Saxagliptin

Usage

• Saxagliptin is prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is used in multiple clinical settings, including as monotherapy, dual therapy, or triple therapy.
• Pharmacological Classification: Dipeptidyl peptidase-4 (DPP-4) inhibitor, Antihyperglycemic agent.
• Mechanism of Action: Saxagliptin works by inhibiting the enzyme DPP-4. This enzyme breaks down incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By preventing the breakdown of these incretins, saxagliptin increases their levels. Incretins stimulate insulin release in a glucose-dependent manner and decrease glucagon secretion, thereby lowering blood glucose levels.

Alternate Names

• International Nonproprietary Name (INN): Saxagliptin
• Brand Names: Onglyza, Kombiglyze XR (in combination with metformin)

How It Works

• Pharmacodynamics: Saxagliptin increases levels of active incretins GLP-1 and GIP, leading to increased insulin secretion and decreased glucagon secretion. These effects are glucose-dependent, minimizing the risk of hypoglycemia.
• Pharmacokinetics:
  • Absorption: Saxagliptin is rapidly absorbed after oral administration, reaching peak plasma concentrations within 2 hours. Food does not affect the overall exposure to saxagliptin.
  • Metabolism: Saxagliptin is primarily metabolized by cytochrome P450 3A4/5 (CYP3A4/5) enzymes to its major active metabolite, 5-hydroxy saxagliptin. This metabolite has similar pharmacological activity.
  • Elimination: Saxagliptin and its metabolites are eliminated via both renal and hepatic pathways. The elimination half-life of saxagliptin is approximately 2.5 hours, and the half-life of the active metabolite is about 3.1 hours.
• Mode of Action: Saxagliptin exerts its effect by binding to and inhibiting the DPP-4 enzyme.
• Receptor binding, enzyme inhibition, or neurotransmitter modulation: Enzyme inhibition (DPP-4).
• Elimination pathways: Renal and hepatic excretion, metabolism by CYP3A4/5 enzymes.

Dosage

Standard Dosage

Adults:

• 2.5 mg or 5 mg orally once daily, regardless of meals.
• The maximum recommended dose is 5 mg once daily.

Children:

• The safety and efficacy of saxagliptin have not been established in pediatric patients. Use is not recommended.

Special Cases:

• Elderly Patients: Initial and maintenance dosing should be conservative due to potential age-related decline in renal function.
• Patients with Renal Impairment:
  • Mild renal impairment (CrCl > 50 mL/min): No dosage adjustment necessary.
  • Moderate or severe renal impairment (CrCl ≤ 50 mL/min): 2.5 mg orally once daily.
  • End-stage renal disease (ESRD) requiring hemodialysis: Not recommended. If use is unavoidable, administer 2.5 mg after hemodialysis.
• Patients with Hepatic Dysfunction:
  • Mild or moderate hepatic impairment: No dosage adjustment necessary, but use with caution in moderate impairment.
  • Severe hepatic impairment: Not recommended.
• Patients with Comorbid Conditions: For patients with a history of pancreatitis or heart failure, saxagliptin should be used with caution. If used concomitantly with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Clinical Use Cases

Saxagliptin’s use is limited to glycemic management in type 2 diabetes mellitus. It is not indicated for:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations

Dosage Adjustments

• Dose reduction is necessary in patients with moderate or severe renal impairment (CrCl ≤ 50 mL/min).
• When co-administered with strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, ritonavir), the dose should be reduced to 2.5 mg once daily.

Side Effects

Common Side Effects:

• Upper respiratory tract infection
• Nasopharyngitis
• Headache
• Urinary tract infection

Rare but Serious Side Effects:

• Pancreatitis
• Hypersensitivity reactions (angioedema, anaphylaxis)
• Bullous pemphigoid
• Heart failure (especially in patients with pre-existing heart or kidney disease)

Long-Term Effects:

• The long-term safety profile of saxagliptin is still being evaluated.

Adverse Drug Reactions (ADR):

• Angioedema, anaphylaxis, acute pancreatitis, heart failure. These require immediate medical attention.

Contraindications

• Hypersensitivity to saxagliptin
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• History of serious hypersensitivity reactions to any DPP-4 inhibitor.

Drug Interactions

• Strong CYP3A4/5 inhibitors: Increase saxagliptin concentrations. Dose reduction to 2.5 mg daily is recommended.
• CYP3A4/5 inducers: May decrease saxagliptin concentrations.
• Sulfonylureas, Insulin: Increased risk of hypoglycemia. Dosage adjustments of these agents may be required.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Category B. Saxagliptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: It is unknown if saxagliptin is excreted in human milk. Caution should be exercised when administering to breastfeeding mothers.

Drug Profile Summary

• Mechanism of Action: DPP-4 inhibitor, increases incretin levels.
• Side Effects: Upper respiratory tract infection, nasopharyngitis, headache, pancreatitis (rare), heart failure (rare).
• Contraindications: Type 1 diabetes, diabetic ketoacidosis, hypersensitivity to saxagliptin.
• Drug Interactions: Strong CYP3A4/5 inhibitors, sulfonylureas, insulin.
• Pregnancy & Breastfeeding: Category B, use with caution.
• Dosage: 2.5 mg or 5 mg once daily, adjustments needed for renal impairment and concomitant use with CYP3A4/5 inhibitors.
• Monitoring Parameters: HbA1c, fasting and postprandial blood glucose, renal function, signs and symptoms of pancreatitis or heart failure.

Popular Combinations

• Metformin
• Sulfonylureas
• Insulin

Precautions

• General Precautions: Assess renal function prior to and periodically during treatment. Monitor for signs of pancreatitis or heart failure.
• Specific Populations: Use with caution in patients with a history of pancreatitis or heart failure.
• Pregnant Women: Use only if potential benefit outweighs risk.
• Breastfeeding Mothers: Exercise caution.
• Children & Elderly: Not recommended for children. Use with caution in the elderly.
• Lifestyle Considerations: Encourage diet and exercise.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Saxagliptin?

A: 2.5 mg or 5 mg orally once daily. Adjustments are required for renal impairment and drug interactions.

Q2: How does saxagliptin work?

A: It inhibits DPP-4, increasing incretin levels which lead to increased insulin secretion and decreased glucagon secretion.

Q3: What are the common side effects of saxagliptin?

A: Upper respiratory tract infections, nasopharyngitis, and headache.

Q4: Can saxagliptin be used in patients with renal impairment?

A: Yes, but dose adjustments are necessary for moderate or severe renal impairment. It is not recommended for patients with ESRD requiring hemodialysis.

Q5: Does saxagliptin cause hypoglycemia?

A: It has a low risk of hypoglycemia when used as monotherapy. The risk increases when combined with insulin or sulfonylureas.

Q6: What are the serious side effects to watch out for with saxagliptin?

A: Pancreatitis, heart failure, and hypersensitivity reactions.

Q7: Can saxagliptin be used during pregnancy?

A: It is a pregnancy category B drug; use only if the benefit outweighs the risk.

Q8: What are the contraindications to saxagliptin use?

A: Type 1 diabetes, diabetic ketoacidosis, and hypersensitivity to saxagliptin.

Q9: What other medications interact with saxagliptin?

A: Strong CYP3A4/5 inhibitors, sulfonylureas, and insulin.