Saxagliptin

1. Drug Name

• Generic Name: Saxagliptin

• Brand Names: Onglyza

2. Drug Classification

• Class: Antidiabetic Agent

• Subclass: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor

3. Mechanism of Action

Saxagliptin is an oral antihyperglycemic agent that belongs to the class of DPP-4 inhibitors. It works by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the breakdown of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These incretin hormones play a key role in regulating blood glucose levels.

By inhibiting DPP-4, saxagliptin increases the levels of active incretin hormones. This results in enhanced insulin secretion from pancreatic β-cells in response to meals (in a glucose-dependent manner) and reduced glucagon secretion from pancreatic α-cells, leading to a decrease in hepatic glucose production. As a result, saxagliptin helps lower blood glucose levels, particularly postprandial glucose levels.

Saxagliptin does not typically cause hypoglycemia when used alone but may increase the risk of hypoglycemia when combined with other antihyperglycemic agents like insulin or sulfonylureas.

4. Pharmacokinetics

• Absorption: Saxagliptin is well absorbed after oral administration, with a bioavailability of approximately 67%. Peak plasma concentrations occur within 2–4 hours post-dose.

• Distribution: The volume of distribution (Vd) is approximately 78 L, indicating a broad distribution in the body. It is approximately 38% bound to plasma proteins.

• Metabolism: Saxagliptin is metabolized primarily in the liver by the CYP3A4 enzyme to an active metabolite (BMS-510,742). A small fraction undergoes renal excretion without metabolism.

• Excretion: Saxagliptin has a half-life of about 2.5 hours, while the half-life of its active metabolite is approximately 3–6 hours. The majority of saxagliptin (approximately 75%) is excreted unchanged in the urine, and the remainder is excreted in the feces.

• Special Considerations:

  • Renal Impairment: Dose adjustment is required in patients with renal dysfunction. In moderate renal impairment (eGFR ≥30 to <50 mL/min/1.73 m²), the dose is 2.5 mg once daily. In severe renal impairment (eGFR <30 mL/min/1.73 m²), saxagliptin is contraindicated.

  • Hepatic Impairment: No dose adjustment is necessary for mild to moderate hepatic impairment. Use caution in patients with severe hepatic impairment.

5. Indications

• Primary Indication:

  • Type 2 Diabetes Mellitus: Saxagliptin is indicated for the treatment of type 2 diabetes mellitus to improve blood glucose control, either as monotherapy or in combination with other antidiabetic agents (such as metformin, sulfonylureas, or insulin) when diet and exercise alone do not provide adequate control.

• Off-label Uses:

  • Saxagliptin may be used off-label as part of a combination regimen for patients with difficult-to-control type 2 diabetes or when other classes of drugs are contraindicated.

• Specific Populations: Saxagliptin is typically used in adults with type 2 diabetes, particularly in those who require additional glucose-lowering effects and have contraindications or intolerance to other classes of medications.

6. Dosage and Administration

• Adult Dosing:

  • Monotherapy or Combination Therapy: 5 mg once daily, with or without food.

  • Renal Impairment Dosing:

    • Mild renal impairment (eGFR ≥50 to <80 mL/min/1.73 m²): No dose adjustment needed.

    • Moderate renal impairment (eGFR ≥30 to <50 mL/min/1.73 m²): 2.5 mg once daily.

    • Severe renal impairment (eGFR <30 mL/min/1.73 m²) or End-stage renal disease: Saxagliptin is contraindicated.

• Pediatric Dosing: Saxagliptin is not approved for use in children under 18 years of age.

• Administration: Saxagliptin can be taken with or without food. It should be taken at the same time each day to improve adherence.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to saxagliptin or any of its components.

  • Severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease.

• Relative Contraindications:

  • History of serious hypersensitivity reactions (e.g., angioedema) to saxagliptin or other DPP-4 inhibitors.

  • Caution in patients with a history of pancreatitis, as there have been rare reports of acute pancreatitis.

8. Warnings and Precautions

• Pancreatitis: There have been reports of acute pancreatitis in patients taking saxagliptin. If pancreatitis is suspected, discontinue saxagliptin immediately and investigate further.

• Renal Impairment: Saxagliptin is primarily excreted by the kidneys, so dose adjustments are necessary in patients with renal dysfunction. It should not be used in severe renal impairment.

• Hypoglycemia: Saxagliptin alone does not typically cause hypoglycemia, but when combined with insulin or sulfonylureas, there is an increased risk of hypoglycemia. Monitoring of blood glucose levels is essential in these combinations.

• Allergic Reactions: Serious allergic reactions, including angioedema, anaphylaxis, and rash, have been reported. Discontinue saxagliptin if these reactions occur.

