SGLT2 Inhibitors
Mechanism of action
- Highly selective, reversible inhibition of the SGLT‑2 exchanger in the S1‑segment of the proximal renal tubule → ↓ ≈ 90 % of filtered glucose re‑absorption → glucosuria, osmotic diuresis, modest natriuresis.
- Glucose lowering is insulin‑independent, so efficacy is preserved across the spectrum of β‑cell function, and hypoglycaemia is rare unless combined with insulin or sulfonylurea.
- provide triple benefit – glycaemic control, heart‑failure risk reduction, and reno‑protection – with a tolerable safety profile.
- Cardiorenal outcome data showed benefits independent of glucose lowering and extend to people without diabetes in HF and CKD trials (DAPA‑HF (2019), MPEROR‑Reduced (2020))
Transient drop in renal function
- SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) are associated with a transient drop in renal function (as measured by eGFR) shortly after initiation — but this is expected, usually mild, and reversible.
- eTG (2024) and KDIGO (2022) recommend:
- Continue if initial eGFR ≥ 30 mL/min/1.73m² (some agents like empagliflozin and dapagliflozin are now approved down to 20 mL/min/1.73m² depending on indication).
- Do not repeat eGFR immediately unless symptomatic or risk factors for AKI (e.g., diuretics, NSAIDs, hypotension).
- Temporary withholding during acute illness, volume depletion, or perioperative period is prudent.
- eTG (2024) and KDIGO (2022) recommend:
2. Glycaemic efficacy
| Outcome | Typical effect (monotherapy or add‑on) | Notes |
|---|---|---|
| HbA1c | ↓ 0.5 – 1.0 % (5–11 mmol/mol) | Attenuates as eGFR falls <45 mL/min/1.73 m² |
| Weight | ↓ 1.8 – 3 kg | Predominantly fat mass |
| SBP | ↓ 3–5 mm Hg | Via osmotic diuresis/natriuresis |
Adverse‑effect profile & monitoring
| Common | How to mitigate |
|---|---|
| Genital mycotic infection (3–13 %) – Candida albicans | Counsel on hygiene treat promptly consider prophylaxis if recurrent |
| UTI (1–13 %) | Usually mild rule‑out urosepsis if systemically unwell |
| Volume depletion / symptomatic hypotension | Pause diuretics on initiation in frail or eGFR <45 monitor BP/renal function 1‑2 weeks after starting |
| Euglycaemic ketoacidosis (rare, <0.1 %) | Hold drug – peri‑operatively – during prolonged fasting or acute illness educate patients on “Sick‑day rules” |
| Fournier gangrene (very rare) | Instruct to seek urgent care for perineal pain/swelling |
No signal for ↑ fractures or amputations with dapagliflozin/empagliflozin; canagliflozin is not PBS‑listed.
current guidelines:
| Indication | Drugs Eligible | Initiation Criteria | Exclusion / Stop Criteria | Notes |
|---|---|---|---|---|
| T2DM – Add-on therapy | Dapagliflozin Empagliflozin Ertugliflozin (± combinations) | – Must be used with at least one of: – Metformin – Sulfonylurea or – Insulin AND – Inadequate response: HbA1c > 7% after ≥3 months of therapy OR capillary BGL > 10 mmol/L in > 20 % of readings over 2 weeks. (if HbA1c unsuitable) | → No concomitant PBS-subsidised GLP-1 receptor agonist or another SGLT2 inhibitor. | – Must retain evidence (HbA1c or BGL profile) – Use BGL profile if HbA1c invalid (e.g. haemoglobinopathies, recent transfusion) mmol/L in > 20 % of readings over 2 weeks. Exclusion rule → No concomitant PBS-subsidised GLP-1 receptor agonist or another SGLT2 inhibitor. |
| T2DM – Initial combination (Met + SGLT2i) | Dapagliflozin Empagliflozin | – Must be prescribed with metformin AND at least one of: • Established CVD • 5-year CV risk ≥10% • ATSI ≥25y | → No concomitant PBS-subsidised GLP-1 receptor agonist or another SGLT2 inhibitor. | – Metformin intolerance/contraindication acceptable |
| Heart Failure (HFrEF, NYHA II–IV, LVEF ≤40%) | Dapagliflozin Empagliflozin | – On guideline-directed therapy (ACEi/ARB/ARNI + β-blocker ± MRA) Unless contraindicated | – N/A | – No diabetes required – Based on DAPA-HF & EMPEROR-Reduced |
| Chronic Kidney Disease (CKD) | Dapagliflozin Empagliflozin 1 | Both required: • eGFR 25–75 mL/min/1.73 m² • uACR 22.6–565 mg/mmol (200–5000 mg/g) • Stable RAAS blockade (unless contraindicated) | – eGFR <25 or uACR <22.6 or >565 – Not stable on RAAS therapy (unless contraindicated) | – No diabetes required – Based on DAPA-CKD & EMPA-KIDNEY trials |
- Concurrent GLP‑1 RA + SGLT2i in T2DM is not subsidised unless each agent is prescribed for a different PBS‑listed indication (e.g., SGLT2i for HFrEF, GLP‑1 RA for T2DM).
