What are the current evidence‑based indications, recommended doses, common pitfalls, adverse effects, contraindications, and criteria for stopping or restarting sodium‑glucose co‑transporter‑2 (SGLT2) inhibitors?

Evidence-Based Indications for SGLT2 Inhibitors

SGLT2 inhibitors are strongly recommended for all adults with chronic kidney disease (CKD) and eGFR ≥20 mL/min/1.73 m², regardless of diabetes status, with the strongest evidence supporting use in high-risk patients with significant albuminuria or heart failure. 1

Primary Indications

Chronic Kidney Disease (All Patients)

• Strong recommendation (1A): Adults with CKD and eGFR ≥20 mL/min/1.73 m² with urine albumin-to-creatinine ratio (ACR) ≥200 mg/g (≥20 mg/mmol) 1
• Strong recommendation (1A): Adults with CKD and heart failure, irrespective of albuminuria level 1
• Weak recommendation (2B): Adults with eGFR 20-45 mL/min/1.73 m² and ACR <200 mg/g 1
• Weak recommendation: Adults at low to moderate risk of CKD progression 1

Type 2 Diabetes with CKD

• Strong recommendation (1A): All patients with type 2 diabetes, CKD, and eGFR ≥20 mL/min/1.73 m² 1
• Initiate regardless of current glycemic control or HbA1c level 2, 3
• Benefits include reduced all-cause mortality (48 fewer deaths per 1000 patients), kidney failure (58 fewer per 1000), cardiovascular mortality, heart failure hospitalization, myocardial infarction, and stroke 1

Heart Failure

• Recommended for heart failure with reduced ejection fraction (HFrEF) to reduce hospitalization, major adverse cardiovascular events (MACE), and cardiovascular death 1, 4
• Evidence supports use in heart failure with preserved ejection fraction (HFpEF) 5

Specific Agents and Dosing

Approved SGLT2 Inhibitors

The three agents with documented kidney and cardiovascular benefits are: canagliflozin, dapagliflozin, and empagliflozin 1, 3

Dosing by eGFR

eGFR ≥45 mL/min/1.73 m²:

• Empagliflozin: 10 mg once daily, may increase to 25 mg 6
• Dapagliflozin: 10 mg once daily 3
• Canagliflozin: Standard dosing 3

eGFR 20-44 mL/min/1.73 m²:

• Empagliflozin: 10 mg once daily (no titration required for cardiorenal protection) 2
• Dapagliflozin: 10 mg once daily 3
• Canagliflozin: Can initiate down to eGFR 30 mL/min/1.73 m² 3
• Do NOT initiate if eGFR <20 mL/min/1.73 m² 1, 7

eGFR <20 mL/min/1.73 m² (if already on therapy):

• Continue SGLT2 inhibitor until dialysis initiation unless not tolerated 1, 2
• Do not initiate new therapy at this level 1, 7

Administration

• Take once daily in the morning, with or without food 6
• Glucose-lowering effects are minimal below eGFR 45 mL/min/1.73 m², but cardiorenal benefits persist 3, 7

Common Pitfalls and How to Avoid Them

Pitfall 1: Discontinuing for Initial eGFR Decline

• Expected: 3-5 mL/min/1.73 m² reversible decline in first 4 weeks 1, 7
• Action: Recheck eGFR within 1-2 weeks after initiation, then every 3-6 months 2
• Do NOT discontinue unless >30% drop with signs of hypovolemia 7
• This initial decline is hemodynamic and central to long-term renal benefits 5

Pitfall 2: Waiting for "Optimal" Glycemic Control

• Correct approach: Initiate SGLT2 inhibitor immediately as foundational therapy for cardiorenal protection, independent of HbA1c level 2, 3
• The indication is organ protection, not glucose lowering 7

Pitfall 3: Withholding ACE Inhibitors/ARBs

• Correct approach: Continue maximum tolerated dose of ACE inhibitor or ARB when starting SGLT2 inhibitor 7
• All major kidney outcome trials tested SGLT2 inhibitors on background RAS inhibition 1
• The combination provides additive renoprotection 7

Pitfall 4: Stopping When eGFR Falls Below 45 mL/min/1.73 m²

• Correct approach: Continue therapy even when glycemic efficacy is lost 2
• Cardiovascular and renal protective benefits persist at lower eGFR 2, 3

