluconeogenesis.
  • Rosiglitazone: Activates peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor that modulates gene expression involved in glucose and lipid metabolism, improving insulin sensitivity.

• Elimination Pathways:

  • Glibenclamide: Hepatic metabolism with biliary and renal excretion.
  • Metformin: Primarily renal excretion.
  • Rosiglitazone: Hepatic metabolism with fecal and urinary excretion.

Dosage

This combination is not available as a single fixed-dose formulation. Therefore, the dosage of each component needs to be individualized based on the patient’s specific needs and response. The following are general guidelines, and the prescriber should adjust them according to clinical judgment:

Standard Dosage

Adults:

• Glibenclamide: Starting dose of 2.5-5 mg daily, taken with breakfast. The dose can be titrated up by 2.5 mg at weekly intervals, based on blood glucose monitoring, to a maximum of 15-20 mg daily. Higher doses may be divided into two doses.
• Metformin: Starting dose of 500 mg twice daily or 850 mg once daily, taken with meals. The dose can be increased gradually by 500 mg every week or 850 mg every two weeks to a maximum of 2550 mg/day divided into 2-3 doses.
• Rosiglitazone: Starting dose of 4 mg once daily or divided into two doses. If the response is inadequate after 8-12 weeks, the dose may be increased to a maximum of 8 mg per day.

Children:

This combination is not generally recommended for children.

Special Cases:

• Elderly Patients: Start with lower doses and titrate cautiously due to the increased risk of hypoglycemia and renal impairment.
• Patients with Renal Impairment: Metformin should be avoided in patients with severe renal impairment. Rosiglitazone and glibenclamide doses may need to be adjusted based on renal function.
• Patients with Hepatic Dysfunction: Rosiglitazone and glibenclamide should be used with caution in patients with hepatic impairment, as they are metabolized by the liver. Metformin is contraindicated in severe liver disease.
• Patients with Comorbid Conditions: Careful consideration should be given to patients with cardiovascular disease, as rosiglitazone has been associated with an increased risk of heart failure.

Clinical Use Cases

The listed clinical situations (intubation, surgery, mechanical ventilation, ICU, emergencies) are not directly related to the primary indications for this medication combination (type 2 diabetes). Specific dosage recommendations for these settings are not relevant.

Dosage Adjustments

Dose adjustments are necessary for patients with renal or hepatic dysfunction, and those with other comorbid conditions affecting drug metabolism. Dosage should be individualized based on the patient’s specific situation and response.

Side Effects

Common Side Effects

• Glibenclamide: Hypoglycemia, weight gain, gastrointestinal upset.
• Metformin: Diarrhea, nausea, vomiting, abdominal discomfort, lactic acidosis (rare but serious).
• Rosiglitazone: Fluid retention, edema, weight gain, headache, upper respiratory tract infections.

Rare but Serious Side Effects

• Glibenclamide: Severe hypoglycemia, blood disorders.
• Metformin: Lactic acidosis.
• Rosiglitazone: Heart failure, myocardial infarction, hepatotoxicity, macular edema.

Long-Term Effects

• Rosiglitazone: Increased risk of fractures, particularly in women.

Adverse Drug Reactions (ADR)

• Glibenclamide: Severe hypoglycemia, hypersensitivity reactions.
• Metformin: Lactic acidosis.
• Rosiglitazone: Heart failure, hepatotoxicity, angioedema.

Contraindications

• Glibenclamide: Type 1 diabetes, diabetic ketoacidosis, severe renal or hepatic impairment, hypersensitivity to sulfonylureas.
• Metformin: Severe renal or hepatic impairment, conditions that predispose to lactic acidosis (e.g., heart failure, severe infection), hypersensitivity.
• Rosiglitazone: New York Heart Association (NYHA) Class III or IV heart failure, active liver disease, hypersensitivity to thiazolidinediones.

