Linagliptin

Linagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor given as a fixed 5 mg once daily. It is the only common gliptin that needs no dose change in kidney or liver impairment, because it is cleared mainly through bile and the gut. It lowers HbA1c by about 0.5 to 0.7%, is weight neutral, rarely causes hypoglycaemia when used alone, and is neutral for cardiovascular events, heart failure admission and kidney outcomes.

Classification. DPP-4 inhibitor (gliptin), xanthine-based. Tablets 5 mg; fixed-dose combinations with metformin and with empagliflozin.

Mechanism. Inhibits DPP-4, the enzyme that inactivates GLP-1 and GIP. Higher active incretin levels raise glucose-dependent insulin release and suppress glucagon.

Pharmacodynamics. Over 80% DPP-4 inhibition is sustained for 24 hours at 5 mg. Insulin release falls as glucose normalises, which keeps hypoglycaemia risk low.

Pharmacokinetics. Bioavailability about 30%; peak about 1.5 hours; protein binding is concentration dependent. Minimal metabolism; about 90% is excreted unchanged, mostly in faeces through bile and gut, and only about 5% in urine. Effective half-life about 12 hours; the long terminal half-life reflects tight tissue binding. A substrate of P-glycoprotein and CYP3A4.

Type 2 diabetes, adults.

• 5 mg orally once daily, with or without food. No titration and no loading dose.
• Continue long term if HbA1c falls by at least 0.5% (5.5 mmol/mol) within 6 months; otherwise stop.

Combination use. Adds to metformin, sulphonylureas, pioglitazone, SGLT2 inhibitors and insulin. When adding to a sulphonylurea or insulin, reduce their dose to limit hypoglycaemia. Do not combine with a GLP-1 receptor agonist or another DPP-4 inhibitor.

Adjustments.

• Kidney: no change at any eGFR, including dialysis.
• Liver: no change in mild, moderate or severe impairment.
• Older adults: no change.
• Weight: no weight-based dosing.
• Children: not licensed in most markets.

Contraindications. Hypersensitivity to linagliptin, including previous urticaria, angioedema or bronchial hyperreactivity from it; type 1 diabetes; diabetic ketoacidosis.

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Hypersensitivity reactions including angioedema and exfoliative skin conditions.
• Bullous pemphigoid: stop and refer if blisters appear.
• Severe disabling arthralgia, resolving on withdrawal.

Common adverse effects. Nasopharyngitis, cough, headache; hypoglycaemia only with sulphonylureas or insulin.

Major interactions.

• Rifampicin and other strong P-glycoprotein or CYP3A4 inducers (carbamazepine, phenytoin, phenobarbital, St John's wort) reduce exposure and effect; use another agent.
• Sulphonylureas and insulin: more hypoglycaemia.
• ACE inhibitors: higher angioedema risk with DPP-4 inhibitors.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid; no human data.
• Older adults: favoured when hypoglycaemia must be avoided.
• Kidney and liver impairment: no dose change at any stage; the preferred gliptin in advanced kidney disease where it is available.
• Heart failure: neutral for heart failure admission.
• East Africa: rifampicin during TB treatment lowers effect, so choose another agent for the duration. Cost and supply limit use in public facilities.

Administration. Once daily at any time, with or without food. Continues safely through Ramadan fasting without dose change.

Baseline. HbA1c, eGFR, history of pancreatitis.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• eGFR at least annually, for the wider diabetes review rather than for dose adjustment.
• Ask about abdominal pain, blisters and joint pain.

Stopping thresholds. Stop with suspected pancreatitis, hypersensitivity, bullous pemphigoid, disabling arthralgia, or HbA1c reduction under 0.5% after 6 months.

Referral and escalation. Admit suspected pancreatitis or anaphylaxis. Refer blistering eruptions to dermatology.