What is the recommended starting dose and treatment approach for patients who may benefit from Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

SGLT2 Inhibitor Starting Dose and Treatment Approach

For patients with type 2 diabetes and chronic kidney disease (eGFR ≥25 mL/min/1.73 m²), start with dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily, prioritizing agents with documented cardiovascular and renal benefits regardless of whether additional glycemic control is needed. 1

Patient Selection and Indications

SGLT2 inhibitors should be initiated in the following populations:

• All patients with type 2 diabetes and eGFR ≥30 mL/min/1.73 m² (KDIGO 2020 strong recommendation) 1
• Patients with eGFR <60 mL/min/1.73 m² without albuminuria 1
• Patients with albuminuria ≥200 mg/g regardless of eGFR (down to 25 mL/min/1.73 m²) 1
• Patients with heart failure or established cardiovascular disease 2, 3

The 2022 KDIGO guidelines recommend SGLT2 inhibitors for all patients with eGFR >20 mL/min/1.73 m² independent of albuminuria presence, which is broader than the 2022 ADA guidance that requires either eGFR <60 or significant albuminuria. 1

Specific Agent Selection and Dosing

For Glycemic Control

• Dapagliflozin: Start 5 mg once daily, may increase to 10 mg daily if additional glycemic control needed and eGFR ≥45 mL/min/1.73 m² 2, 3
• Empagliflozin: Start 10 mg once daily, may increase to 25 mg daily for additional glycemic control 4
• Canagliflozin: Start 100 mg once daily before first meal, may increase to 300 mg daily if eGFR ≥60 mL/min/1.73 m² and additional control needed 5

For Cardiovascular/Renal Protection (Non-Glycemic Indications)

Use fixed doses without titration: 2, 3

• Dapagliflozin 10 mg once daily (preferred for eGFR 25-44 mL/min/1.73 m²) 6, 2
• Empagliflozin 10 mg once daily (not recommended for initiation if eGFR <45 mL/min/1.73 m²) 4
• Canagliflozin 100 mg once daily 5

Prioritize agents with documented kidney and cardiovascular benefits - specifically dapagliflozin, empagliflozin, and canagliflozin have the strongest evidence base. 1

Renal Function-Based Dosing Algorithm

eGFR ≥60 mL/min/1.73 m²

• Any SGLT2 inhibitor at standard doses 1, 2
• Full dose titration permitted for glycemic control 2, 3

eGFR 45-59 mL/min/1.73 m²

• Continue empagliflozin 25 mg if already established 6
• Dapagliflozin 10 mg daily (no adjustment needed) 2, 3
• Canagliflozin: use 100 mg daily only 5

eGFR 25-44 mL/min/1.73 m²

• Switch from empagliflozin to dapagliflozin 10 mg daily for continued cardiovascular and renal protection 6
• Dapagliflozin 10 mg daily is the preferred agent in this range 6, 2
• Do not initiate empagliflozin in this range 4
• Canagliflozin may be used at 100 mg daily 5

eGFR <25 mL/min/1.73 m²

• Do not initiate any SGLT2 inhibitor 2, 3
• Continue dapagliflozin 10 mg if already established unless not tolerated or dialysis initiated 1, 2
• Discontinue empagliflozin 4

Pre-Initiation Assessment and Adjustments

Volume Status Assessment (Critical)

Before starting any SGLT2 inhibitor: 1, 2

• Assess and correct volume depletion first 3, 4
• Reduce thiazide or loop diuretic doses in patients at risk for hypovolemia 1, 2
• Use particular caution in elderly patients, those with low systolic blood pressure, and patients on diuretics 2, 3, 4

Concomitant Medication Adjustments

If patient is on insulin or sulfonylureas and meeting glycemic targets: 1

• Reduce insulin dose by approximately 20% to prevent hypoglycemia 6, 2
• Consider stopping or reducing sulfonylurea dose 1
• Metformin can be continued without adjustment 1

Monitoring After Initiation

Expected eGFR Changes

• Expect a transient eGFR decline of 3-5 mL/min/1.73 m² in the first 1-4 weeks - this is reversible and associated with better long-term renal outcomes 6
• This initial decline is NOT an indication to discontinue therapy 1
• Monitor eGFR within 1-2 weeks after initiation 6

Ongoing Monitoring

• Monitor volume status and blood pressure after initiation 1, 2
• Continue SGLT2 inhibitor even if eGFR falls below 30 mL/min/1.73 m² during treatment (for dapagliflozin) unless not tolerated 1, 2
• Discontinue empagliflozin if eGFR falls persistently below 45 mL/min/1.73 m² 4

Critical Safety Precautions

Withhold SGLT2 Inhibitors During:

• At least 3 days before major surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis 6, 2, 3, 5
• Prolonged fasting periods 1
• Critical medical illness when patients are at greater risk for ketosis 1

Common Adverse Effects to Counsel Patients About:

• Genital mycotic infections (most common, particularly in women: 11-14% vs 2% with comparators) 3, 7, 8
• Urinary tract infections (6% incidence) 3, 8
• Volume depletion symptoms 2, 3
• Osmotic diuresis-related events (polyuria, pollakiuria) 8

Rare but Serious Adverse Effects:

• Euglycemic diabetic ketoacidosis - assess for ketoacidosis regardless of blood glucose level if metabolic acidosis symptoms present 3, 4, 7
• Fournier's gangrene (necrotizing fasciitis of the perineum) - assess patients with genital/perineal pain, tenderness, erythema, swelling with fever 3

Special Populations

Kidney Transplant Recipients

• SGLT2 inhibitors are NOT recommended due to insufficient data and increased infection risk with immunosuppression 1

Patients with Polycystic Kidney Disease

• Not recommended - SGLT2 inhibitors are not expected to be effective in this population 3

Patients Requiring Immunosuppression for Kidney Disease

• Not recommended - insufficient evidence of benefit 3

Combination Therapy Approach

The preferred treatment sequence is: 1

• Start with metformin (if eGFR permits) AND SGLT2 inhibitor together as first-line therapy 1
• If additional glycemic control needed, add a long-acting GLP-1 RA with proven cardiovascular benefits (dulaglutide, liraglutide, or semaglutide) 1
• SGLT2 inhibitors can be used with or without metformin for patients with cardiovascular disease, heart failure, or kidney disease 1