How can SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors be used to protect the kidney?

SGLT2 Inhibitors for Kidney Protection

For patients with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors should be initiated to protect kidney function and reduce cardiovascular events, with treatment recommended down to an eGFR of 20 mL/min/1.73 m², regardless of albuminuria level or baseline glucose control needs. 1

Primary Mechanism of Kidney Protection

SGLT2 inhibitors protect kidneys through multiple complementary mechanisms beyond glucose lowering:

• Hemodynamic effects: These agents increase sodium delivery to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption, which increases tubuloglomerular feedback and reduces intraglomerular pressure 2, 3
• Reduced hyperfiltration: By lowering glomerular capillary hypertension, SGLT2 inhibitors decrease physical stress on the filtration barrier and reduce albuminuria 3
• Improved oxygenation: Reduced oxygen demand for tubular reabsorption improves cortical oxygenation, which helps preserve tubular function and glomerular filtration rate long-term 3

Evidence-Based Kidney Outcomes

The kidney protective effects are established by multiple landmark trials:

• CREDENCE trial (canagliflozin): Demonstrated a 30% reduction in the primary composite renal outcome (end-stage kidney disease, doubling of serum creatinine, or renal/cardiovascular death) in patients with eGFR 30-90 mL/min/1.73 m² and albuminuria >300 mg/g 1, 4
• DAPA-CKD trial (dapagliflozin): Showed a 39% reduction in kidney failure risk (HR 0.61) in CKD patients with mean eGFR 43 mL/min/1.73 m² and median albuminuria 949 mg/g, with benefits seen in both diabetic (67.5%) and non-diabetic patients 1
• EMPA-KIDNEY trial (empagliflozin): Demonstrated 24% lower risk of major kidney disease events in patients with eGFR as low as 20 mL/min/1.73 m² 1

Specific Indications and Initiation Criteria

Start SGLT2 inhibitors in the following populations:

• Type 2 diabetes with any degree of CKD: Use when eGFR ≥20 mL/min/1.73 m², regardless of albuminuria level 1
• Diabetic kidney disease with albuminuria: Particularly beneficial when UACR ≥300 mg/g, but effective even with normal urinary albumin 1
• CKD with cardiovascular disease: SGLT2 inhibitors reduce cardiovascular death or heart failure hospitalization by 31% in advanced CKD 1
• Combination therapy: Use alongside ACE inhibitors or ARBs (>99% of CREDENCE patients were on background RAAS blockade) 1

Agent-Specific Considerations

Different SGLT2 inhibitors have varying approval thresholds:

• Canagliflozin: FDA-approved to initiate down to eGFR 30 mL/min/1.73 m² 1
• Empagliflozin and dapagliflozin: Can be started with eGFR >20 mL/min/1.73 m² based on recent trial data 1
• Glucose-lowering effects: These are blunted below eGFR 45 mL/min/1.73 m², but kidney and cardiovascular benefits persist down to eGFR 20 mL/min/1.73 m² 1

Critical Safety Considerations and Contraindications

Temporarily discontinue SGLT2 inhibitors during:

• Critical illness or surgery: Hold during acute medical illness when patients are at greater risk for ketosis 5
• Steroid therapy: The combination of steroid-induced fluid retention and SGLT2i-induced volume contraction creates unpredictable hemodynamic effects; hold during steroid therapy and for 2-3 days after discontinuation 5
• Prolonged fasting or intercurrent illness: Implement "STOP DKA" protocol (Stop SGLT2 inhibitor, Test for ketones, maintain fluid/carbohydrate intake) during nausea, vomiting, or diarrhea 6
• Elective procedures: Discontinue 3 days before surgery (4 days for ertugliflozin) 6

Monitor for specific adverse events:

• Euglycemic ketoacidosis: Can occur even without significant hyperglycemia; monitor for nausea, vomiting, abdominal pain, and dyspnea 6
• Volume depletion: Due to osmotic diuresis, particularly in patients on diuretics 7
• Genital mycotic infections: More common than urinary tract infections 8, 7
• Hyperkalemia risk: When combined with ACE inhibitors/ARBs, though SGLT2 inhibitors may actually reduce this risk 1

Practical Implementation Algorithm

Step 1: Screen all type 2 diabetes patients for CKD by measuring serum creatinine (calculate eGFR) and urine albumin-to-creatinine ratio 1

Step 2: If eGFR ≥20 mL/min/1.73 m², initiate SGLT2 inhibitor regardless of current glucose control or albuminuria level 1

Step 3: Continue SGLT2 inhibitor even as eGFR declines below the glucose-lowering threshold (45 mL/min/1.73 m²) for ongoing kidney and cardiovascular protection 1

Step 4: Educate patients on sick day rules: stop medication during acute illness, maintain hydration, and seek medical attention for ketoacidosis symptoms 6

Step 5: Resume SGLT2 inhibitor after resolution of acute illness, surgery, or steroid therapy, maintaining at least low-dose insulin in insulin-requiring patients to prevent ketoacidosis recurrence 5, 6

Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m²—kidney and cardiovascular benefits persist independent of glucose lowering 1
• Do not combine ACE inhibitors with ARBs alongside SGLT2 inhibitors, as this increases adverse events without additional benefit 1
• Do not delay initiation waiting for worsening kidney function—earlier treatment provides greater cumulative benefit 1, 7
• Do not avoid in patients with normal albuminuria—DECLARE-TIMI 58 demonstrated effectiveness even with normal urinary albumin levels 1