Usage
- Dapagliflozin + Pioglitazone is prescribed for type 2 diabetes mellitus in adults to improve glycemic control when metformin alone or in combination with other antidiabetic agents (including insulin) does not provide adequate glycemic control.
- Pharmacological classification: Antidiabetic combination comprised of a sodium-glucose co-transporter 2 (SGLT2) inhibitor (dapagliflozin) and a thiazolidinedione (pioglitazone).
- Mechanism of Action: Dapagliflozin inhibits SGLT2 in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion. Pioglitazone enhances insulin sensitivity in peripheral tissues (muscle, liver, and adipose tissue) by activating peroxisome proliferator-activated receptor gamma (PPAR-γ).
Alternate Names
- No commonly used alternate generic names.
- Brand Names: Qtern, Xigduo XR
How It Works
- Pharmacodynamics: Dapagliflozin exerts its effect by promoting glucosuria, independent of insulin secretion or action. Pioglitazone improves insulin sensitivity, thereby enhancing glucose uptake and utilization by peripheral tissues. It also decreases hepatic glucose output. The combined effect lowers blood glucose levels. This combination can also modestly lower systolic blood pressure.
- Pharmacokinetics:
- Dapagliflozin: Rapidly absorbed after oral administration. Peak plasma concentration reached within 2 hours. Primarily metabolized by UGT1A9 to dapagliflozin 3-O-glucuronide (inactive metabolite). Excreted in urine (75%) and feces (21%).
- Pioglitazone: Well absorbed following oral administration, reaching peak plasma levels in 2-4 hours. Extensively metabolized by the liver, primarily via CYP2C8 and CYP3A4. Elimination half-life of 3-7 hours. Excreted primarily in bile and feces.
- Mode of Action: Dapagliflozin acts by inhibiting SGLT2 in the renal proximal tubule. Pioglitazone activates PPAR-γ, a nuclear receptor that regulates gene expression involved in glucose and lipid metabolism.
- Receptor Binding/Enzyme Inhibition: Pioglitazone is a PPAR-γ agonist. Dapagliflozin inhibits SGLT2.
- Elimination Pathways: Dapagliflozin is primarily excreted in urine as dapagliflozin 3-O-glucuronide. Pioglitazone is excreted mainly in feces via biliary elimination.
Dosage
Standard Dosage
Adults:
- Initial: Dapagliflozin 5 mg + Pioglitazone 15 mg orally once daily with or without food.
- If glycemic control is inadequate, the dose may be increased to Dapagliflozin 10 mg + Pioglitazone 30 mg once daily or 45 mg once daily, as tolerated.
Children:
- Not recommended for patients under 18 years of age.
Special Cases:
- Elderly Patients: Initiate with lowest dose (Dapagliflozin 5 mg + Pioglitazone 15 mg) due to increased risk of volume depletion and monitor closely.
- Patients with Renal Impairment:
- eGFR ≥ 60 mL/min/1.73 m²: No dose adjustment.
- eGFR 45 - <60 mL/min/1.73 m²: Dapagliflozin 5 mg + Pioglitazone starting dose depending on renal function. Maximum daily dose 5 mg for dapagliflozin. Not recommended if on dialysis.
- eGFR < 45 mL/min/1.73 m² and dialysis: Not recommended.
- Patients with Hepatic Dysfunction: No dosage adjustment necessary for mild to moderate hepatic impairment. Use with caution in severe hepatic impairment.
- Patients with Comorbid Conditions: Monitor carefully for volume depletion, especially in those with heart failure or on diuretics. If starting patient with eGFR between 45-60 start with lowest available dose.
Clinical Use Cases
- Not typically indicated for acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
- Adjust dose based on patient’s renal function, glycemic control, and tolerability.
