What is the dose and mechanism of action of SGLT2 (Sodium-Glucose Linked Transporter 2) receptor antagonists, including canagliflozin (Canagliflozin), dapagliflozin (Dapagliflozin), empagliflozin (Empagliflozin), and ertugliflozin (Ertugliflozin)?

SGLT2 Inhibitor Dosages and Mechanism of Action

SGLT2 inhibitors work by blocking renal glucose reabsorption in the proximal tubule, reducing the renal glucose threshold and promoting urinary glucose excretion, which lowers blood glucose levels without increasing the risk of hypoglycemia when used alone. 1

Mechanism of Action

SGLT2 inhibitors function through an insulin-independent mechanism by:

• Inhibiting the sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules
• Blocking reabsorption of filtered glucose from urine
• Reducing the renal glucose threshold
• Promoting urinary glucose excretion (50-90g of glucose daily) 2
• Increasing sodium delivery to the distal tubule, which increases tubuloglomerular feedback and reduces intraglomerular pressure 3

This mechanism results in:

• HbA1c reduction of approximately 0.5-1.0%
• Weight reduction of 1.5-3.5 kg
• Systolic blood pressure reduction of 3-5 mmHg 4

Available SGLT2 Inhibitors and Dosages

1. Canagliflozin (Invokana)

• Dosage: 100 mg PO daily; may increase to 300 mg daily if needed in patients with eGFR ≥60 mL/min/1.73 m² 4, 3
• Renal Adjustments:
  • eGFR ≥60 mL/min/1.73 m²: No dose adjustment required
  • eGFR 45-59 mL/min/1.73 m²: Do not exceed 100 mg/day
  • eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control 4, 3

2. Empagliflozin (Jardiance)

• Dosage: 10 mg PO daily; may increase to 25 mg PO daily 4
• Renal Adjustments:
  • eGFR ≥45 mL/min/1.73 m²: No dose adjustment required
  • eGFR <45 mL/min/1.73 m²: Do not initiate; discontinue if eGFR persistently falls below 45 mL/min/1.73 m² 4

3. Dapagliflozin (Farxiga)

• Dosage: 5-10 mg PO daily 1
• Renal Adjustments:
  • Should be used with caution in patients with renal insufficiency (GFR <45 mL/min/1.73 m²) 1

4. Ertugliflozin (Steglatro)

• Dosage: 5 mg PO daily; may increase to 15 mg PO daily 5
• Renal Adjustments:
  • No dosage adjustment needed in patients with eGFR ≥45 mL/min/1.73 m²
  • Not recommended for use in patients with eGFR <30 mL/min/1.73 m² 5

Clinical Benefits Beyond Glycemic Control

SGLT2 inhibitors provide significant benefits beyond glucose control:

• Reduce risk of major cardiovascular adverse events
• Reduce risk of renal events
• Lower hospitalization rates for heart failure 4, 1
• Cardiovascular benefits appear to be present down to eGFR of 30 mL/min/1.73 m² 4

Important Safety Considerations

• Common adverse effects: Genitourinary tract infections 4, 1

• Rare but serious adverse effects:

  • Euglycemic ketoacidosis
  • Acute kidney injury
  • Bone fracture
  • Toe amputation (canagliflozin) 4, 6

• SGLT2 inhibitors do not increase the risk of hypoglycemia when used alone 4

• Should be used with caution in patients with renal insufficiency 1

• May need to be discontinued during acute illness or surgical procedures to prevent ketoacidosis 6

Comparative Efficacy

In indirect comparisons for HbA1c reduction:

• Ertugliflozin 5 mg was more effective than dapagliflozin 5 mg when added to metformin
• Ertugliflozin 15 mg was more effective than dapagliflozin 10 mg and empagliflozin 25 mg when added to diet/exercise and metformin monotherapy
• No significant differences were found between ertugliflozin and canagliflozin across all populations 7

SGLT2 inhibitors represent a valuable addition to diabetes management with their unique insulin-independent mechanism of action and additional cardiovascular and renal benefits.