Sitagliptin

1. Drug Name

• Generic Name: Sitagliptin

• Brand Names: Januvia, Janumet (combination with metformin), and others.

2. Drug Classification

• Class: Antidiabetic Agent

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

3. Mechanism of Action

Sitagliptin is an oral antihyperglycemic agent that works by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 normally inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which play an important role in regulating blood glucose levels.

By inhibiting DPP-4, sitagliptin increases the levels of active incretin hormones. These hormones promote insulin secretion from pancreatic β-cells in a glucose-dependent manner (i.e., they increase insulin release only when blood glucose levels are elevated) and decrease glucagon secretion from α-cells, which reduces hepatic glucose production. This results in better control of blood glucose, particularly postprandial glucose levels.

Additionally, sitagliptin has a mild effect on weight loss or weight neutrality, unlike other sulfonylureas or thiazolidinediones, which can lead to weight gain.

4. Pharmacokinetics

• Absorption: Sitagliptin is well absorbed after oral administration, with a bioavailability of around 87%. Peak plasma concentrations occur within 1–4 hours of ingestion.

• Distribution: The volume of distribution (Vd) of sitagliptin is approximately 197 L, indicating widespread distribution in tissues. It has a moderate protein-binding capacity of approximately 38%.

• Metabolism: Sitagliptin is minimally metabolized in the liver, primarily through non-CYP-mediated hydrolysis to an inactive metabolite. A small portion undergoes metabolism via CYP3A4 and CYP2C8 enzymes.

• Excretion: Sitagliptin has a half-life of about 12.4 hours. It is predominantly excreted unchanged in the urine (about 80%) and a small fraction is eliminated via feces.

• Special Considerations:

  • Renal Impairment: Dosage adjustments are required in patients with renal dysfunction. In severe renal impairment, the dose should be reduced to 25 mg once daily.

  • Hepatic Impairment: No dose adjustment is necessary in patients with mild to moderate hepatic impairment. There is insufficient data in severe hepatic impairment, so caution is advised.

5. Indications

• Primary Indication:

  • Type 2 Diabetes Mellitus: Sitagliptin is indicated for the management of type 2 diabetes mellitus, either as monotherapy or in combination with other antidiabetic agents such as metformin, sulfonylureas, or insulin when these are insufficient for controlling blood glucose levels.

• Off-label Uses:

  • It may also be used in combination therapy for type 2 diabetes in patients who are not adequately controlled on diet and exercise alone, particularly for patients who cannot tolerate other classes of drugs.

• Specific Populations: It is typically used in adult patients with type 2 diabetes and can be beneficial in those who require additional glucose-lowering effects.

6. Dosage and Administration

• Adult Dosing:

  • Monotherapy or Combination Therapy: 100 mg once daily, with or without food.

  • Renal Impairment Dosing:

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

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

    • Severe renal impairment or end-stage renal disease (eGFR <30 mL/min/1.73 m²): 25 mg once daily.

• Pediatric Dosing: Safety and efficacy have not been established in pediatric patients under 18 years of age.

• Administration: Sitagliptin can be taken with or without food. The dose should be taken at the same time each day to help with adherence.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to sitagliptin or any of its components.

• Relative Contraindications:

  • Patients with a history of serious hypersensitivity reactions (e.g., angioedema) to sitagliptin or other DPP-4 inhibitors.

  • Patients with severe renal impairment, unless dose adjustments are followed.

  • Pregnancy (use only if clearly needed, as insulin is typically preferred in pregnancy).

  • Lactation (use with caution, as safety during breastfeeding has not been established).

8. Warnings and Precautions

• Pancreatitis: There have been reports of acute pancreatitis in patients treated with DPP-4 inhibitors, including sitagliptin. If pancreatitis is suspected, the drug should be discontinued immediately.

• Renal Impairment: Sitagliptin is primarily eliminated by the kidneys. In patients with renal dysfunction, dosage adjustments are necessary to prevent drug accumulation and reduce the risk of side effects.

• Hypoglycemia: Sitagliptin is less likely to cause hypoglycemia when used alone. However, when combined with other agents (e.g., sulfonylureas or insulin), the risk of hypoglycemia may increase.

• Allergic Reactions: Serious allergic reactions, including angioedema and anaphylaxis, have been reported. If symptoms of hypersensitivity occur, discontinuation of therapy is recommended.

