Usage
- Dapagliflozin + Saxagliptin is prescribed as an adjunct to diet and exercise for the treatment of type 2 diabetes mellitus in adults. It is specifically indicated for patients who have inadequate glycemic control with dapagliflozin alone or who are already being treated with dapagliflozin and saxagliptin as separate medications. It is not indicated for type 1 diabetes or diabetic ketoacidosis.
- Pharmacological Classification: Antidiabetic combination therapy; Dipeptidyl Peptidase-4 (DPP-4) inhibitor (Saxagliptin) and Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitor (Dapagliflozin).
- Mechanism of Action: This combination therapy works through two distinct mechanisms: Saxagliptin increases insulin release and decreases glucagon secretion, both in a glucose-dependent manner, while Dapagliflozin blocks reabsorption of glucose in the kidneys, leading to increased urinary glucose excretion and lowered blood glucose levels.
Alternate Names
- While the generic name is Dapagliflozin + Saxagliptin, a popular brand name under which it is marketed is Qtern.
How It Works
- Pharmacodynamics: Saxagliptin, a DPP-4 inhibitor, prolongs the action of incretin hormones, leading to increased insulin secretion and decreased glucagon secretion, primarily in response to elevated blood glucose levels. Dapagliflozin, an SGLT2 inhibitor, inhibits glucose reabsorption in the kidneys, increasing urinary glucose excretion and lowering blood glucose levels independently of insulin.
- Pharmacokinetics: Both drugs are orally administered. Saxagliptin is rapidly absorbed, reaching peak plasma concentrations within 2 hours. It is primarily metabolized to an active metabolite. Dapagliflozin is also rapidly absorbed and reaches peak plasma concentrations within 2 hours. It’s primarily eliminated through the kidneys, with some hepatic metabolism.
- Mode of Action: Saxagliptin inhibits the enzyme DPP-4, preventing the breakdown of incretin hormones like GLP-1 and GIP. These hormones then stimulate insulin release and suppress glucagon secretion from the pancreas. Dapagliflozin blocks SGLT2 in the renal proximal tubules, reducing glucose reabsorption and promoting its excretion in urine.
- Elimination Pathways: Saxagliptin is excreted both renally and hepatically. Dapagliflozin is primarily excreted through the kidneys (75%) with the rest through hepatic metabolism (via glucuronidation).
Dosage
Standard Dosage
Adults:
- Initial dose: One tablet of Dapagliflozin 5 mg + Saxagliptin 5 mg once daily, taken in the morning, with or without food.
- Maintenance dose: For patients tolerating the initial dose but requiring additional glycemic control, the dose can be increased to one tablet of Dapagliflozin 10 mg + Saxagliptin 5 mg once daily in the morning.
Children:
- The safety and efficacy of Dapagliflozin + Saxagliptin have not been established in pediatric patients. Use is not recommended.
Special Cases:
- Elderly Patients: Dose adjustment may be necessary due to age-related decline in renal function. Initiate therapy with caution.
- Patients with Renal Impairment: For patients with an eGFR of 45 mL/min/1.73 m² or greater, no dose adjustment is needed. The drug is contraindicated in patients with eGFR persistently less than 45 mL/min/1.73 m² or end-stage renal disease.
- Patients with Hepatic Dysfunction: Use with caution, especially in those with severe hepatic impairment. An individual benefit-risk assessment is recommended as safety and efficacy haven’t been specifically studied in this population.
- Patients with Comorbid Conditions: Careful consideration is needed in patients with a history of pancreatitis, volume depletion, or urinary tract infections. Volume depletion should be corrected before starting treatment.
Clinical Use Cases
The drug is not typically used in these settings. Its usage is mainly for chronic management of Type 2 diabetes.
Dosage Adjustments
- Renal/Hepatic Dysfunction: See special cases above.
- Metabolic disorders/Genetic polymorphisms: No specific dosage adjustments are outlined for these conditions, but individual patient factors should be considered.
Side Effects
Common Side Effects
- Upper respiratory tract infection
- Urinary tract infection (UTI)
- Dyslipidemia
- Headache
- Diarrhea
- Back pain
- Genital infections
- Joint pain
Rare but Serious Side Effects
- Diabetic ketoacidosis (DKA)
- Acute pancreatitis
- Severe hypoglycemia (especially with concomitant insulin or sulfonylurea use)
- Necrotizing fasciitis of the perineum (Fournier’s gangrene)
- Serious UTIs (including urosepsis and pyelonephritis)
- Renal impairment
Long-Term Effects
- Long-term side effects are not specifically delineated but should be monitored as with any chronic medication.
