Usage
- Glibenclamide + Metformin is an oral antidiabetic combination medication prescribed for the management of type 2 diabetes mellitus in adults. It is used when diet and exercise alone or treatment with either glibenclamide or metformin monotherapy do not adequately control blood glucose levels.
- Pharmacological Classification: Antidiabetic, Biguanide/Sulfonylurea Combination.
- Mechanism of Action: This combination works by targeting two different mechanisms involved in glucose regulation. Metformin decreases hepatic glucose production, reduces glucose absorption in the intestines, and improves insulin sensitivity. Glibenclamide stimulates insulin release from the pancreas.
Alternate Names
- No widely recognized alternate generic names.
- Brand Names: Glucovance, Zomet, and others (brand names vary regionally).
How It Works
- Pharmacodynamics: Metformin exerts its antihyperglycemic effects through multiple mechanisms, including reduction of hepatic glucose output, improvement of insulin sensitivity in peripheral tissues (e.g., skeletal muscle), and decreased intestinal glucose absorption. Glibenclamide binds to sulfonylurea receptors on pancreatic beta cells, which closes ATP-sensitive potassium channels, depolarizes the cell membrane, opens voltage-dependent calcium channels, and promotes insulin secretion.
- Pharmacokinetics: Metformin is absorbed from the gastrointestinal tract, not extensively metabolized, and eliminated primarily renally. Glibenclamide is well-absorbed, metabolized in the liver (mainly by CYP2C9), and excreted as metabolites primarily in the bile and secondarily in the urine.
- Mode of Action: Metformin’s precise mode of action is not fully elucidated but involves activation of AMP-activated protein kinase (AMPK). Glibenclamide’s action involves binding to and closing ATP-sensitive potassium channels on pancreatic beta cells, ultimately increasing insulin secretion.
- Elimination Pathways: Metformin is excreted unchanged primarily via the kidneys. Glibenclamide undergoes hepatic metabolism with biliary and renal excretion of inactive metabolites.
Dosage
Standard Dosage
Adults:
- Initial Therapy (First-line): 1.25 mg glibenclamide/250 mg metformin once daily with meals. In patients with HbA1c >9% or FPG >200 mg/dL, start with 1.25 mg/250 mg twice daily.
- Second-line (after monotherapy with either drug): 2.5 mg/500 mg or 5 mg/500 mg once or twice daily with meals.
- Replacement Therapy (from previous combination): Dosage should not exceed the previous daily dose of glibenclamide and metformin.
- Dosage adjustments: Increase in increments of 1.25 mg/250 mg every two weeks or more, based on blood glucose monitoring, up to a maximum of 20 mg glibenclamide/2000 mg metformin per day.
Children: Not recommended.
Special Cases:
- Elderly Patients: Start with a lower dose and titrate cautiously due to potential age-related decline in renal function.
- Patients with Renal Impairment: Contraindicated in patients with creatinine clearance (CrCl) less than 60 mL/min.
- Patients with Hepatic Dysfunction: Contraindicated.
- Patients with Comorbid Conditions: Dosage adjustments may be needed based on coexisting conditions such as cardiovascular disease. Close monitoring is necessary.
Clinical Use Cases
Glibenclamide + Metformin is not indicated for use in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
- Adjust dosage based on individual patient response, renal function (contraindicated if CrCl < 60 mL/min), and hepatic function (contraindicated in hepatic impairment).
- Dosage modification may be needed in patients with specific metabolic disorders or genetic polymorphisms affecting drug metabolism, especially those influencing CYP2C9 activity for glibenclamide.
Side Effects
Common Side Effects
- Hypoglycemia
- Gastrointestinal disturbances (nausea, diarrhea, abdominal discomfort)
- Weight gain
Rare but Serious Side Effects
- Lactic acidosis (metformin)
- Hepatotoxicity (glibenclamide)
- Blood dyscrasias (glibenclamide)
Long-Term Effects
- Vitamin B12 deficiency (metformin)
Adverse Drug Reactions (ADR)
- Severe hypoglycemia requiring medical intervention.