Side Effects
Common Side Effects
- Genital mycotic infections (vulvovaginitis, balanitis)
- Urinary tract infections (UTIs)
- Increased urination
- Back pain
- Nasopharyngitis
- Peripheral edema (with Pioglitazone)
- Upper respiratory tract infections
Rare but Serious Side Effects
- Diabetic ketoacidosis (DKA), especially in patients with type 1 diabetes or those with risk factors
- Necrotizing fasciitis of the perineum (Fournier’s gangrene)
- Acute kidney injury
- Hypoglycemia (when used with insulin or sulfonylureas)
- Volume depletion (especially in patients with renal impairment, elderly, or those taking diuretics)
- Bladder cancer (with Pioglitazone)
- Bone fractures (with Pioglitazone)
Long-Term Effects
- Chronic kidney disease progression
- Cardiovascular events in patients with established cardiovascular disease
Adverse Drug Reactions (ADR)
- Angioedema
- Hypersensitivity reactions
Contraindications
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease requiring dialysis
- History of bladder cancer
- Active bladder cancer
- Hypersensitivity to dapagliflozin or pioglitazone
Drug Interactions
- Insulin and insulin secretagogues: Increased risk of hypoglycemia.
- Diuretics: Increased risk of volume depletion.
- Rifampin: Reduced dapagliflozin exposure.
- UGT1A9 inhibitors: Increased dapagliflozin exposure.
Pregnancy and Breastfeeding
- Pregnancy: Not recommended during the second and third trimesters. Limited data available for the first trimester.
- Breastfeeding: Not recommended as both drugs can be excreted in human milk.
Drug Profile Summary
- Mechanism of Action: Dapagliflozin: SGLT2 inhibitor; Pioglitazone: PPAR-γ agonist.
- Side Effects: Genital mycotic infections, UTIs, increased urination, back pain, peripheral edema, hypoglycemia, DKA.
- Contraindications: Type 1 diabetes, DKA, severe renal impairment, bladder cancer, hypersensitivity.
- Drug Interactions: Insulin, sulfonylureas, diuretics, rifampin.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Dapagliflozin 5-10 mg + Pioglitazone 15-45 mg once daily.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (eGFR, creatinine), blood pressure, signs of volume depletion, hepatic function, lipid profile, ophthalmologic examination (for macular edema with pioglitazone).
Popular Combinations
- Metformin: Commonly used in triple therapy with Dapagliflozin + Pioglitazone when dual therapy is not sufficient.
Precautions
- General Precautions: Assess renal function before initiating therapy and periodically thereafter. Monitor for symptoms of UTIs and genital infections.
- Specific Populations: Use with caution in elderly, patients with renal impairment, and those on diuretics.
- Lifestyle Considerations: Encourage lifestyle modifications including diet and exercise.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dapagliflozin + Pioglitazone?
A: Initial dose is Dapagliflozin 5 mg + Pioglitazone 15 mg once daily. It can be increased to Dapagliflozin 10 mg + Pioglitazone 30 mg/45 mg once daily based on glycemic control and tolerability.
Q2: Can this combination be used in patients with type 1 diabetes?
A: No, it is contraindicated in type 1 diabetes and may increase the risk of DKA.
Q3: How does this combination affect renal function?
A: May cause a decrease in eGFR and an increase in serum creatinine. Monitor renal function closely, especially in elderly and those with pre-existing renal impairment.
Q4: Are there any drug interactions to be aware of?
A: Concomitant use with insulin or sulfonylureas can increase the risk of hypoglycemia. Diuretics may increase the risk of volume depletion. Rifampicin can decrease dapagliflozin levels.
Q5: What are the most common side effects?
A: Genital mycotic infections, UTIs, increased urination, and back pain.
Q6: Can this drug be used during pregnancy or breastfeeding?
A: Not recommended during the second and third trimesters of pregnancy. Not recommended during breastfeeding.
Q7: What monitoring parameters are essential for patients on this medication?
A: Blood glucose, HbA1c, renal function, blood pressure, signs of volume depletion, and signs of heart failure should be monitored. Monitor for macular edema if on pioglitazone.
Q8: What is the mechanism of action of Dapagliflozin + Pioglitazone?
A: Dapagliflozin inhibits SGLT2, reducing renal glucose reabsorption, while pioglitazone increases insulin sensitivity by activating PPAR-γ.
Q9: What should be done if a patient develops symptoms of a UTI while on this medication?
A: The UTI should be treated promptly, and the patient should be monitored closely.
