Saxagliptin

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
• As monotherapy to improve glycemic control in adults when diet and exercise alone are inadequate.
• In combination with:
• Metformin (dual therapy or fixed-dose combination)
• A sulfonylurea (e.g., glibenclamide)
• A thiazolidinedione (e.g., pioglitazone)
• Insulin (with or without metformin)

Off-label / Clinically Accepted Use:

• Occasionally used in clinical practice for glycemic control in elderly patients with high hypoglycemia risk, though not formally approved.
• Not indicated for:
• Type 1 Diabetes Mellitus
• Diabetic ketoacidosis (DKA)
• Glycemic control in patients with recent history of pancreatitis

Adults:

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

Renal Impairment:

• Moderate (eGFR ≥30 to <45 mL/min/1.73 m²): 2.5 mg once daily
• Severe (eGFR <30 mL/min/1.73 m² or on hemodialysis): 2.5 mg once daily
• Assess renal function prior to initiation and periodically thereafter

Hepatic Impairment:

• No dosage adjustment required for mild to moderate hepatic impairment
• Use with caution in severe hepatic dysfunction due to limited data

Elderly (≥65 years):

• No dosage adjustment needed solely due to age
• Monitor renal function closely

Pediatric Use:

• Safety and effectiveness have not been established in patients under 18 years

Route of Administration: Oral
Timing: Once daily at any time of the day, with or without food
Duration: Long-term use depending on glycemic targets and clinical judgment

Saxagliptin selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which breaks down incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These incretins play a key role in glucose homeostasis by stimulating insulin release and suppressing glucagon secretion in a glucose-dependent manner. By preventing incretin degradation, saxagliptin enhances endogenous insulin secretion and reduces hepatic glucose production, thereby improving fasting and postprandial blood glucose levels without causing significant hypoglycemia.

• Absorption: Rapidly absorbed; peak plasma levels (Tmax) occur within 2 hours
• Bioavailability: Approximately 75%
• Protein Binding: ~30%
• Distribution: Widely distributed in body tissues
• Metabolism: Primarily metabolized by CYP3A4/5 to an active metabolite (5-hydroxy saxagliptin)
• Half-life: Saxagliptin ~2.5 hours; Active metabolite ~3.1 hours
• Excretion:
• ~75% excreted in urine (unchanged drug + metabolite)
• ~22% excreted via feces
• Clearance: Reduced in renal impairment, requiring dose adjustment

• Pregnancy: FDA Pregnancy Category B
• No evidence of fetal harm in animal studies
• Human data are insufficient; use only if clearly needed
• Lactation:
• Unknown whether saxagliptin is excreted into human breast milk
• Excretion in animal milk has been observed
• Caution is advised; consider benefits vs. risks when prescribing during lactation

• Primary Class: Antidiabetic Agent
• Subclass: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
• Related Agents: Sitagliptin, Linagliptin, Vildagliptin

• Known hypersensitivity to saxagliptin or any of its components
• History of serious hypersensitivity reactions to other DPP-4 inhibitors
• Patients with Type 1 Diabetes Mellitus
• Diabetic ketoacidosis (DKA)
• Caution in patients with history of pancreatitis

• Heart Failure Risk:
• Increased risk of hospitalization for heart failure, especially in patients with pre-existing heart disease or renal impairment
• Monitor for signs and symptoms (e.g., weight gain, dyspnea)
• Pancreatitis:
• Cases of acute and fatal necrotizing pancreatitis have been reported
• Discontinue if pancreatitis is suspected
• Hypoglycemia:
• Risk increases when combined with sulfonylureas or insulin
• Consider dose adjustment of those agents
• Severe Joint Pain:
• Rare cases reported; typically reversible upon discontinuation
• Renal Function Monitoring:
• Evaluate renal function at baseline and periodically during therapy

Common Adverse Effects (≥1%):

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

Less Common (0.1–1%):

• Peripheral edema
• Arthralgia
• Fatigue
• Skin rash

Serious or Rare Side Effects:

• Acute pancreatitis (including fatal hemorrhagic pancreatitis)
• Heart failure
• Hypersensitivity reactions (angioedema, anaphylaxis)
• Bullous pemphigoid
• Hepatic dysfunction (rare elevation of liver enzymes)

• CYP3A4/5 Inhibitors (e.g., ketoconazole, diltiazem): May increase saxagliptin levels; monitor closely
• CYP3A4/5 Inducers (e.g., rifampin, carbamazepine): May decrease effectiveness; avoid if possible
• Sulfonylureas or Insulin: Increased risk of hypoglycemia
• Alcohol: May affect glycemic control and increase hypoglycemia risk

No significant food interactions.

• FDA Alert:
• Warning added regarding increased risk of heart failure; providers advised to monitor cardiac status in high-risk patients
• ADA Guidelines:
• Saxagliptin is a second-line agent after metformin in patients without compelling cardiovascular or renal indications
• Not recommended in patients with heart failure (especially NYHA Class III/IV)
• EMA Advisory:
• Recommends close monitoring of renal and cardiac status during saxagliptin therapy
• Highlights risk of pancreatitis and hypersensitivity

• Recommended Temperature: Store at 20°C to 25°C
• Permissible Range: 15°C to 30°C
• Humidity & Light: Store in a dry place, away from excessive moisture and light
• Handling Instructions:
• Do not freeze
• Keep tablets in original packaging until administration
• Keep out of reach of children
• Shelf Life: As per manufacturer label; typically 24–36 months