- Lactic acidosis presenting with hyperventilation, myalgia, malaise, unusual somnolence, and other nonspecific symptoms.
Contraindications
- Hypersensitivity to glibenclamide or metformin.
- Type 1 diabetes mellitus.
- Diabetic ketoacidosis.
- Severe renal impairment (CrCl < 60 mL/min).
- Hepatic impairment.
- Acute or chronic conditions predisposing to tissue hypoxia (e.g., heart failure, respiratory failure).
- Acute or chronic metabolic acidosis.
Drug Interactions
- Alcohol (increased risk of lactic acidosis with metformin).
- Cationic drugs (e.g., cimetidine) compete for renal tubular transport with metformin.
- CYP2C9 inducers (e.g., rifampin) and inhibitors (e.g., fluconazole) can alter glibenclamide metabolism.
- Other antidiabetic agents (additive hypoglycemic effects).
- Beta-blockers (can mask signs of hypoglycemia).
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not generally recommended during pregnancy. Insulin is usually preferred for glycemic control.
- Breastfeeding: Metformin is present in breast milk. Glibenclamide use during breastfeeding is generally not advised.
Drug Profile Summary
- Mechanism of Action: Metformin reduces hepatic glucose production and improves insulin sensitivity. Glibenclamide stimulates insulin release.
- Side Effects: Hypoglycemia, GI disturbances, lactic acidosis (rare), hepatotoxicity (rare).
- Contraindications: Type 1 diabetes, renal/hepatic impairment, ketoacidosis.
- Drug Interactions: Alcohol, CYP2C9 inhibitors/inducers, other antidiabetic drugs.
- Pregnancy & Breastfeeding: Not generally recommended.
- Dosage: Individualized titration up to a maximum of 20 mg glibenclamide/2000 mg metformin.
- Monitoring Parameters: Blood glucose levels, HbA1c, renal function tests.
Popular Combinations
Often used as a standalone combination due to its dual mechanism. May occasionally be combined with other antidiabetic medications if dual therapy is insufficient.
Precautions
- Monitor renal function before starting and periodically during therapy.
- Counsel patients on signs and symptoms of hypoglycemia and lactic acidosis.
- Adjust dosage carefully in elderly patients and those with renal impairment.
FAQs (Frequently Asked Questions)
A: Initial dosage depends on several factors, including whether it is being used as first-line, second-line, or replacement therapy. Refer to the detailed dosage section above for specific recommendations. Dose adjustments are made based on individual patient response and should be titrated up gradually every two weeks or more, with careful blood glucose monitoring.
Q2: What are the common side effects?
A: The most common side effects are hypoglycemia and gastrointestinal disturbances like nausea, diarrhea, and abdominal discomfort.
A: Not generally recommended. Insulin is the preferred treatment for managing diabetes during pregnancy.
Q4: What are the contraindications to using this drug?
A: Contraindications include type 1 diabetes, diabetic ketoacidosis, severe renal or hepatic impairment, and conditions predisposing to tissue hypoxia.
Q5: How does this combination work at the cellular level?
A: Metformin activates AMPK, while glibenclamide binds to sulfonylurea receptors on pancreatic beta cells, closing ATP-sensitive potassium channels, and eventually increasing insulin secretion.
Q6: What are the key drug interactions to be aware of?
A: Significant interactions exist with alcohol, CYP2C9 inducers/inhibitors, and other antidiabetic medications.
Q7: How should the dosage be adjusted in elderly patients?
A: Start with a lower dose and titrate carefully due to age-related decline in renal function.
Q8: What are the monitoring parameters for this drug?
A: Blood glucose levels, HbA1c, and renal function tests are essential parameters to monitor.
Q9: What should I do if a patient develops lactic acidosis?
A: Lactic acidosis is a rare but serious side effect of metformin. Immediately discontinue the medication and provide supportive care.
Q10: Can this combination be used in type 1 diabetes?
A: No. Glibenclamide + Metformin is specifically indicated for type 2 diabetes mellitus.
