Usage
Gliclazide + Metformin is prescribed for the treatment of type 2 diabetes mellitus in adults, specifically when diet and exercise alone do not adequately control blood glucose levels. This combination therapy is particularly useful when metformin monotherapy is insufficient or not tolerated. It falls under the pharmacological classification of oral antihyperglycemic agents, specifically combining a sulfonylurea (gliclazide) with a biguanide (metformin).
Gliclazide works primarily by stimulating insulin release from the pancreas. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Alternate Names
While “Gliclazide + Metformin” represents the generic name, various brand names exist depending on the region and manufacturer. One example is K-GEM. There are no widely recognized international variations for the combined formulation’s name. However, individual components might have regional variations.
How It Works
Gliclazide:
- Pharmacodynamics: Gliclazide stimulates insulin secretion by binding to sulfonylurea receptors (SUR1) on pancreatic beta cells, closing ATP-sensitive potassium channels, leading to membrane depolarization and calcium influx. This triggers insulin exocytosis. It also improves peripheral insulin sensitivity and reduces microthrombotic events.
- Pharmacokinetics: Gliclazide is well-absorbed orally, reaching peak plasma concentration in 4-6 hours (immediate release) or displays sustained levels with modified-release formulations. It is highly protein-bound and extensively metabolized in the liver, with primarily renal excretion of inactive metabolites.
Metformin:
- Pharmacodynamics: Metformin’s primary action is reducing hepatic glucose production. It also increases peripheral glucose uptake and utilization and decreases intestinal glucose absorption. It does not stimulate insulin secretion.
- Pharmacokinetics: Metformin is absorbed slowly and incompletely from the gastrointestinal tract. It is not metabolized in the liver and is excreted unchanged primarily by the kidneys.
Dosage
Standard Dosage
Adults:
Gliclazide: Initial dose is usually 30-40 mg daily (immediate release or modified release), adjusted according to blood glucose response up to a maximum of 320 mg for immediate release or 120 mg for modified release. Doses above 160 mg (immediate release) should be divided into two doses.
Metformin: Initial dose is typically 500 mg twice daily or 850 mg once daily, taken with meals. The dose can be titrated upwards, not exceeding 2550 mg daily, divided into 2-3 doses. Extended-release formulations allow once-daily administration up to a maximum of 2000 mg.
Children:
The combined formulation is not typically used in children. Metformin is approved for use in children 10 years and older.
Special Cases:
- Elderly Patients: Start at lower doses and titrate cautiously.
- Patients with Renal Impairment: Gliclazide can be used with caution and dosage reduction. Metformin is contraindicated with an eGFR <30 ml/min, not recommended to initiate if eGFR 30-45 mL/min, and dosage reduction is recommended if eGFR is 45-60 ml/min.
- Patients with Hepatic Dysfunction: Metformin is contraindicated in severe hepatic impairment. Gliclazide should be used with caution in patients with hepatic impairment.
- Patients with Comorbid Conditions: Dosage adjustments might be necessary depending on the specific comorbid conditions.
Clinical Use Cases
The Gliclazide + Metformin combination is not indicated for use in acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dosage adjustments should be individualized based on the patient’s blood glucose response, renal function, hepatic function, and any comorbid conditions.
Side Effects
Common Side Effects
- Hypoglycemia
- Gastrointestinal disturbances (nausea, diarrhea, abdominal pain)
- Weight gain
- Headache
Rare but Serious Side Effects
- Lactic acidosis (metformin)
- Hepatotoxicity
- Severe hypoglycemia
- Blood dyscrasias
Long-Term Effects
- Vitamin B12 deficiency (metformin)
Adverse Drug Reactions (ADR)
- Lactic acidosis
- Severe cutaneous adverse reactions (SCARs)
Contraindications
- Type 1 diabetes
- Diabetic ketoacidosis
- Severe renal or hepatic impairment
- Hypersensitivity to sulfonylureas or biguanides
- Pregnancy and breastfeeding
Drug Interactions
- Miconazole
- Fluconazole
- Alcohol
- Certain medications (e.g., corticosteroids, thiazide diuretics, beta-blockers)
- CYP450 inducers or inhibitors
Pregnancy and Breastfeeding
Gliclazide + Metformin is contraindicated during pregnancy and breastfeeding. Insulin is the preferred treatment for diabetes during pregnancy.
Drug Profile Summary
- Mechanism of Action: Gliclazide: Stimulates insulin release. Metformin: Decreases hepatic glucose production and improves insulin sensitivity.
- Side Effects: Hypoglycemia, gastrointestinal disturbances, lactic acidosis (rare).
- Contraindications: Type 1 diabetes, severe renal/hepatic impairment, pregnancy.
- Drug Interactions: Miconazole, fluconazole, alcohol.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Individualized based on response and renal function.
- Monitoring Parameters: Blood glucose, HbA1c, renal function.
Popular Combinations
Gliclazide + Metformin is itself a popular combination. Other antidiabetic agents, like DPP-4 inhibitors or SGLT2 inhibitors, can be added if needed.
Precautions
- Monitor renal function regularly.
- Educate patients about hypoglycemia risks and management.
- Adjust dosage cautiously in elderly patients and those with renal/hepatic impairment.
- Monitor for signs of lactic acidosis.
FAQs (Frequently Asked Questions)
A: The dosage is individualized, but generally starts with Gliclazide 30-40 mg and Metformin 500 mg twice daily or 850 mg once daily, adjusted as needed.
Q2: What are the primary side effects of this combination?
A: Common side effects include hypoglycemia and gastrointestinal upset (e.g., nausea, diarrhea).
Q3: Can this combination be used during pregnancy?
A: No, it’s contraindicated. Insulin is preferred.
Q4: How does renal impairment affect dosing?
A: Gliclazide dosage might need reduction. Metformin is contraindicated in severe impairment (eGFR <30 mL/min) and requires dose adjustments in moderate impairment (eGFR 30-45 mL/min).
Q5: What are the key drug interactions to consider?
A: Miconazole, fluconazole, and alcohol can significantly interact with this combination.
A: Gliclazide stimulates insulin secretion, while metformin primarily reduces hepatic glucose production and improves insulin sensitivity. These complementary mechanisms enhance blood glucose control.
Q7: What are the signs of lactic acidosis?
A: Signs include malaise, myalgia, respiratory distress, and unusual somnolence. It requires immediate medical attention.
Q8: How often should renal function be monitored in patients taking this combination?
A: Renal function should be monitored at least annually, or more frequently in patients with risk factors for renal impairment.
Q9: Is this combination appropriate for all patients with type 2 diabetes?
A: No. It’s not suitable for patients with type 1 diabetes, severe renal or hepatic impairment, or during pregnancy. Individualized assessment is essential.
Q10: What patient education is crucial for this combination?
A: Patients must understand how to recognize and manage hypoglycemia, the importance of regular blood glucose monitoring, and the potential risks of lactic acidosis (though rare). Adherence to diet and exercise recommendations is also crucial.