• Joint Pain: Severe and disabling joint pain has been reported in patients taking DPP-4 inhibitors. If a patient experiences joint pain, the drug should be discontinued.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Upper respiratory tract infections.

  • Headache.

  • Nasopharyngitis.

  • Gastrointestinal issues, including diarrhea, nausea, or abdominal discomfort.

• Less Common but Clinically Significant Side Effects:

  • Hypoglycemia, particularly when used in combination with sulfonylureas or insulin.

  • Pancreatitis (rare but serious).

  • Allergic reactions, including angioedema.

  • Renal complications, such as renal failure (in patients with preexisting renal disease).

• Rare/Serious Adverse Reactions:

  • Acute pancreatitis (discontinue immediately if suspected).

  • Severe hypersensitivity reactions, including anaphylaxis, angioedema, and rash.

  • Severe joint pain.

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

10. Drug Interactions

• Major Drug Interactions:

  • Insulin or Sulfonylureas: When used in combination, sitagliptin may enhance the glucose-lowering effects, increasing the risk of hypoglycemia. Dosage adjustments of these agents may be necessary.

  • Digoxin: Sitagliptin may slightly increase digoxin levels. Monitoring of digoxin levels may be required.

  • CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): These may increase sitagliptin concentrations slightly, although no dose adjustments are typically required.

• Food Interactions: No significant food-drug interactions have been noted with sitagliptin.

• Lab Test Interactions: Sitagliptin may interfere with certain lab tests for creatinine or liver enzymes, leading to slight elevations in these markers.

11. Clinical Pharmacology

• Pharmacodynamics: Sitagliptin enhances insulin secretion in a glucose-dependent manner and suppresses glucagon secretion, leading to improved glycemic control. Its effects are mediated through increased levels of incretin hormones, particularly GLP-1.

• Additional Pharmacological Effects: Sitagliptin has a mild effect on body weight, making it a useful option for patients who are concerned about weight gain associated with other oral antidiabetic drugs.

12. Special Populations

• Pregnancy: Category B. Sitagliptin is not recommended during pregnancy unless necessary, as insulin is preferred for managing blood glucose in pregnant women.

• Lactation: It is unknown whether sitagliptin is excreted in human breast milk. It should be used with caution during breastfeeding, and alternative therapies may be considered.

• Elderly: Older patients are more likely to experience renal impairment, which can affect sitagliptin clearance. Dose adjustments are recommended based on renal function.

• Renal and Hepatic Dysfunction: Dosing adjustments are necessary for patients with moderate to severe renal impairment. No adjustments are needed in hepatic impairment, but caution should be exercised in severe cases.

13. Therapeutic Uses

• Type 2 Diabetes Mellitus: Sitagliptin is used as an adjunct to diet and exercise to improve blood sugar control in patients with type 2 diabetes. It is often used when monotherapy is insufficient and may be combined with other antidiabetic agents like metformin or sulfonylureas.

• Combination Therapy: Sitagliptin can be used in combination with other oral antidiabetic agents, such as metformin or thiazolidinediones, or with insulin therapy when appropriate.

14. Monitoring and Follow-Up

• Recommended Lab Tests:

  • Monitoring of renal function (serum creatinine and eGFR) regularly, particularly in patients with pre-existing renal conditions.

  • Regular monitoring of blood glucose and HbA1c levels to assess the effectiveness of therapy.

• Patient-Reported Symptoms: Monitor for symptoms of hypoglycemia, pancreatitis, or severe joint pain.

• Monitoring of Therapeutic Levels: Regularly assess for therapeutic response to ensure effective glucose control.

15. Overdose Management

• Symptoms of Overdose: Symptoms of overdose may include hypoglycemia, nausea, vomiting, and dizziness, though sitagliptin is generally well-tolerated, even at higher doses.

• Treatment Protocols: There is no specific antidote for sitagliptin overdose. In cases of overdose, supportive care should be provided. If hypoglycemia occurs, glucose should be administered.

• Supportive Measures: In case of severe overdose, patients should be observed for signs of severe hypoglycemia or renal complications.

16. Patient Counseling Information

• Key Points:

  • Take sitagliptin as prescribed, either with or without food.

  • Monitor blood glucose levels regularly, especially if diet or exercise routines change.

  • Be aware of the signs and symptoms of hypoglycemia and have a fast-acting carbohydrate on hand.

  • Report any new or unusual joint pain to your healthcare provider.

• Lifestyle Recommendations: Maintain a balanced diet and exercise program to support overall blood glucose control.