sitagliptin
DPP-4 inhibitor· Brands: JanuviaPO
Mechanism of action
Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By preventing their breakdown, sitagliptin increases the circulating levels of these incretins, which enhances glucose-dependent insulin secretion from pancreatic beta cells and suppresses glucagon release from alpha cells. This results in improved glycaemic control, particularly in the postprandial period, and is largely glucose-dependent, so the risk of hypoglycaemia is low when used as monotherapy.
Pharmacokinetics
Sitagliptin is rapidly and well absorbed after oral administration, with an absolute bioavailability of approximately 87%. Peak plasma concentrations occur about 1 to 4 hours after a dose. Plasma protein binding is modest at around 38%. The drug is cleared primarily by renal excretion as unchanged drug (about 79% of a dose is excreted in urine), with renal clearance matching glomerular filtration rate. Metabolism is minor, involving CYP3A4 and CYP2C8, but does not contribute significantly to elimination. The elimination half-life is approximately 12 to 14 hours, allowing once-daily dosing. Dose adjustment is recommended in patients with moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m²) based on local guidelines. Age and mild hepatic impairment do not require dose adjustment.
Indications & dosing
Type 2 diabetes mellitus (monotherapy)
Adjunct to diet and exercise. Reduce dose in renal impairment: 50 mg if eGFR 30-45 ml/min, 25 mg if eGFR <30 ml/min.
- adult · PO: 100 mg once daily · Adjunct to diet and exercise. Reduce dose in renal impairment: 50 mg if eGFR 30-45 ml/min, 25 mg if eGFR <30 ml/min.
Type 2 diabetes mellitus (combination therapy)
With metformin, sulfonylurea, thiazolidinedione, or insulin when monotherapy is inadequate. Reduce dose in renal impairment.
- adult · PO: 100 mg once daily · With metformin, sulfonylurea, thiazolidinedione, or insulin when monotherapy is inadequate. Reduce dose in renal impairment.
Contraindications & precautions
- Hypersensitivity to sitagliptin or any excipient of the formulation · Includes previous anaphylaxis, angioedema, or severe cutaneous reactions.
- History of serious hypersensitivity reaction to any other dipeptidyl peptidase-4 (DPP-4) inhibitor · Cross-reactivity may occur; avoid use in these patients.
- Reduce the dose based on renal function: eGFR 30–44 mL/min/1.73 m²: 50 mg once daily; eGFR <30 mL/min/1.73 m²: 25 mg once daily; no adjustment if eGFR ≥45.
- Monitor renal function before initiation and periodically during treatment, particularly in patients with pre-existing renal impairment.
- Use with caution in patients with a history of pancreatitis or risk factors for pancreatitis (e.g., gallstones, alcoholism); advise patients to stop the drug immediately if symptoms of pancreatitis occur.
- If used with sulfonylureas or insulin, consider reducing the dose of the sulfonylurea or insulin to minimize the risk of hypoglycaemia.
- Caution in patients with a history of hypersensitivity to any DPP-4 inhibitor; advise patients to seek urgent medical attention if symptoms of angioedema or severe skin reactions develop.
Adverse effects
- Nasopharyngitis
- Headache
- Upper respiratory tract infection
- Hypoglycemia (especially when combined with sulfonylureas or insulin)
- Pancreatitis (acute)serious
- Angioedemaserious
- Severe hypersensitivity reactions including anaphylaxisserious
Renal & hepatic adjustment
- eGFR 45+: No dose adjustment required. Usual dose is 100 mg once daily.
- eGFR 30–44: Reduce dose to 50 mg once daily.
- eGFR 0–29: Reduce dose to 25 mg once daily. For patients on dialysis, give 25 mg once daily.
Monitoring, pregnancy & toxicity
- Blood glucose · Regularly, as clinically indicated
- HbA1c · Every 3-6 months
- Renal function (eGFR) · Periodically, at least annually; more frequently if renal impairment
- Signs and symptoms of pancreatitis · At each review
- Pregnancy: Sitagliptin is not recommended during pregnancy; use insulin as the preferred treatment for diabetes in pregnancy.
- Toxicity: Overdose may cause gastrointestinal symptoms such as nausea, vomiting, and abdominal pain. · Supportive care; monitor blood glucose. Sitagliptin is dialyzable; consider haemodialysis in severe overdose, particularly with renal impairment.
- Toxicity: Risk of pancreatitis has been reported; patients should be advised to seek medical attention if persistent severe abdominal pain. · Discontinue sitagliptin and treat any accompanying symptoms appropriately.
- Toxicity: Hypoglycaemia is uncommon as monotherapy but may occur if used with sulphonylureas or insulin; dosage of these may need to be reduced. · Monitor blood glucose; adjust concomitant therapy if needed.
Clinical notes
Sitagliptin is used for the management of type 2 diabetes mellitus, either as monotherapy or in combination with other agents such as metformin, sulfonylureas, or insulin. It is generally weight-neutral and has a low intrinsic risk of hypoglycaemia when used alone, but the risk may be increased when combined with insulin or sulfonylureas. Common adverse effects include nasopharyngitis, headache, and gastrointestinal symptoms. Rare but serious events include acute pancreatitis, which requires immediate discontinuation if suspected, and severe cutaneous reactions. It is not indicated for type 1 diabetes or diabetic ketoacidosis. Renal function should be assessed before and periodically during treatment. The dose should be reduced in patients with moderate or severe renal impairment according to available prescribing information.
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BNF; local formulary