Empagliflozin

Empagliflozin is an oral sodium-glucose co-transporter 2 (SGLT2) inhibitor taken once daily. It lowers HbA1c by about 0.5 to 0.8% in preserved kidney function, with a smaller effect as eGFR falls. Its larger value is organ protection: it reduces cardiovascular death in type 2 diabetes with established cardiovascular disease, heart failure admission across the ejection fraction range, and kidney disease progression, with or without diabetes.

Classification. SGLT2 inhibitor (gliflozin). Tablets 10 and 25 mg; fixed-dose combinations with metformin and with linagliptin.

Mechanism. Blocks SGLT2 in the proximal tubule, which reabsorbs most filtered glucose. Glucose, sodium and water are lost in urine, independent of insulin. Natriuresis, lower intraglomerular pressure and metabolic effects probably explain the heart and kidney benefit.

Pharmacodynamics. Urinary glucose loss of about 60 to 80 g daily at normal eGFR, falling with eGFR. Causes modest weight loss (2 to 3 kg), blood pressure fall (3 to 5 mmHg systolic) and a small LDL cholesterol rise. Hypoglycaemia risk is low alone.

Pharmacokinetics. Bioavailability about 78%; peak 1.5 hours; about 86% protein bound. Metabolised by glucuronidation (UGT2B7, UGT1A3, UGT1A8, UGT1A9) to inactive metabolites. About 54% is excreted in urine and 41% in faeces. Half-life about 12 hours.

Type 2 diabetes, adults.

• Start 10 mg orally once daily in the morning, with or without food.
• Increase to 25 mg once daily if glucose control is inadequate and eGFR is 60 mL/min/1.73 m2 or more.
• Maximum 25 mg daily. No loading dose.

Heart failure, any ejection fraction, with or without diabetes.

• 10 mg orally once daily. Start during or soon after a decompensation once stable; no titration.

Chronic kidney disease, with or without diabetes.

• 10 mg orally once daily when eGFR is 20 or more, continued until dialysis or transplant.

Type 2 diabetes, children aged 10 years and over.

• 10 mg once daily, increasing to 25 mg if needed. Data are limited.

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: for glucose lowering, avoid starting when eGFR is under 30 because the effect is small. For heart failure and kidney protection, start at eGFR 20 or more and continue. Not studied on dialysis; stop at dialysis.
• Liver: no change.
• Older adults: check volume status and blood pressure; no dose change.
• Weight: no weight-based dosing.

Contraindications. Hypersensitivity; dialysis; type 1 diabetes (not licensed).

Serious adverse effects.

• Ketoacidosis, including euglycaemic ketoacidosis with near-normal glucose. Risk is higher with insulin deficiency, low-carbohydrate or fasting states, heavy alcohol use, acute illness, surgery and rapid insulin dose reduction.
• Volume depletion, hypotension and acute kidney injury, especially with loop diuretics, older age and low blood pressure.
• Genital mycotic infections (about 5 to 10% in women, 2 to 4% in men) and urinary tract infections.
• Necrotising fasciitis of the perineum (Fournier gangrene): rare; urgent surgical review for severe genital or perineal pain with fever or malaise.
• Hypoglycaemia with sulphonylureas or insulin.

Expected change. A small early eGFR dip of about 3 to 5 mL/min/1.73 m2 is expected and usually does not need a change in treatment.

Major interactions.

• Loop and thiazide diuretics: volume depletion; reduce diuretic dose if overloaded status allows.
• Insulin and sulphonylureas: hypoglycaemia.
• Probenecid and other OAT3 inhibitors raise exposure slightly; no dose change.
• Lithium level may fall; monitor.

Special groups.

• Pregnancy: avoid; renal development concerns in animals in the second and third trimesters.
• Breastfeeding: avoid.
• Children: licensed from 10 years for type 2 diabetes in some markets.
• Older adults: higher volume depletion risk; review diuretics and blood pressure.
• Kidney and liver impairment: avoid starting for glucose control when eGFR is under 30; start heart failure and kidney protection at eGFR 20 or more; no liver adjustment.
• East Africa: advise genital hygiene and sick-day rules. Be careful in lean, insulin-deficient or ketosis-prone patients, and during prolonged fasting or Ramadan, when volume depletion and ketosis are more likely. Cost limits access, but the heart failure and kidney indications justify priority use where funded.

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 once eating and drinking normally for 24 to 48 hours. Check blood ketones in anyone unwell with nausea, vomiting, abdominal pain, malaise or breathlessness, even with normal glucose; blood beta-hydroxybutyrate of 3 mmol/L or more with acidosis confirms ketoacidosis.

Surgery. Stop at least 3 days before planned surgery or procedures needing prolonged fasting; restart once eating normally.

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.
• Genital and urinary symptoms at each visit.

Stopping thresholds. Stop with ketoacidosis, recurrent severe genital infection, Fournier gangrene, symptomatic hypotension not corrected by diuretic reduction, or at dialysis.

Referral and escalation. Admit suspected ketoacidosis for fluids, insulin and glucose with potassium replacement, and do not restart afterwards unless a clear precipitant is corrected. Refer urgently to surgery for perineal infection.