Sitagliptin

Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor that raises active incretin levels. It lowers HbA1c by about 0.5 to 0.8%, is weight neutral, does not cause hypoglycaemia when used alone, is neutral for cardiovascular events and heart failure, and needs dose reduction in kidney disease.

Classification. DPP-4 inhibitor (gliptin). Tablets 25, 50 and 100 mg; fixed-dose combinations with metformin.

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

Pharmacodynamics. About 80% DPP-4 inhibition over 24 hours at 100 mg. Insulin release falls as glucose normalises, which keeps hypoglycaemia risk low.

Pharmacokinetics. Bioavailability about 87%; peak 1 to 4 hours; 38% protein bound. Minimal metabolism by CYP3A4 and CYP2C8; about 79% excreted unchanged in urine by filtration and tubular secretion. Half-life about 12 hours.

Type 2 diabetes, adults.

• 100 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.

Dose adjustment for kidney function.

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; there is no added benefit.

Other adjustments.

• Liver: no change in mild to moderate impairment; not studied in severe impairment.
• Older adults: dose by eGFR; a useful low-hypoglycaemia option.
• Weight: no weight-based dosing.

Contraindications. Hypersensitivity to sitagliptin, including previous anaphylaxis, angioedema or Stevens-Johnson syndrome; type 1 diabetes; diabetic ketoacidosis.

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed. Use with caution after previous pancreatitis.
• Hypersensitivity: anaphylaxis, angioedema, exfoliative skin reactions.
• Bullous pemphigoid: stop and refer if blisters appear.
• Severe disabling arthralgia, resolving on withdrawal.

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

Major interactions.

• Sulphonylureas and insulin: more hypoglycaemia.
• ACE inhibitors: higher angioedema risk with DPP-4 inhibitors.
• Digoxin levels rise slightly; monitor in older adults and kidney disease.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid; no human data.
• Children: not licensed; efficacy was not shown in adolescents.
• Older adults: favoured when hypoglycaemia must be avoided.
• Kidney impairment: 100 mg when eGFR is 45 or more, 50 mg when 30 to 44, 25 mg when under 30.
• Heart failure: neutral for heart failure hospitalisation, unlike saxagliptin.
• East Africa: cost limits use in many public facilities; generic supply varies by country.

Administration. Once daily at any time, with or without food. Safe to continue during 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; every 3 to 6 months when eGFR is under 60, adjusting the dose as eGFR crosses 45 and 30.
• 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.