Empagliflozin

Empagliflozin reduces blood glucose by inhibiting glucose reabsorption in the kidney, causing it to be excreted in the urine. The same renal action drives natriuretic, haemodynamic, and metabolic effects that produce cardiovascular and renal protection independent of glycaemic control.

Mechanism of Action

• SGLT2 inhibition in the proximal tubule: under normal conditions, approximately 90% of filtered glucose is reabsorbed by SGLT2 on the apical membrane of proximal tubular cells, with Na⁺/K⁺-ATPase on the basolateral side maintaining the sodium gradient that powers transport. Empagliflozin blocks this co-transport, producing marked glucosuria and natriuresis.
• Glycaemic effect: glucose excretion equivalent to ~60–80 g/day (≈240–320 kcal/day), translating to HbA1c reductions of approximately 0.6–0.8%, weight loss of 2–3 kg, and modest blood pressure reduction.
• Cardiovascular benefits (mechanism not fully resolved): proposed contributors include reduced preload via osmotic diuresis and natriuresis, decreased afterload via blood pressure reduction, improved myocardial energetics (shift toward ketone bodies as an efficient cardiac fuel), inhibition of cardiac and renal Na⁺/H⁺ exchangers (NHE1 myocardial, NHE3 tubular), suppression of pro-fibrotic and pro-inflammatory pathways, and reduction in epicardial fat. The benefits are observed in patients without diabetes, confirming non-glycaemic mechanisms.
• Renal protection: restores tubuloglomerular feedback by delivering sodium to the macula densa, reducing intraglomerular pressure and hyperfiltration — analogous to RAAS inhibition but additive.

Pharmacokinetics

• Absorption: peak plasma concentration in approximately 1.5 hours. Food does not clinically affect absorption.
• Volume of distribution: 73.8 L apparent steady-state.
• Protein binding: 86.2%.
• Metabolism: minimal; primarily glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9 to three inactive glucuronide metabolites. No metabolite exceeds 10% of total drug-related material. Negligible CYP involvement.
• Half-life: approximately 12.4 hours, supporting once-daily dosing.
• Excretion: approximately 54% urine, 41% faeces; about half of urinary and most of faecal excretion as unchanged drug.
• Clearance: apparent oral clearance approximately 10.6 L/h.

• Type 2 diabetes mellitus in adults and children ≥10 years, as adjunct to diet and exercise — monotherapy or in combination with other antidiabetic agents including insulin.
• Cardiovascular risk reduction in adults with type 2 diabetes and established cardiovascular disease: reduction in cardiovascular mortality.
• Heart failure (HFrEF and HFpEF) in adults — first SGLT2 inhibitor approved across the full ejection fraction range — to reduce cardiovascular mortality and heart failure hospitalisation, regardless of diabetes status.
• Chronic kidney disease in adults at risk of progression — reduction in sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalisation, regardless of diabetes status.

• Hypersensitivity to empagliflozin or any of the excipients.
• Severe renal impairment with eGFR persistently below thresholds set in current labelling for the relevant indication (refer to current SmPC for indication-specific cut-offs).
• Type 1 diabetes mellitus (off-label, not approved; substantially elevates DKA risk).
• Diabetic ketoacidosis.

Very common (≥1/10): hypoglycaemia (when combined with insulin or sulphonylureas); volume depletion.

Common (≥1/100 to <1/10): urinary tract infection (including pyelonephritis and urosepsis), genital mycotic infection (vulvovaginitis, balanitis, vaginal moniliasis), thirst, increased urination, serum lipids increased (mild LDL-C elevation), pruritus (generalised), rash.

Uncommon (≥1/1,000 to <1/100): constipation, urticaria, angioedema, dysuria, blood creatinine increased / glomerular filtration rate decreased, haematocrit increased.

Rare (<1/1,000): diabetic ketoacidosis (including euglycaemic DKA — clinically critical to recognise), necrotising fasciitis of the perineum (Fournier’s gangrene — very rare but life-threatening), tubulo-interstitial nephritis.

• Insulin and insulin secretagogues (sulphonylureas, meglitinides): increased risk of hypoglycaemia — dose reduction of the partner agent often required.
• Diuretics (especially loop diuretics): additive volume depletion and risk of hypotension; consider reducing diuretic dose at initiation.
• ACE inhibitors / ARBs: additive eGFR dip at initiation — typically transient and not a reason to discontinue either agent.
• Lithium: increased urinary lithium excretion may decrease lithium levels; monitor.
• Glucuronidation enzyme inducers (e.g., rifampicin): may modestly reduce empagliflozin exposure; clinical impact generally not requiring dose change.

Tablets are taken once daily, with or without food, at the same time each day. Swallow whole with water.

Type 2 Diabetes

• Starting dose: 10 mg once daily.
• Maintenance: may be increased to 25 mg once daily if additional glycaemic control is needed and the medicine is tolerated.

Heart Failure or Chronic Kidney Disease

• Dose: 10 mg once daily (irrespective of diabetes status). The 25 mg dose has not demonstrated additional benefit in these indications.

Renal Impairment

Refer to current product labelling for indication-specific eGFR thresholds. Initiation is generally not recommended below specific eGFR cut-offs that differ between diabetes, heart failure, and CKD indications.

Hepatic Impairment

No dose adjustment in mild to moderate impairment. Use cautiously in severe impairment (limited data).

Missed Dose

Take as soon as remembered on the same day. If close to the next scheduled dose, skip the missed dose; do not double up.

Diabetic Ketoacidosis (including Euglycaemic DKA)

SGLT2 inhibitors can cause DKA at glucose levels that are normal or only modestly elevated, masking the diagnosis. Patients should be educated on warning signs (nausea, vomiting, abdominal pain, malaise, rapid breathing, sweet/fruity breath) and instructed to seek immediate care. Withhold empagliflozin during major surgery, prolonged fasting, severe acute illness, or extreme low-carbohydrate intake.

Fournier’s Gangrene

A rare but severe necrotising fasciitis of the perineum has been reported. Seek immediate surgical evaluation for pain, tenderness, swelling, or erythema in the genital or perineal region accompanied by fever or malaise.

Volume Status and Hypotension

Assess volume status before initiation, particularly in the elderly, those on diuretics, and patients with low systolic blood pressure. Correct dehydration before starting.

Genitourinary Infections

Counsel on hygiene; treat infections as standard. Recurrent genital mycotic infections may require partner treatment and lifestyle counselling.

Surgery and Acute Illness

Withhold empagliflozin at least 3 days before scheduled major surgery (longer intervals for higher-risk procedures) and during acute illnesses associated with reduced oral intake or volume depletion. Restart only after the patient is clinically stable and eating normally.

Pregnancy and Lactation

• Pregnancy: not recommended; switch to insulin-based regimens.
• Breastfeeding: not recommended — animal data suggest excretion in milk and potential effects on the developing kidney.

Elderly

No specific dose adjustment for age alone, but caution due to higher risk of volume depletion. Renal function declines with age — reassess regularly.

Paediatric

Approved from age 10 for type 2 diabetes; paediatric dosing follows specialist guidance.

Effect on Driving

Empagliflozin has no or negligible influence on the ability to drive and use machines. Patients should be cautioned about hypoglycaemia symptoms when combined with insulin or sulphonylureas.

This medicinal product does not require any special storage conditions. Keep in the original packaging.

Typically 3 years for the film-coated tablets. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).