Ertugliflozin

Ertugliflozin is an oral SGLT2 inhibitor taken once daily. It lowers HbA1c by about 0.5 to 0.8% in preserved kidney function. A cardiovascular outcome study showed non-inferiority for major cardiovascular events but no clear benefit, and it lacks the licensed heart failure and chronic kidney disease indications of empagliflozin and dapagliflozin. Availability is limited.

Classification. SGLT2 inhibitor (gliflozin). Tablets 5 and 15 mg; fixed-dose combinations with sitagliptin and with metformin.

Mechanism. Inhibits SGLT2 in the proximal tubule, causing urinary glucose, sodium and water loss independent of insulin.

Pharmacodynamics. Lowers the renal glucose threshold; modest weight loss (2 to 3 kg) and systolic blood pressure fall (3 to 5 mmHg). Effect falls with eGFR.

Pharmacokinetics. Bioavailability about 100%; peak 1 hour; about 94% protein bound. Glucuronidated by UGT1A9 and UGT2B7; minor CYP3A4 and CYP-mediated oxidation. About 50% is excreted in urine and 41% in faeces, largely as metabolites. Half-life about 17 hours.

Type 2 diabetes, adults.

• Start 5 mg orally once daily in the morning, with or without food.
• Increase to 15 mg once daily if tolerated and glucose control is inadequate.
• Maximum 15 mg daily. No loading dose.

Combination use. Adds to metformin, DPP-4 inhibitors, GLP-1 receptor agonists, insulin and sulphonylureas. Reduce the sulphonylurea or insulin dose when starting if HbA1c is near target. Do not combine with another SGLT2 inhibitor.

Adjustments.

• Kidney: not advised to start when eGFR is under 45 mL/min/1.73 m2; contraindicated in severe impairment, end-stage kidney disease and dialysis (eGFR under 30).
• Liver: no change in mild to moderate impairment; not studied in severe impairment.
• Rifampicin and other UGT inducers: no dose change; monitor glucose.
• Older adults: check volume status and blood pressure.
• Weight: no weight-based dosing.
• Children: not licensed.

Contraindications. Hypersensitivity; severe renal impairment, end-stage kidney disease or dialysis; type 1 diabetes (not licensed).

Serious adverse effects.

• Ketoacidosis, including euglycaemic ketoacidosis.
• Volume depletion, hypotension and acute kidney injury.
• Genital mycotic infections and urinary tract infections.
• Fournier gangrene: rare and urgent.
• Hypoglycaemia with sulphonylureas or insulin.

Major interactions.

• Loop and thiazide diuretics: volume depletion.
• Insulin and sulphonylureas: hypoglycaemia.
• Rifampicin and other UGT inducers lower exposure.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: higher volume depletion risk.
• Kidney and liver impairment: not advised to start when eGFR is under 45 and contraindicated when under 30; not studied in severe liver impairment.
• East Africa: usually unavailable; empagliflozin or dapagliflozin are the usual gliflozins.

Administration. Once daily in the morning, with or without food. Maintain fluids.

Sick-day rules. Withhold during vomiting, diarrhoea, fever, poor oral intake or acute illness. Restart after 24 to 48 hours of normal eating and drinking. Check blood ketones in anyone unwell with nausea, vomiting, abdominal pain, malaise or breathlessness, even with normal glucose.

Surgery. Stop at least 4 days before planned surgery or procedures needing prolonged fasting.

Baseline. HbA1c, eGFR, blood pressure, volume status, genital and foot examination.

Monitoring.

• eGFR and blood pressure within 2 to 4 weeks of starting, then at least every 6 months.
• HbA1c at 3 and 6 months, then every 6 months.
• Ketones whenever unwell.

Stopping thresholds. Stop with ketoacidosis, Fournier gangrene, recurrent severe genital infection, symptomatic hypotension, or when eGFR falls under 30.

Referral and escalation. Admit suspected ketoacidosis for fluids, insulin and glucose with potassium replacement. Refer urgently to surgery for perineal infection.