SGLT2 Inhibitors in Heart Failure

Sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalisation and, in reduced ejection fraction, cardiovascular death, across the whole ejection fraction range and whether or not diabetes is present. They also slow the decline in kidney function. They are now a fourth pillar of treatment in reduced ejection fraction.

Members for heart failure. Dapagliflozin and empagliflozin (10 mg daily). Sotagliflozin (dual SGLT1 and SGLT2) is available in some regions. Canagliflozin and ertugliflozin have less heart failure evidence.

Mechanism. Blocking SGLT2 in the proximal tubule causes glucosuria with osmotic diuresis and natriuresis, reducing preload and plasma volume without strong neurohormonal activation. Other proposed effects: lower intraglomerular pressure, improved myocardial energetics through ketone use, reduced sodium-hydrogen exchange, and less inflammation and fibrosis.

Pharmacokinetics. Once daily, well absorbed, half-life about 12 to 13 hours, mostly metabolised by glucuronidation. Glucose-lowering effect falls with reduced eGFR but heart and kidney benefit persists.

Kidney effect. An early fall in eGFR of about 3 to 5 mL/min/1.73 m2 is expected and reflects haemodynamic change, not injury.

• Dapagliflozin: heart failure across ejection fraction, chronic kidney disease.
• Empagliflozin: heart failure across ejection fraction, chronic kidney disease, type 2 diabetes with cardiovascular disease.
• Sotagliflozin: heart failure with diabetes and chronic kidney disease in some regions.

• Heart failure with reduced or preserved ejection fraction: dapagliflozin 10 mg or empagliflozin 10 mg orally once daily, with no titration. Start in hospital once stable, or in clinic.
• eGFR limits: dapagliflozin should not be started below 25 mL/min/1.73 m2, empagliflozin below 20 mL/min/1.73 m2. Continue if eGFR falls later, unless dialysis starts.
• Diabetes: continue the glucose-lowering effect, and reduce insulin or sulphonylurea doses if hypoglycaemia risk rises.
• Diuretic: consider lowering the loop diuretic dose if the patient is euvolaemic with low blood pressure.
• Selection: use in all symptomatic reduced ejection fraction patients without a contraindication, and as the first drug in preserved ejection fraction.

Contraindications. Type 1 diabetes (high ketoacidosis risk), dialysis, history of serious hypersensitivity, and eGFR under the starting limit. Avoid in pregnancy and breastfeeding.

Adverse effects. Genital mycotic infection (more frequent in women), urinary tract infection, volume depletion and postural hypotension, and euglycaemic diabetic ketoacidosis (rare, mainly with insulin deficiency, acute illness, fasting, alcohol excess or surgery). Fournier gangrene is rare. Canagliflozin has an amputation signal.

Ketoacidosis precautions. Stop 3 days before planned surgery (4 days for ertugliflozin) and during acute illness with poor intake. Check blood ketones when unwell with nausea, vomiting, abdominal pain or fast breathing, even when glucose is normal.

Interactions. Loop and thiazide diuretics add volume loss. Insulin and sulphonylureas add hypoglycaemia. Lithium levels may change.

Monitoring. eGFR at 1 to 2 weeks, volume status, blood pressure, genital hygiene and infection symptoms, and ketones when unwell.

Sick day rule. Withhold during vomiting, diarrhoea or dehydrating illness and restart after recovery.

Special groups. Older adults: monitor for volume depletion. Kidney disease: benefit persists to the eGFR limits. Women: counsel on genital hygiene. Type 1 diabetes: do not use.