Usage
- This combination drug is prescribed for the treatment of type 2 diabetes mellitus in adults when blood sugar levels are not adequately controlled by metformin alone or in combination with either dapagliflozin or sitagliptin. It is also indicated to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.
- Pharmacological Classification: Antidiabetic combination therapy comprising a sodium-glucose cotransporter-2 (SGLT2) inhibitor (dapagliflozin), a biguanide (metformin), and a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin).
- Mechanism of Action: Dapagliflozin increases urinary glucose excretion. Metformin decreases hepatic glucose production and increases insulin sensitivity. Sitagliptin increases incretin levels, leading to increased insulin secretion and decreased glucagon secretion.
Alternate Names
- No widely used alternate names exist for this specific combination product.
- Brand Names: This combination is available under various brand names depending on the region and manufacturer. Qternmet XR is one example.
How It Works
- Pharmacodynamics: The combined effects of the three drugs improve glycemic control by targeting different aspects of glucose regulation. Dapagliflozin acts independently of insulin to increase urinary glucose excretion. Metformin reduces hepatic glucose production and enhances insulin sensitivity in peripheral tissues. Sitagliptin augments incretin hormone levels, stimulating glucose-dependent insulin release and suppressing glucagon secretion.
- Pharmacokinetics: Dapagliflozin is primarily eliminated via renal excretion, while metformin is mainly excreted unchanged in the urine. Sitagliptin is predominantly eliminated via hepatic metabolism, with a minor portion excreted renally. The pharmacokinetic profiles of each component are not significantly altered when administered in combination.
- Mode of Action: Dapagliflozin inhibits SGLT2 in the renal proximal tubules, blocking glucose reabsorption. Metformin activates AMP-activated protein kinase (AMPK), impacting various metabolic pathways involved in glucose regulation. Sitagliptin inhibits DPP-4, the enzyme responsible for degrading incretin hormones like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
- Elimination Pathways: Dapagliflozin: Renal excretion (primarily). Metformin: Renal excretion (primarily). Sitagliptin: Hepatic metabolism (primarily), with some renal excretion.
Dosage
Standard Dosage
Adults:
- Starting dose is individualized based on the patient’s current regimen.
- Usual starting dose: Dapagliflozin 5 mg or 10 mg once daily, metformin 500 mg or 1000 mg twice daily, and sitagliptin 50 mg or 100 mg once daily.
- Maximum dose: Dapagliflozin 10 mg once daily, metformin 2000 mg daily, and sitagliptin 100 mg once daily.
Children:
- Not recommended for use in patients under 18 years of age.
Special Cases:
- Elderly Patients: Initiate therapy cautiously, considering renal function. Dose adjustment may be necessary.
- Patients with Renal Impairment: Dose adjustments are necessary based on estimated glomerular filtration rate (eGFR). Contraindicated in patients with severe renal impairment.
- Patients with Hepatic Dysfunction: Metformin should be used with caution in patients with hepatic impairment. Dapagliflozin and sitagliptin can generally be used without dose adjustments.
- Patients with Comorbid Conditions: Assess for potential drug interactions and contraindications based on individual patient conditions.
Clinical Use Cases
- This combination medication is specifically designed for the management of type 2 diabetes and is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
- Adjustments are based on patient-specific factors, including renal function, hepatic function, and concomitant medications.
Side Effects
Common Side Effects
- Upper respiratory tract infection, nasopharyngitis, urinary tract infection, diarrhea, nausea, vomiting, headache, genital mycotic infections.
Rare but Serious Side Effects
- Acute pancreatitis, lactic acidosis (with metformin), severe hypoglycemia, acute kidney injury, angioedema, bullous pemphigoid.
Long-Term Effects
- Potential long-term side effects may include vitamin B12 deficiency (with metformin), bladder cancer (with dapagliflozin), and heart failure (with dapagliflozin, although the drug is also used to reduce the risk of heart failure hospitalization in certain patients).
Adverse Drug Reactions (ADR)
- Any serious side effects, such as angioedema, pancreatitis, or lactic acidosis, should be considered as ADRs and require immediate intervention.
