SGLT2 Inhibitors

SGLT2 inhibitors (gliflozins) are oral agents that increase urinary glucose loss. They lower HbA1c by 0.5 to 0.8% and weight by 2 to 3 kg, and have strong cardiorenal benefits in heart failure and chronic kidney disease, with or without diabetes.

Mechanism. They block sodium-glucose cotransporter 2 in the proximal tubule, reducing glucose reabsorption and causing glucosuria of about 60 to 80 g daily. They also produce natriuresis, a small fall in blood pressure and restoration of tubuloglomerular feedback, which reduces intraglomerular pressure.

Pharmacokinetics. Once daily oral dosing. Glucose lowering falls with eGFR (little effect under 45 mL/min), but heart and kidney protection persist down to an eGFR of 20 to 25 mL/min. An initial eGFR dip of 3 to 5 mL/min is expected and does not need treatment to be stopped.

Differences. Empagliflozin, dapagliflozin and canagliflozin have outcome evidence in heart failure, chronic kidney disease or atherosclerotic disease. Canagliflozin carried an amputation signal in earlier studies. Sotagliflozin also inhibits SGLT1 and is licensed for heart failure in some regions.

• Heart failure (reduced or preserved ejection fraction): empagliflozin or dapagliflozin 10 mg daily, with or without diabetes.
• Chronic kidney disease: dapagliflozin 10 mg for eGFR 25 mL/min or more, empagliflozin 10 mg for eGFR 20 mL/min or more, particularly with albuminuria, with or without diabetes.
• Type 2 diabetes with atherosclerotic disease, heart failure or kidney disease: started independent of HbA1c, alongside metformin.
• Starting on diuretics: reduce the loop diuretic dose by 25 to 50% if the patient is euvolaemic or volume deplete.
• Peri-procedural: stop 3 days before elective surgery (4 days for ertugliflozin) and restart when eating normally.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: dapagliflozin and empagliflozin are licensed from 10 years for type 2 diabetes in some regions. Older adults: watch volume depletion and falls. Kidney impairment: continue for cardiorenal benefit down to an eGFR of 20 to 25 mL/min. Liver impairment: no adjustment in mild to moderate disease. Regional: heat, manual labour and reduced fluid access increase dehydration risk, and Ramadan fasting requires dose review and ketone vigilance.

Adverse effects. Genital mycotic infection (women about 10 to 15%), urinary tract infection, volume depletion and postural hypotension, euglycaemic ketoacidosis, and rarely necrotising fasciitis of the perineum (Fournier gangrene).

Euglycaemic ketoacidosis. Risk rises in type 1 diabetes, insulin deficiency, low carbohydrate diets, alcohol excess, acute illness, fasting and surgery. Stop the drug in any acutely ill patient and check ketones even if glucose is normal.

Contraindications. Previous ketoacidosis on the drug, pregnancy and dialysis. Not licensed in type 1 diabetes.

Interactions. Loop and thiazide diuretics and antihypertensives add to volume depletion. Insulin and sulphonylureas need dose reduction to prevent hypoglycaemia.

Monitoring. eGFR and potassium 1 to 4 weeks after starting in kidney disease, blood pressure and volume status, genital hygiene and symptoms, and ketones when unwell.

Referral and escalation. Ketoacidosis, genital pain or swelling, recurrent urosepsis, or eGFR fall over 30% after starting.