Usage
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This fixed-dose combination (FDC) medication is prescribed for the management of type 2 diabetes mellitus in adults when diet and exercise alone do not adequately control blood sugar levels. It is specifically indicated when metformin monotherapy or dual therapy with metformin and glimepiride is insufficient. This combination may also be used to lower the risk of cardiovascular events and kidney disease progression in certain patients with type 2 diabetes.
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Pharmacological Classification:
- Dapagliflozin: Sodium-glucose co-transporter 2 (SGLT2) inhibitor
- Glimepiride: Sulfonylurea
- Metformin: Biguanide
- This FDC belongs to the class of antidiabetic agents.
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Mechanism of Action: This triple therapy targets multiple pathways involved in glucose regulation:
- Dapagliflozin inhibits SGLT2 in the kidneys, promoting urinary glucose excretion.
- Glimepiride stimulates insulin release from pancreatic beta-cells.
- Metformin decreases hepatic glucose production and improves insulin sensitivity.
Alternate Names
- No formally recognized alternate names exist for the specific FDC. However, the individual components have synonyms (e.g., dapagliflozin is sometimes referred to as BMS-512148).
- Brand Names: Brand names may vary by region. Xigduo is an example, though this brand may not incorporate all three components in some regions. Refer to regional formularies for specific brand names.
How It Works
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Pharmacodynamics:
- Dapagliflozin: Reduces renal glucose reabsorption, leading to glycosuria and lower blood glucose levels.
- Glimepiride: Binds to sulfonylurea receptors on pancreatic beta-cells, closing ATP-sensitive potassium channels, depolarizing the cell, and triggering insulin release.
- Metformin: Activates AMP-activated protein kinase (AMPK), leading to reduced hepatic gluconeogenesis and increased peripheral glucose uptake.
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Pharmacokinetics:
- Dapagliflozin: Well absorbed orally; primarily excreted unchanged in urine; minimally metabolized.
- Glimepiride: Completely absorbed orally; metabolized in the liver by CYP2C9; excreted in urine and bile.
- Metformin: Absorbed from the small intestine; not metabolized; excreted by the kidneys.
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Elimination Pathways:
- Dapagliflozin: Primarily renal excretion.
- Glimepiride: Hepatic metabolism (CYP2C9), renal and biliary excretion.
- Metformin: Renal excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: This depends on the patient’s current regimen and is individualized by the physician. A typical starting dose might involve dapagliflozin 5 mg + glimepiride 1 or 2 mg + metformin 500 or 1000 mg once or twice daily. Dosage can be titrated based on blood glucose control up to a maximum of 10 mg dapagliflozin, 4 mg glimepiride and 2000 mg metformin daily as separate doses of the individual components.
- Administration: Oral, typically with food to reduce gastrointestinal side effects.
Children:
- This combination is not recommended for use in pediatric patients.
Special Cases:
- Elderly Patients: Start at a lower dose and titrate cautiously, considering renal function.
- Patients with Renal Impairment: Contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Dose adjustments are required for mild to moderate renal impairment.
- Patients with Hepatic Dysfunction: Use with caution in patients with hepatic impairment. Metformin is contraindicated in severe hepatic disease. Glimepiride dose adjustment may be needed.
- Patients with Comorbid Conditions: Careful assessment and dose adjustments may be necessary.
Clinical Use Cases
The use of this specific FDC in the contexts of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like cardiac arrest or status epilepticus is not standard practice. Diabetes management is generally individualized in these situations.
Dosage Adjustments
- Dose modifications are based on renal function, hepatic function, concomitant medications, and individual patient response to therapy.
Side Effects
Common Side Effects:
- Hypoglycemia
- Nausea, vomiting, diarrhea
- Urinary tract infections
- Headache
- Back pain
Rare but Serious Side Effects:
- Lactic acidosis (metformin)
- Ketoacidosis
- Severe hypoglycemia
- Acute kidney injury
- Angioedema
- Fournier’s gangrene
Long-Term Effects:
- Vitamin B12 deficiency (metformin)
Adverse Drug Reactions (ADR):
- Lactic acidosis: Requires immediate medical attention.