Contraindications
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Severe renal impairment (eGFR less than 30 mL/min/1.73 m²)
- End-stage renal disease
- Hypersensitivity to any component of the drug
- History of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) to DPP-4 inhibitors
- Acute or chronic metabolic acidosis
Drug Interactions
- Many drug interactions are possible with this combination therapy. Consult a comprehensive drug interaction database for a complete list. Some notable interactions include:
- Alcohol (increased risk of lactic acidosis with metformin)
- Carbonic anhydrase inhibitors (increased risk of urinary tract infections with dapagliflozin)
- Urinary tract infection
- Insulin and insulin secretagogues (increased risk of hypoglycemia with sitagliptin)
- Medications affecting renal function
- Medications that lower the seizure threshold
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not established for this specific combination.
- Limited data available. Generally not recommended during pregnancy.
- Breastfeeding: Not recommended. Metformin and dapagliflozin are excreted in breast milk. The effect on infants is unknown.
Drug Profile Summary
- Mechanism of Action: SGLT2 inhibition (dapagliflozin), hepatic glucose production reduction (metformin), incretin enhancement (sitagliptin)
- Side Effects: Urinary tract infections, genital mycotic infections, hypoglycemia, lactic acidosis (metformin), pancreatitis (sitagliptin)
- Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal impairment, end-stage renal disease, hypersensitivity
- Drug Interactions: Numerous drug interactions are possible. Consult a drug interaction database.
- Pregnancy & Breastfeeding: Not recommended
- Dosage: Individualized based on current regimen, not to exceed dapagliflozin 10 mg, metformin 2000 mg, sitagliptin 100 mg daily.
- Monitoring Parameters: Blood glucose, HbA1c, renal function, hepatic function, electrolytes, lipid panel
Popular Combinations
- This combination itself represents a popular triple therapy for type 2 diabetes. Sometimes other antidiabetic agents like insulin may be added, but these decisions should be made on a case-by-case basis.
Precautions
- General Precautions: Assess renal function, hepatic function, and history of pancreatitis.
- Specific Populations: See “Dosage - Special Cases” section.
- Lifestyle Considerations: Encourage lifestyle modifications including diet and exercise. Advise patients to monitor blood glucose regularly. Alcohol should be avoided or consumed in moderation due to the risk of lactic acidosis with metformin.
FAQs (Frequently Asked Questions)
A: The dosage is individualized based on the patient’s current regimen, effectiveness, and tolerability, not to exceed dapagliflozin 10 mg once daily, metformin 2000 mg daily (divided doses), and sitagliptin 100 mg once daily.
Q2: How should this combination be taken?
A: Orally, once daily, with or without food.
Q3: What are the common side effects?
A: Common side effects include upper respiratory tract infection, urinary tract infection, genital mycotic infections, diarrhea, nausea, and headache.
Q4: Can this combination be used during pregnancy?
A: It’s generally not recommended during pregnancy. Discuss risks and benefits with a specialist.
Q5: What should be monitored while a patient is on this medication?
A: Blood glucose, HbA1c, renal function, hepatic function, and electrolytes should be monitored regularly.
Q6: Can patients with kidney disease take this medication?
A: Patients with severe kidney disease or end-stage renal disease should not take this medication. Dose adjustments are required for those with mild to moderate renal impairment.
Q7: What is lactic acidosis, and how does it relate to this drug?
A: Lactic acidosis is a rare but serious metabolic complication associated with metformin use. It involves a buildup of lactic acid in the blood. The risk is increased in patients with renal or hepatic impairment.
Q8: What are the major drug interactions to be aware of?
A: Consult a drug interaction database for a comprehensive list. Notable interactions include alcohol (increased risk of lactic acidosis with metformin) and medications affecting renal function.
Q9: What should a patient do if they miss a dose?
A: Patients should take the missed dose as soon as they remember, unless it’s close to the time for the next dose. Do not double the dose.
Q10: How does this combination compare to other diabetes treatments?
A: This combination offers the combined benefits of three different mechanisms of action, which can lead to improved glycemic control. The choice of antidiabetic therapy depends on individual patient factors.