Drug Interactions

Many drugs can interact with this combination. Some clinically significant interactions include:

• CYP450 Interactions: Rosiglitazone is primarily metabolized by CYP2C8 and CYP2C9. Drugs that inhibit or induce these enzymes can alter its metabolism and affect its efficacy and safety.
• Other Drug Interactions:
  • Concomitant use with other antidiabetic agents can increase the risk of hypoglycemia.
  • Certain medications (e.g., some antibiotics, antifungals, NSAIDs) can affect renal function and increase the risk of metformin-associated lactic acidosis.
• Food and Lifestyle Factors: Alcohol consumption can increase the risk of lactic acidosis with metformin and hypoglycemia with glibenclamide.

Pregnancy and Breastfeeding

• Glibenclamide: Generally avoided during pregnancy and breastfeeding.
• Metformin: May be used during pregnancy if clinically needed but is generally avoided during breastfeeding.
• Rosiglitazone: Contraindicated during pregnancy and breastfeeding.

Drug Profile Summary

• Mechanism of Action: Increases insulin secretion (glibenclamide), decreases hepatic glucose production (metformin), and enhances insulin sensitivity (rosiglitazone).
• Side Effects: Hypoglycemia, gastrointestinal disturbances, fluid retention, edema, weight gain, lactic acidosis (rare but serious), heart failure (rosiglitazone).
• Contraindications: Type 1 diabetes, severe renal or hepatic impairment, heart failure (rosiglitazone), hypersensitivity.
• Drug Interactions: Multiple drug interactions, including CYP450 interactions.
• Pregnancy & Breastfeeding: Generally avoided or contraindicated.
• Dosage: Individualized based on patient response and specific drug.
• Monitoring Parameters: Blood glucose levels, HbA1c, renal function, liver function tests, weight, signs and symptoms of heart failure.

Popular Combinations

This triple combination itself is not a commonly prescribed regimen. Dual combinations of metformin with either glibenclamide or other sulfonylureas are more frequently used. The use of rosiglitazone has declined due to safety concerns.

Precautions

• General Precautions: Monitor for hypoglycemia, lactic acidosis, fluid retention, and changes in liver and renal function.
• Specific Populations: See section on dosage adjustments for elderly patients, renal impairment, and hepatic dysfunction.
• Lifestyle Considerations: Advise patients on lifestyle modifications, including diet, exercise, and alcohol consumption.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Glibenclamide + Metformin + Rosiglitazone?

A: This combination is not available as a fixed-dose combination. The dosage of each component should be titrated individually based on the patient’s response and tolerance.

Q2: What are the major side effects of this combination?

A: Hypoglycemia, gastrointestinal disturbances, fluid retention, weight gain, lactic acidosis, and heart failure are among the potential side effects.

Q3: Can this combination be used in patients with renal impairment?

A: Metformin should be avoided in severe renal disease. Caution is advised with glibenclamide and rosiglitazone, and dose adjustments may be necessary.

Q4: Is this combination safe during pregnancy?

A: No, Rosiglitazone is contraindicated in pregnancy. Glibenclamide is generally avoided and metformin should be used judiciously if deemed absolutely necessary.

Q5: What are the key drug interactions to be aware of?

A: Many drugs interact with this combination. Pay close attention to drugs affecting CYP2C8 and CYP2C9, as well as those affecting renal function.

Q6: What monitoring parameters are essential for patients on this combination?

A: Regular monitoring of blood glucose levels, HbA1c, renal and liver function, and signs and symptoms of heart failure and lactic acidosis is recommended.

Q7: Why is rosiglitazone used less frequently now?

A: Concerns regarding increased cardiovascular risk, especially heart failure, have led to decreased use of rosiglitazone.

Q8: Are there any alternatives to rosiglitazone in this combination?

A: Other insulin sensitizers like pioglitazone can be considered, but they also carry some cardiovascular risks. Other antidiabetic drugs like DPP-4 inhibitors, SGLT2 inhibitors, or GLP-1 receptor agonists might be more appropriate.

Q9: Can this combination be used in type 1 diabetes?

A: No, glibenclamide is contraindicated in type 1 diabetes. This combination is specifically intended for type 2 diabetes management.