Alogliptin

Alogliptin is an oral DPP-4 inhibitor given once daily, with dose reduction as kidney function falls. It lowers HbA1c by about 0.5 to 0.8% and has low hypoglycaemia risk alone. A cardiovascular outcome study in people with recent acute coronary syndrome showed no excess of major cardiovascular events, but heart failure admissions were not clearly neutral, so caution is advised in heart failure. Rare liver injury needs monitoring.

Classification. DPP-4 inhibitor (gliptin), pyrimidinedione. Tablets 6.25, 12.5 and 25 mg; fixed-dose combinations with metformin and with pioglitazone.

Mechanism. Inhibits DPP-4, raising active GLP-1 and GIP, which increases glucose-dependent insulin release and suppresses glucagon.

Pharmacodynamics. More than 80% DPP-4 inhibition is sustained for 24 hours at 25 mg.

Pharmacokinetics. Bioavailability about 100%; peak 1 to 2 hours; about 20% protein bound. Minimal metabolism by CYP2D6 and CYP3A4. About 60 to 70% is excreted unchanged in urine. Half-life about 21 hours.

Type 2 diabetes, adults.

• 25 mg orally once daily, with or without food. No loading dose.
• Continue long term if HbA1c falls by at least 0.5% within 6 months; otherwise stop.

Dose adjustment for kidney function.

Combination use. Adds to metformin, pioglitazone, sulphonylureas and insulin. Reduce the sulphonylurea or insulin dose when adding it. Do not combine with a GLP-1 receptor agonist or another DPP-4 inhibitor.

Other adjustments.

• Liver: no change in mild to moderate impairment; not studied in severe impairment.
• Older adults: dose by eGFR.
• Weight: no weight-based dosing.
• Children: not licensed.

Contraindications. Hypersensitivity to alogliptin, including previous anaphylaxis, angioedema or severe skin reaction; type 1 diabetes; diabetic ketoacidosis.

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Hepatic injury, rarely fatal: stop if ALT is more than 3 times the upper limit of normal with raised bilirubin, or if jaundice or an unexplained liver illness appears.
• Hypersensitivity: anaphylaxis, angioedema, Stevens-Johnson syndrome.
• Bullous pemphigoid and disabling arthralgia.
• Heart failure: use with caution in patients with heart failure or high risk of it; stop if it develops.

Common adverse effects. Nasopharyngitis, headache, upper respiratory infection; hypoglycaemia mostly with sulphonylureas or insulin.

Major interactions.

• Sulphonylureas and insulin: more hypoglycaemia.
• ACE inhibitors: higher angioedema risk.
• Few pharmacokinetic interactions; no CYP-mediated effects of note.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid; excreted in rat milk, no human data.
• Older adults: dose by eGFR.
• Kidney impairment: 25 mg when eGFR is 60 or more, 12.5 mg when 30 to 59, 6.25 mg when under 30.
• Heart failure: use with caution and stop if it develops, since a heart failure admission signal was seen in a post hoc analysis.
• East Africa: availability is limited; sitagliptin or linagliptin are usual alternatives.

Administration. Once daily at any time, with or without food.

Baseline. HbA1c, eGFR, ALT and bilirubin, history of pancreatitis, assessment for heart failure.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• eGFR at least annually; every 3 to 6 months when under 60, adjusting the dose as eGFR crosses 60 and 30.
• Liver tests periodically and with any unexplained symptoms.
• Ask about abdominal pain, blisters and joint pain.

Stopping thresholds. Stop with suspected pancreatitis, ALT more than 3 times the upper limit of normal with raised bilirubin, hypersensitivity, bullous pemphigoid, heart failure, disabling arthralgia, or HbA1c reduction under 0.5% after 6 months.

Referral and escalation. Admit suspected pancreatitis, acute liver injury or anaphylaxis. Refer blistering eruptions to dermatology.