- Not subsidised as monotherapy for glycaemic control.
- in CKD
- Initiation: Treatment should be initiated only if both eGFR and uACR criteria are met.Kidney Medicine
- Estimated Glomerular Filtration Rate (eGFR): Between 25–75 mL/min/1.73 m²
- Urine Albumin-to-Creatinine Ratio (uACR): Between 22.6–565 mg/mmol (equivalent to 200–5000 mg/g)
- Renin-Angiotensin System (RAS) Blockade: Patients should be stabilized on a maximally tolerated dose of an ACE inhibitor or ARB for at least four weeks, unless contraindicated
- Continuation: If a patient’s eGFR falls below 25 mL/min/1.73 m² after initiation, continuation of therapy may be appropriate based on clinical judgment.
- Monitoring: An initial dip in eGFR may occur after starting therapy; this is typically transient and should not prompt discontinuation unless clinically indicated.
- Contraindications: Use is not recommended in patients undergoing dialysis or those with conditions such as polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
- Initiation: Treatment should be initiated only if both eGFR and uACR criteria are met.Kidney Medicine
Dapagliflozin (Forxiga) PBS stremline codes:
| ✅ 1. Type 2 Diabetes Mellitus (T2DM) PBS Streamlined Authority Codes: 16220, 15311, 16164, 15265 a. Criteria for cardiovascular risk (Codes: 16220, 16164) – Must be used in combination with metformin (unless contraindicated). – AND one of the following applies: > Patient has established CVD. > Patient is at high CVD risk (≥10% 5-year risk using www.cvdcheck.org.au). > Patient identifies as Aboriginal or Torres Strait Islander. – Cannot be used with a GLP-1 receptor agonist or another SGLT2 inhibitor. b. Criteria for inadequate glycaemic control (Codes: 15311, 15265) – Must be used with metformin, sulfonylurea, or insulin. – Condition must be inadequately controlled, defined as: > HbA1c >7% despite therapy, or > If HbA1c inappropriate: >20% of BGLs >10 mmol/L over 2 weeks. – Must not be on another GLP-1 RA or SGLT2 inhibitor. – Document HbA1c or BGL records in clinical file. |
| ✅ 2. Chronic Kidney Disease (CKD) PBS Streamlined Authority Code: 13230 Criteria: Diagnosed CKD with: – eGFR 25–75 mL/min/1.73 m², – uACR 22.6–565 mg/mmol (200–5000 mg/g), – Abnormal kidney structure/function present ≥3 months. Must be stabilised for ≥4 weeks on: – ACE inhibitor or ARB, unless contraindicated. – Must not be on dialysis or post-transplant. Excluded conditions: – Polycystic kidney disease, – Lupus nephritis or ANCA vasculitis, – Cytotoxic/immunosuppressive therapy, – Kidney transplant recipients. – Cannot be used with another SGLT2 inhibitor. |
| ✅ 3. Chronic Heart Failure (CHF) PBS Streamlined Authority Codes: 15047 & 15051 (HFrEF ≤40%) 14471 (HFpEF >40%) a. Heart failure with reduced EF (HFrEF): – NYHA Class II–IV symptoms. – LVEF ≤40%. – On optimal therapy including: – – – Beta-blocker, and – – – ACEi / ARB / ARNi (unless intolerant). – – – Not used with another SGLT2 inhibitor. b. Heart failure with preserved EF (HFpEF): – NYHA Class II–IV. – LVEF >40% with structural heart changes. – PLUS ≥1 of the following: – – – Diastolic dysfunction with high filling pressures, – – – Hospitalisation for HF in last 12 months, – – – IV diuretics in past 12 months, – – – Elevated NT-proBNP (no alternate cause). – No concurrent use of another SGLT2 inhibitor. |