Saxagliptin

Saxagliptin is an oral DPP-4 inhibitor given once daily at 5 mg, or 2.5 mg in kidney impairment or with strong CYP3A4 inhibitors. It lowers HbA1c by about 0.5 to 0.8% and rarely causes hypoglycaemia alone. It is the one gliptin with a signal for more heart failure admissions, so it is not preferred in patients with heart failure or high risk of it.

Classification. DPP-4 inhibitor (gliptin), cyanopyrrolidine. Tablets 2.5 and 5 mg; fixed-dose combinations with metformin and with dapagliflozin.

Mechanism. Inhibits DPP-4 and so raises active GLP-1 and GIP, increasing glucose-dependent insulin release and suppressing glucagon.

Pharmacodynamics. About 70 to 80% DPP-4 inhibition over 24 hours at 5 mg. Hypoglycaemia risk stays low because insulin release falls as glucose normalises.

Pharmacokinetics. Bioavailability about 67%; peak about 2 hours; low protein binding. Metabolised by CYP3A4 and CYP3A5 to an active metabolite, 5-hydroxysaxagliptin, about half as potent as the parent. Excreted in urine as parent (about 24%) and active metabolite (about 36%). Half-life about 2.5 hours for the parent and 3 hours for the metabolite.

Type 2 diabetes, adults.

• 5 mg orally once daily, with or without food. No loading dose.
• Use 2.5 mg once daily when eGFR is 45 mL/min/1.73 m2 or less (some labels use a creatinine clearance of 50 mL/min or less) and with strong CYP3A4 or CYP3A5 inhibitors.
• Continue long term if HbA1c falls by at least 0.5% within 6 months; otherwise stop.

Combination use. Adds to metformin, sulphonylureas, pioglitazone, SGLT2 inhibitors and insulin. Reduce the sulphonylurea or insulin dose when adding saxagliptin. Do not combine with a GLP-1 receptor agonist or another DPP-4 inhibitor.

Adjustments.

• Kidney: 5 mg when eGFR is over 45; 2.5 mg when 45 or under, including end-stage kidney disease. On haemodialysis give 2.5 mg once daily after the session. Data in peritoneal dialysis are limited.
• Liver: no change in mild to moderate impairment; use with caution in severe impairment.
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir): 2.5 mg.
• Older adults: dose by eGFR.
• Weight: no weight-based dosing.
• Children: not licensed.

Contraindications. Hypersensitivity to saxagliptin or other DPP-4 inhibitors, including previous anaphylaxis, angioedema or severe skin reaction; type 1 diabetes; diabetic ketoacidosis.

Heart failure. A large cardiovascular outcome study found about 27% more heart failure admissions with saxagliptin, with the highest risk in patients with raised natriuretic peptides, previous heart failure or kidney impairment. Avoid or use with great caution in these groups, and stop if heart failure develops.

Other serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Hypersensitivity including anaphylaxis and angioedema.
• Bullous pemphigoid: stop and refer if blisters appear.
• Severe disabling arthralgia.

Common adverse effects. Upper respiratory infection, urinary tract infection, headache; hypoglycaemia mostly with sulphonylureas or insulin.

Major interactions.

• Strong CYP3A4 or CYP3A5 inhibitors raise levels; cap at 2.5 mg.
• Strong inducers such as rifampicin lower levels and effect.
• Sulphonylureas and insulin: more hypoglycaemia.
• ACE inhibitors: higher angioedema risk.

Special groups.

• Pregnancy: avoid; use insulin.
• Breastfeeding: avoid; no human data.
• Older adults: dose by eGFR and screen for heart failure before starting.
• Kidney impairment: 2.5 mg when eGFR is 45 or under, and the higher heart failure risk with kidney disease argues for another gliptin.
• East Africa: where heart failure from hypertensive, rheumatic or peripartum disease is frequent, prefer linagliptin, sitagliptin or another class. Rifampicin during TB treatment lowers effect; ritonavir-boosted antiretrovirals raise it.

Administration. Once daily at any time, with or without food. Swallow whole; do not split or crush tablets.

Baseline. HbA1c, eGFR, history of pancreatitis, assessment for heart failure and natriuretic peptide where available.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• eGFR at least annually, and every 3 to 6 months when under 60; adjust dose as eGFR crosses 45.
• Weight, oedema and breathlessness at each visit.
• Ask about abdominal pain, blisters and joint pain.

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

Referral and escalation. Admit new heart failure, suspected pancreatitis or anaphylaxis. Refer blistering eruptions to dermatology.