- Severe hypoglycemia: Requires immediate intervention.
- Angioedema: Requires urgent medical management.
- Fournier’s gangrene: Requires surgical intervention.
Contraindications
- Hypersensitivity to any component of the FDC.
- Type 1 diabetes
- Diabetic ketoacidosis
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²)
- Acute or chronic metabolic acidosis
- Severe hepatic impairment
- History of lactic acidosis
Drug Interactions
- Alcohol: Increases risk of lactic acidosis with metformin.
- Cationic drugs (e.g., cimetidine): May increase metformin levels.
- CYP2C9 inducers/inhibitors: May affect glimepiride levels.
- Diuretics: May increase risk of dehydration and hypotension, especially with dapagliflozin.
- Insulin/sulfonylureas: Increase risk of hypoglycemia.
Pregnancy and Breastfeeding
- Pregnancy: This combination should not be used during pregnancy. Insulin is the preferred agent for managing diabetes during pregnancy.
- Breastfeeding: This combination is not recommended during breastfeeding due to potential risk to the neonate.
Drug Profile Summary
- Mechanism of Action: SGLT2 inhibition (dapagliflozin), increased insulin secretion (glimepiride), reduced hepatic glucose production, increased insulin sensitivity (metformin).
- Side Effects: Hypoglycemia, nausea, diarrhea, UTI, headache, back pain.
- Contraindications: Hypersensitivity, type 1 diabetes, ketoacidosis, severe renal/hepatic impairment, metabolic acidosis.
- Drug Interactions: Alcohol, cationic drugs, CYP2C9 modulators, diuretics, insulin, sulfonylureas.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Individualized based on patient’s current regimen, not to exceed 10/4/2000 mg per day of respective components.
- Monitoring Parameters: HbA1c, fasting and postprandial glucose, renal function (eGFR), electrolytes.
Popular Combinations
This FDC itself is a combination, meant to be used when dual therapy (metformin + glimepiride) isn’t sufficient. Further additions would be based on patient specifics.
Precautions
- General Precautions: Renal and hepatic function monitoring.
- Specific Populations: Use with caution in the elderly, patients with renal or hepatic impairment.
FAQs (Frequently Asked Questions)
A: The dosage is individualized based on the patient’s current regimen. The maximum recommended daily dose is 10 mg dapagliflozin, 4 mg glimepiride, and 2000 mg metformin, usually taken as separate doses of the individual components.
Q2: What are the common side effects?
A: Common side effects include hypoglycemia, gastrointestinal issues (nausea, vomiting, diarrhea), urinary tract infections, headache, and back pain.
Q3: What are the serious side effects?
A: Serious side effects include lactic acidosis, ketoacidosis, severe hypoglycemia, renal impairment, and Fournier’s gangrene.
Q4: Can this FDC be used in pregnancy?
A: No, it is contraindicated in pregnancy. Insulin is the preferred agent for managing diabetes during pregnancy.
Q5: Can this FDC be used during breastfeeding?
A: It’s not recommended due to the potential for neonatal exposure.
Q6: What are the key drug interactions to be aware of?
A: Interactions may occur with alcohol, cationic drugs, CYP2C9 inhibitors/inducers, diuretics, insulin, and other antidiabetic agents.
Q7: How should the dose be adjusted for renal impairment?
A: The dose should be reduced or the combination avoided in patients with moderate to severe renal impairment. Consult current guidelines for specific recommendations.
Q8: What monitoring is recommended for patients on this therapy?
A: Regular monitoring of HbA1c, blood glucose, renal function (eGFR), and electrolytes is recommended.
Q9: What should a patient do if they experience symptoms of hypoglycemia?
A: Patients should immediately consume a fast-acting carbohydrate source (e.g., glucose tablets, fruit juice). If severe, medical assistance may be needed.
