Dapagliflozin

Dapagliflozin is an oral SGLT2 inhibitor taken once daily. Its glucose-lowering effect is modest (HbA1c about 0.5 to 0.8%) and falls with eGFR, but it reduces heart failure admission and cardiovascular death in heart failure at any ejection fraction and slows progression of chronic kidney disease, with or without diabetes.

Classification. SGLT2 inhibitor (gliflozin). Tablets 5 and 10 mg; fixed-dose combinations with metformin and with saxagliptin.

Mechanism. Inhibits SGLT2 in the proximal tubule, causing urinary loss of glucose, sodium and water independent of insulin. Natriuresis and lower intraglomerular pressure underlie heart and kidney benefit.

Pharmacodynamics. Urinary glucose loss of about 70 g daily at normal eGFR, falling with eGFR. Modest weight loss (2 to 3 kg), systolic blood pressure fall of 3 to 5 mmHg and a small LDL cholesterol rise. Low hypoglycaemia risk alone.

Pharmacokinetics. Bioavailability about 78%; peak within 2 hours; about 91% protein bound. Metabolised mainly by UGT1A9 to an inactive glucuronide, which is excreted in urine (about 75%); under 2% is excreted unchanged. Half-life about 13 hours.

Type 2 diabetes, adults.

• Start 5 mg orally once daily in the morning, with or without food.
• Increase to 10 mg once daily if needed and eGFR allows.
• Maximum 10 mg daily. No loading dose.

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

• 10 mg orally once daily. Start once stable; no titration.

Chronic kidney disease, with or without diabetes.

• 10 mg orally once daily when eGFR is 25 mL/min/1.73 m2 or more (some labels allow 15 or more), continued until dialysis or transplant.

Type 2 diabetes, children aged 10 years and over.

• 5 mg once daily, increasing to 10 mg if needed.

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, not advised when eGFR is under 45 because the effect is small. For heart failure and kidney protection, start at eGFR 25 or more and continue at lower values. Stop at dialysis.
• Liver: no change in mild to moderate impairment; start 5 mg in severe impairment and increase to 10 mg if tolerated.
• Older adults: check volume status and blood pressure.
• Weight: no weight-based dosing.

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

Serious adverse effects.

• Ketoacidosis, including euglycaemic ketoacidosis. 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 and in older adults.
• Genital mycotic infections and urinary tract infections.
• Necrotising fasciitis of the perineum (Fournier gangrene): rare and urgent.
• 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.
• Insulin and sulphonylureas: hypoglycaemia.
• Rifampicin and other UGT inducers lower exposure modestly; no dose change is made.
• Lithium level may fall; monitor.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: licensed from 10 years for type 2 diabetes in some markets.
• Older adults: review diuretics and blood pressure.
• Kidney and liver impairment: glucose lowering is weak when eGFR is under 45; heart failure and kidney protection are started at eGFR 25 or more and continued at lower values; start 5 mg in severe liver impairment.
• East Africa: advise genital hygiene and sick-day rules. Take extra care in lean, ketosis-prone or insulin-deficient patients and during prolonged fasting. Cost limits access, but 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 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; 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. Refer urgently to surgery for perineal infection.