Adverse Drug Reactions (ADR)
- Any signs of hypersensitivity reactions, including angioedema, anaphylaxis, and exfoliative skin conditions.
- Signs of acute pancreatitis, such as severe abdominal pain.
Contraindications
- Hypersensitivity to dapagliflozin, saxagliptin, or any component of the formulation.
- Type 1 diabetes mellitus.
- Diabetic ketoacidosis.
- Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m²).
- End-stage renal disease (ESRD).
- Patients on dialysis.
Drug Interactions
- CYP450 interactions: Saxagliptin is a weak inhibitor of CYP3A4/5. Dapagliflozin is not a clinically meaningful inhibitor of CYP enzymes.
- Strong CYP3A4/5 Inhibitors: Co-administration with strong CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) is contraindicated, as they can significantly increase saxagliptin exposure.
- Other Medications: Insulin or insulin secretagogues (e.g., sulfonylureas): Increased risk of hypoglycemia. Dose adjustments may be necessary.
- OTC drugs and supplements: No specific interactions are universally outlined, though individual patient factors and concurrent medications should be considered. Consult a drug interaction checker for specific combinations.
- Food and lifestyle factors: Food does not significantly affect the overall exposure to either drug, although the peak concentration (Cmax) of dapagliflozin may be reduced when taken with food. Alcohol can increase the risk of hypoglycemia and should be used cautiously.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not recommended in the second and third trimesters. Limited data available for the first trimester, but animal studies suggest potential renal risks. If pregnancy is detected, discontinue use.
- Breastfeeding: Dapagliflozin and saxagliptin may be excreted in breast milk and potentially cause adverse reactions in the breastfed infant. Not recommended while breastfeeding.
Drug Profile Summary
- Mechanism of Action: Saxagliptin increases incretin effect (increased glucose-dependent insulin release and reduced glucagon). Dapagliflozin inhibits renal glucose reabsorption.
- Side Effects: UTIs, upper respiratory infections, dyslipidemia, headache, diarrhea, genital infections, hypoglycemia, pancreatitis.
- Contraindications: Type 1 diabetes, DKA, moderate to severe renal impairment, ESRD, dialysis.
- Drug Interactions: Strong CYP3A4/5 inhibitors, insulin/sulfonylureas.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Adults: 5/5 mg or 10/5 mg once daily. Not established for children.
- Monitoring Parameters: HbA1c, fasting and postprandial glucose, renal function (eGFR), signs of UTIs or other infections, signs of DKA or pancreatitis.
Popular Combinations
- Metformin: Often used in combination with Dapagliflozin + Saxagliptin for enhanced glycemic control.
Precautions
- Assess renal function before initiating and periodically thereafter.
- Monitor for signs of UTIs, pancreatitis, and DKA.
- Correct volume depletion before starting treatment.
- Caution in patients with a history of bladder cancer, genital infections, or pancreatitis.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dapagliflozin + Saxagliptin?
A: The standard initial adult dose is Dapagliflozin 5 mg + Saxagliptin 5 mg once daily, which can be increased to 10/5 mg once daily if needed. Not for pediatric use.
Q2: What are the most common side effects?
A: Common side effects include UTIs, upper respiratory infections, genital infections, headache, diarrhea, dyslipidemia.
Q3: Can this drug be used during pregnancy or breastfeeding?
A: It is not recommended during pregnancy, especially the second and third trimesters, or during breastfeeding.
Q4: What are the contraindications for using this drug?
A: Contraindications include type 1 diabetes, DKA, moderate/severe renal impairment, ESRD, dialysis, hypersensitivity.
Q5: How does this drug combination work?
A: Saxagliptin increases insulin release and reduces glucagon secretion. Dapagliflozin increases urinary glucose excretion by inhibiting SGLT2 in the kidneys.
Q6: What are the serious side effects to watch out for?
A: DKA, severe hypoglycemia, acute pancreatitis, necrotizing fasciitis of the perineum, serious UTIs, and worsening renal function.
Q7: Does this medication interact with other drugs?
A: Yes. Significant interactions include strong CYP3A4/5 inhibitors and concomitant use of insulin or sulfonylureas. Always check for potential drug interactions.
Q8: How should I monitor patients on this medication?
A: Monitor HbA1c, glucose levels, renal function, and watch for signs of UTIs, DKA, or pancreatitis.
Q9: Should any specific precautions be taken before starting this medication?
A: Yes. Assess renal function and ensure volume depletion is corrected before initiating therapy. Be cautious in patients with a history of pancreatitis, bladder cancer, or genital mycotic infections.
