linagliptin
DPP-4 inhibitor· Brands: Trajenta, TradjentaPO
Mechanism of action
Linagliptin is a selective, competitive inhibitor of dipeptidyl peptidase-4 (DPP-4), an enzyme that rapidly degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, linagliptin increases the concentrations of these incretins in the bloodstream. This enhances glucose-dependent insulin secretion from pancreatic beta cells and reduces glucagon secretion from alpha cells, resulting in a reduction of hepatic glucose output. The effect is glucose-dependent, so the risk of hypoglycaemia is low.
Pharmacokinetics
Linagliptin is rapidly absorbed after oral administration, with peak plasma concentrations occurring about 1.5 to 2 hours after dosing. Its absolute oral bioavailability is approximately 30%. Plasma protein binding is high (about 99%), and the drug is extensively distributed to tissues. Linagliptin is not extensively metabolised; it is predominantly excreted unchanged in bile and faeces, with only a small amount in urine. The elimination half-life is approximately 12 hours. No dose adjustment is required in patients with renal or hepatic impairment.
Indications & dosing
Type 2 diabetes mellitus (as monotherapy)
May be used as initial therapy or in patients not controlled by diet and exercise alone.
- adult · PO: 5 mg once daily · May be used as initial therapy or in patients not controlled by diet and exercise alone.
Type 2 diabetes mellitus (in combination with metformin, sulfonylurea, or insulin)
No dose adjustment required in renal or hepatic impairment.
- adult · PO: 5 mg once daily · No dose adjustment required in renal or hepatic impairment.
Contraindications & precautions
- Hypersensitivity to linagliptin or any component of the formulation · Angioedema, anaphylaxis, or other allergic reactions have been reported.
- Type 1 diabetes mellitus · Not effective; risk of diabetic ketoacidosis if used in place of insulin.
- Diabetic ketoacidosis · Linagliptin is not indicated for this acute metabolic condition.
- History of angioedema with other DPP-4 inhibitors · Use with caution; may increase risk of recurrence.
- Discontinue linagliptin if acute pancreatitis is suspected and monitor carefully.
- Monitor for signs of hypersensitivity reactions; discontinue if serious reactions occur.
- Consider dose reduction of insulin or sulfonylureas when used in combination to minimise hypoglycaemia risk.
- Use with caution in patients with a history of heart failure; monitor for signs and symptoms.
- Avoid use in pregnancy and breastfeeding; safety not established.
Adverse effects
- Nasopharyngitis
- Upper respiratory tract infection
- Headache
- Hypoglycaemia (when used with insulin or sulfonylureas)
- Arthralgia
- Pancreatitis (acute or chronic)serious
- Hypersensitivity reactions (including angioedema, urticaria, anaphylaxis)serious
Monitoring, pregnancy & toxicity
- Blood glucose · Periodically, as clinically indicated
- HbA1c · Every 3 to 6 months
- Serum creatinine and eGFR · Periodically for overall renal assessment
- Signs and symptoms of pancreatitis (e.g., persistent abdominal pain, nausea, vomiting) · Routine clinical monitoring
- Signs and symptoms of hypersensitivity (e.g., skin rash, angioedema) · Routine clinical monitoring
- Pregnancy: Not recommended during pregnancy. There are no adequate data on linagliptin use in pregnant women, and animal studies have shown no direct or indirect harmful effects but are insufficient to establish safety. Alternative antidiabetic agents with established safety profiles are preferable. If treatment with linagliptin is necessary, discuss the potential risks and benefits with the patient.
- Toxicity: Hypoglycemia, particularly when used in combination with insulin or sulfonylureas · Administer oral glucose; adjust the dose of the co-administered agent. Monitor blood glucose frequently.
- Toxicity: Pancreatitis (rare) with symptoms such as persistent severe abdominal pain, nausea, and vomiting · Discontinue linagliptin promptly and initiate supportive care. Monitor for complications. Re-evaluate the use of DPP-4 inhibitors in the future.
- Toxicity: Hypersensitivity reactions, including angioedema and anaphylaxis · Discontinue linagliptin and treat the reaction with appropriate medical therapy. Consider an alternative antidiabetic agent.
- Toxicity: Overdose: No specific clinical features are well characterised. DPP-4 inhibitors have a wide therapeutic margin. · Treat symptomatically and with supportive measures. No specific antidote exists. Consider monitoring blood glucose and hydration.
Clinical notes
Linagliptin is indicated for the treatment of type 2 diabetes mellitus as monotherapy or in combination with other antidiabetic agents when diet and exercise alone do not provide adequate glycaemic control. The recommended dose is 5 mg taken once daily, at any time, and can be given with or without food. It is particularly useful in patients with chronic kidney disease because no dose adjustment is necessary. Common adverse effects include nasopharyngitis and hypersensitivity reactions. Rare but serious effects include pancreatitis, and patients should stop the drug and seek medical advice if symptoms of pancreatitis occur. Monitor liver function in patients with hepatic impairment. Linagliptin should be used with caution in combination with insulin or sulphonylureas due to an increased risk of hypoglycaemia; dose reduction of the insulin or sulphonylurea may be considered. It is not recommended in pregnancy or breastfeeding.
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BNF; local formulary