Canagliflozin

Canagliflozin is an oral SGLT2 inhibitor taken once daily before the first meal. It lowers HbA1c by about 0.6 to 1% in preserved kidney function, reduces major cardiovascular events and slows progression of diabetic kidney disease. Compared with other gliflozins it carries an additional caution about lower-limb amputation and fracture.

Classification. SGLT2 inhibitor (gliflozin), also with weak SGLT1 inhibition. Tablets 100 and 300 mg; fixed-dose combination with metformin.

Mechanism. Inhibits SGLT2 in the proximal tubule, causing urinary glucose, sodium and water loss independent of insulin. Weak intestinal SGLT1 inhibition slightly blunts post-meal glucose.

Pharmacodynamics. Lowers renal glucose threshold; urinary glucose loss of about 100 g daily at normal eGFR at 300 mg. Weight loss of 2 to 4 kg, systolic blood pressure fall of 3 to 5 mmHg, small LDL cholesterol rise.

Pharmacokinetics. Bioavailability about 65%; peak 1 to 2 hours; about 99% protein bound. Glucuronidated by UGT1A9 and UGT2B4 to inactive metabolites; minor CYP3A4. About 33% appears in urine as metabolites and 41% in faeces. Half-life about 11 hours at 100 mg and 13 hours at 300 mg.

Type 2 diabetes, adults.

• Start 100 mg orally once daily before the first meal of the day.
• Increase to 300 mg once daily if tolerated, eGFR is 60 mL/min/1.73 m2 or more and glucose control is inadequate.
• Maximum 300 mg daily. No loading dose.

Diabetic kidney disease with albuminuria (urine albumin to creatinine ratio over 300 mg/g) and eGFR 30 or more.

• 100 mg orally once daily, continued until dialysis.

Type 2 diabetes with established cardiovascular disease.

• 100 mg once daily, increasing to 300 mg if eGFR allows and glucose control needs it.

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: eGFR 60 or more, 100 to 300 mg; 30 to 59, maximum 100 mg; under 30, not advised to start for glucose control and continue 100 mg only for albuminuric kidney disease. Stop at dialysis.
• Liver: no change in mild to moderate impairment; not studied in severe impairment.
• Rifampicin, phenytoin, phenobarbital, ritonavir (UGT inducers): if on 100 mg with eGFR 60 or more and needing more control, increase to 300 mg.
• Older adults: check volume status.
• Weight: no weight-based dosing.

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

Serious adverse effects.

• Ketoacidosis, including euglycaemic ketoacidosis; risk is higher with insulin deficiency, fasting, alcohol excess, acute illness and surgery.
• Volume depletion, hypotension and acute kidney injury.
• Lower-limb amputation, mainly toes and mid-foot, in one large outcome study. Avoid starting with active foot ulcer, infection, gangrene or severe peripheral arterial disease; examine feet at each visit and stop if foot ulceration or infection develops.
• Fractures and bone loss, particularly with low bone density or falls.
• Genital mycotic infections, urinary tract infections, and 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.

Major interactions.

• UGT inducers (rifampicin, phenytoin, phenobarbital, ritonavir) lower exposure; increase to 300 mg when eGFR is 60 or more and control is inadequate.
• Digoxin levels rise; monitor.
• Loop diuretics: volume depletion.
• Insulin and sulphonylureas: hypoglycaemia.
• Lithium level may fall.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: higher risk of volume depletion and falls with fracture.
• Kidney and liver impairment: maximum 100 mg when eGFR is 30 to 59; stop at dialysis; not studied in severe liver impairment.
• East Africa: foot disease and peripheral vascular disease are common in diabetes, so the amputation caution is practical; empagliflozin or dapagliflozin are usual choices when a gliflozin is wanted. Advise genital hygiene and sick-day rules.

Administration. Once daily before the first meal of the day. 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.

Baseline. HbA1c, eGFR, blood pressure, volume status, foot examination with pulses and sensation, fracture risk.

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.
• Feet at every visit.
• Ketones whenever unwell.

Stopping thresholds. Stop with ketoacidosis, foot ulcer, infection or gangrene, Fournier gangrene, recurrent severe genital infection, or at dialysis.

Referral and escalation. Admit suspected ketoacidosis or foot sepsis. Refer urgently to surgery for perineal infection and to a diabetes foot service for ulceration.