• Heart Failure: Saxagliptin should be used with caution in patients with a history of heart failure, as there is some evidence suggesting an increased risk of hospitalization for heart failure with DPP-4 inhibitors.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Upper respiratory tract infections.

  • Headache.

  • Nasopharyngitis.

  • Gastrointestinal disturbances (e.g., nausea, diarrhea).

• Less Common but Clinically Significant Side Effects:

  • Hypoglycemia, especially when combined with insulin or sulfonylureas.

  • Pancreatitis (rare but serious).

  • Renal complications, including renal failure in patients with pre-existing renal conditions.

  • Allergic reactions (angioedema, anaphylaxis).

• Rare/Serious Adverse Reactions:

  • Acute pancreatitis (requires discontinuation).

  • Severe allergic reactions (e.g., anaphylaxis, rash, and angioedema).

  • Bullous pemphigoid (a rare but serious skin condition).

10. Drug Interactions

• Major Drug Interactions:

  • Insulin and Sulfonylureas: Saxagliptin may enhance the glucose-lowering effect of insulin and sulfonylureas, increasing the risk of hypoglycemia. Adjust the doses of these agents as necessary.

  • CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Saxagliptin is metabolized by CYP3A4, and potent inhibitors of this enzyme may increase saxagliptin concentrations, necessitating dose adjustments.

• Food Interactions: Saxagliptin can be taken with or without food, as food does not significantly alter its absorption.

• Lab Test Interactions: Saxagliptin can cause mild to moderate elevations in liver enzymes (ALT, AST), although this is usually not clinically significant. It may also alter serum creatinine levels, so renal function monitoring is advised.

11. Clinical Pharmacology

• Pharmacodynamics: Saxagliptin enhances insulin secretion in response to meals and suppresses glucagon secretion in a glucose-dependent manner, thus improving blood glucose control. Its effects are mediated by increasing the activity of GLP-1 and GIP.

• Additional Pharmacological Effects: Saxagliptin has a minimal effect on body weight and does not usually cause significant weight gain, making it a preferred option for weight-conscious diabetic patients.

12. Special Populations

• Pregnancy: Category C. Saxagliptin should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Insulin is preferred for managing blood glucose in pregnant women.

• Lactation: Saxagliptin is excreted in breast milk, but its effects on a nursing infant are unknown. Use with caution during breastfeeding, and consider alternative therapies.

• Elderly: Older patients may have reduced renal function, which can affect saxagliptin clearance. Dose adjustments are necessary based on renal function.

• Renal and Hepatic Dysfunction: Dose adjustments are required for patients with renal impairment. No adjustment is necessary for mild to moderate hepatic impairment, but saxagliptin should be used with caution in severe hepatic impairment.

13. Therapeutic Uses

• First-Line Indication:

  • Saxagliptin is commonly used as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, particularly when other oral antidiabetic agents are insufficient.

• Combination Therapy: It is frequently used in combination with other oral antidiabetic drugs (e.g., metformin, sulfonylureas) or insulin to achieve better glycemic control.

• Efficacy in Clinical Trials: Clinical trials have shown that saxagliptin effectively lowers HbA1c and fasting blood glucose levels in patients with type 2 diabetes, with a low risk of hypoglycemia when used alone.

14. Monitoring and Follow-Up

• Recommended Lab Tests:

  • Regular renal function tests (serum creatinine, eGFR).

  • Monitoring blood glucose and HbA1c levels to evaluate therapeutic efficacy.

• Patient-Reported Symptoms: Watch for signs of hypoglycemia (especially when combined with other agents), joint pain, or pancreatitis.

• Monitoring of Therapeutic Levels: Ensure that blood glucose is adequately controlled and adjust doses as needed.

15. Overdose Management

• Symptoms of Overdose: Overdose of saxagliptin may lead to symptoms of hypoglycemia, nausea, dizziness, or vomiting.

• Treatment Protocols: There is no specific antidote for saxagliptin overdose. In the case of significant overdose, supportive care, including monitoring of blood glucose levels, should be administered. If hypoglycemia occurs, glucose should be given.

• Supportive Measures: In severe cases, continuous glucose monitoring may be required.

16. Patient Counseling Information

• Key Points:

  • Take saxagliptin as prescribed, with or without food.

  • Be aware of the signs and symptoms of hypoglycemia, especially if combined with insulin or sulfonylureas.

  • Inform healthcare providers if you experience unexplained joint pain, swelling, or pancreatitis symptoms.

• Lifestyle Recommendations: A balanced diet and regular exercise should accompany medication to optimize glycemic control and overall health.