Saxagliptin

Generic Name: Saxagliptin
Brand Name: Onglyza
Drug Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
Formulations: Oral tablets – 2.5 mg and 5 mg
Route of Administration: Oral

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Therapeutic Indications and Clinical Use

Saxagliptin is an oral antihyperglycemic agent used for the management of type 2 diabetes mellitus (T2DM). It is not indicated for type 1 diabetes or diabetic ketoacidosis.

Approved Indications:

1. Type 2 Diabetes Mellitus (T2DM):

   • As monotherapy (when metformin is inappropriate)

   • As add-on therapy to:

     • Metformin

     • Sulfonylurea

     • Thiazolidinedione

     • SGLT2 inhibitors (e.g., dapagliflozin)

     • Insulin (with or without metformin)

Off-Label and Investigational Uses:

• Pre-diabetes (not recommended by guidelines)

• Beta-cell preservation studies (experimental)

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Mechanism of Action

Saxagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 degrades incretin hormones, especially GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide).

By inhibiting DPP-4, saxagliptin:

• Prolongs the action of endogenous incretins

• Increases insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner

• Suppresses glucagon secretion from α-cells

• Reduces fasting and postprandial glucose levels

Saxagliptin does not cause weight gain or hypoglycemia when used as monotherapy.

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Dosing and Administration

Adults:

• Standard dose: 5 mg once daily, with or without food

• Moderate or severe renal impairment (eGFR ≤50 mL/min/1.73 m²): 2.5 mg once daily

• Hepatic impairment: Use with caution; no dosage adjustment generally required, but data are limited

Elderly:

• No dose adjustment required based solely on age; assess renal function

Missed Dose:

• Take as soon as remembered unless it's close to the next dose; do not double the dose

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Pharmacokinetics

• Bioavailability: ~75%

• Time to Peak Plasma Concentration: 2 hours

• Protein Binding: Low (~30%)

• Metabolism: Hepatic via CYP3A4/5 to an active metabolite (approx. 50% of activity)

• Half-Life:

  • Saxagliptin: ~2.5 hours

  • Active metabolite: ~3.1 hours

• Elimination:

  • 25% feces

  • 75% urine (as unchanged and metabolite)

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Contraindications

• Hypersensitivity to saxagliptin or any component of the formulation

• History of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome)

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• History of heart failure (see below under warnings)

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Warnings and Precautions

1. Heart Failure Risk:

   • Observational data and clinical trials (SAVOR-TIMI 53) showed increased hospitalization for heart failure. Use caution in patients with pre-existing cardiac disease or renal impairment.

2. Pancreatitis:

   • Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing forms, reported. Discontinue if pancreatitis suspected.

3. Joint Pain:

   • Severe arthralgia has been reported with DPP-4 inhibitors; symptoms typically resolve upon discontinuation.

4. Hypoglycemia:

   • Risk increases when combined with sulfonylureas or insulin.

5. Renal Impairment:

   • Requires dose adjustment. Monitor renal function regularly.

6. Hypersensitivity Reactions:

   • Rare but serious reactions, including angioedema and anaphylaxis.

7. Bullous Pemphigoid:

   • Rare autoimmune blistering skin condition reported in DPP-4 inhibitor users.

8. Hepatic Impairment:

   • Use cautiously; limited clinical data available.

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Adverse Effects

Common (≥5%):

• Upper respiratory tract infection

• Urinary tract infection

• Headache

• Nasopharyngitis

• Peripheral edema (when combined with thiazolidinediones)

Less Common/Serious:

• Pancreatitis

• Heart failure (increased hospitalization risk)

• Hypersensitivity reactions (rash, urticaria, angioedema)

• Arthralgia (joint pain)

• Hypoglycemia (with insulin or sulfonylureas)

• Bullous pemphigoid

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Drug Interactions

1. Strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin):

   • Increase saxagliptin levels

   • Consider dose reduction to 2.5 mg daily

2. CYP3A4/5 inducers (e.g., rifampin, carbamazepine, phenytoin):

   • May reduce saxagliptin exposure and efficacy

3. Insulin or sulfonylureas:

   • Additive risk of hypoglycemia; dose adjustment may be needed

4. DPP-4 inhibitors should not be co-prescribed together (e.g., saxagliptin + sitagliptin)

5. Renally eliminated drugs:

   • Use caution; ensure renal function is monitored to avoid cumulative toxicity

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Monitoring Parameters

• HbA1c and fasting plasma glucose: Regular monitoring for glycemic control

• Renal function (eGFR): At baseline and periodically

• Signs of pancreatitis: Abdominal pain, nausea, vomiting

• Heart failure symptoms: Dyspnea, weight gain, edema

• Hypoglycemia: Especially with insulin/sulfonylurea co-use

• Skin conditions: Monitor for bullous pemphigoid or other rashes

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Use in Special Populations

• Pregnancy:

  • Category B (US FDA, prior classification)

  • Limited human data; animal studies show no teratogenicity

  • Use only if benefit outweighs risk

• Lactation:

  • Unknown if excreted in breast milk; avoid or use cautiously

• Pediatrics:

  • Safety and efficacy not established in patients <18 years

• Geriatrics:

  • No dosage adjustment based solely on age; monitor renal function

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Comparative Considerations (Within DPP-4 Class)

Drug	Dose	Renal Dose Adjustment	Heart Failure Risk
Saxagliptin	5 mg/day	Yes (≤50 mL/min)	↑ (SAVOR-TIMI 53)
Sitagliptin	100 mg/day	Yes (CrCl thresholds)	Neutral
Linagliptin	5 mg/day	No	Neutral
Alogliptin	25 mg/day	Yes	Possible ↑ risk

Patient Counseling Points

• Take once daily with or without food

• Continue diet and exercise regimen as advised by your healthcare provider

• Report symptoms of pancreatitis (persistent severe abdominal pain)

• Inform your doctor of any new swelling, shortness of breath, or fatigue

• Monitor for signs of low blood sugar, especially if taking insulin or sulfonylurea

• If you miss a dose, take it as soon as remembered; skip if close to the next dose

• Do not take double doses

• Inform all healthcare providers of your diabetes medications before procedures

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Storage and Stability

• Store at room temperature (20°C to 25°C)

• Protect from moisture and light

• Keep in original packaging until use

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Global Regulatory Status

• Prescription-only medication

• Approved by FDA (US) and EMA (EU)

• Marketed as Onglyza by AstraZeneca

• Approved in over 90 countries

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Common Brand and Combination Products

• Onglyza (saxagliptin) – monotherapy

• Kombiglyze XR – saxagliptin + metformin (extended-release)

• Qtern – saxagliptin + dapagliflozin

• Qternmet XR – saxagliptin + dapagliflozin + metformin