Adverse Effects and Management

Common Adverse Effects (≥5% incidence)

• Genital mycotic infections: Most common, usually mild-moderate, easily treated with topical antifungals 6, 8
• Urinary tract infections: Monitor and treat promptly if symptomatic 6, 8
• Provide hygienic counseling to prevent infections 1

Serious Adverse Effects (Rare but Important)

Euglycemic Diabetic Ketoacidosis (DKA):

• Risk increases during acute illness, surgery, or prolonged fasting 1, 2
• Educate patients on "sick day rules" 1, 2
• Maintain at least low-dose insulin in insulin-requiring patients even when SGLT2 inhibitor is held 2

Volume Depletion/Hypotension:

• Assess volume status before initiation, especially in elderly, those on diuretics, or with low systolic blood pressure 6
• Consider reducing thiazide or loop diuretic dose before starting SGLT2 inhibitor 1
• Monitor for symptoms of volume depletion after initiation 6

Acute Kidney Injury:

• Consider temporarily discontinuing during acute illness with reduced oral intake or fluid losses 6
• Recent evidence shows decreased incidence of acute kidney injury with SGLT2 inhibitors compared to placebo 8

Hypoglycemia:

• Reduce insulin or insulin secretagogue doses when initiating SGLT2 inhibitor 1, 6
• Risk primarily when combined with these agents 8

Other Reported Adverse Effects:

• Increased LDL-C: Monitor and treat as appropriate 6
• Amputation risk: Primarily observed with canagliflozin; avoid in patients with active foot ulcers or high amputation risk 1, 8
• Fractures: Observed with canagliflozin but not other agents 8

Contraindications

Absolute Contraindications

• History of serious hypersensitivity reaction to empagliflozin or any excipients 6
• Severe renal impairment (eGFR <20 mL/min/1.73 m² for initiation) 1, 7, 6
• End-stage renal disease or dialysis (for initiation) 6

Relative Contraindications/Special Caution

• Kidney transplant recipients: Not adequately studied due to immunosuppression and infection risk 1, 7
• Active foot ulcers or high amputation risk: Use only after careful shared decision-making with comprehensive foot care education 1
• Type 1 diabetes: Not indicated for treatment 6

When to Withhold, Alter, or Stop

Temporary Withholding (Sick Day Rules)

Withhold during:

• Acute illness with fever, vomiting, diarrhea, or reduced oral intake 2
• Prolonged fasting 1
• Surgery or critical medical illness (when at greater risk for ketosis) 1
• Day of day-stay procedures; withhold at least 2 days before procedures requiring ≥1 day hospitalization or bowel preparation 1

Restart when:

• Patient is eating and drinking normally 1
• Clinically well with blood ketones <1.0 mmol/L 1

Permanent Discontinuation

Stop if:

• Serious hypersensitivity reaction occurs 6
• Intolerable adverse effects despite management 1
• Kidney replacement therapy (dialysis) is initiated 1, 2
• Symptomatic hypotension unresponsive to volume management 1
• Uncontrolled hyperkalemia despite medical treatment (when considering combination with other agents) 1

Do NOT stop for:

• Initial eGFR decline of 3-5 mL/min/1.73 m² 1, 7
• eGFR falling below 45 mL/min/1.73 m² if already on therapy 2, 3
• Achievement of glycemic targets (continue for organ protection) 2, 3

Dose Adjustment

• No dose adjustment needed based on eGFR decline if already initiated 1, 2
• For empagliflozin specifically: Do not initiate if eGFR <45 mL/min/1.73 m² per FDA label, but newer guidelines support initiation down to eGFR 20 mL/min/1.73 m² 6 vs 1
• Metformin dose should be reduced to 1000 mg daily if eGFR 30-44 mL/min/1.73 m² when used in combination 1

Monitoring Algorithm

Before Initiation:

• Measure eGFR and urine ACR 1
• Assess volume status, especially if on diuretics 1
• Review current glucose-lowering medications for hypoglycemia risk 1

1-2 Weeks After Initiation:

• Recheck eGFR to assess expected transient decline 2
• Assess for volume depletion symptoms 1

Ongoing Monitoring:

• eGFR and urine ACR every 3-6 months 2
• Blood glucose monitoring if on insulin or secretagogues 1
• Assess for genital mycotic infections and urinary symptoms 6
• Monitor LDL-C and treat as appropriate 6