Empagliflozin for Chronic Kidney Disease
Recommended Dosing Strategy
Initiate empagliflozin 10 mg once daily in the morning for patients with CKD and eGFR ≥20 mL/min/1.73 m², regardless of diabetes status, to reduce cardiovascular death and kidney disease progression. 1, 2
Dosing by eGFR Level
eGFR ≥45 mL/min/1.73 m²: Start empagliflozin 10 mg once daily; may increase to 25 mg daily if additional glycemic control is needed in diabetic patients 3, 4
eGFR 20-44 mL/min/1.73 m²: Initiate empagliflozin 10 mg once daily for cardiovascular and renal protection; glucose-lowering efficacy is significantly reduced in this range, but cardiorenal benefits remain robust 1, 2
eGFR <20 mL/min/1.73 m²: Do not initiate empagliflozin; the drug is not expected to be effective in this population 4
Critical Distinction from Older FDA Guidance
The 2018 FDA label states not to initiate empagliflozin if eGFR <45 mL/min/1.73 m² 4, but this guidance is outdated. The landmark EMPA-KIDNEY trial (2023) demonstrated a 28% reduction in kidney disease progression or cardiovascular death in patients with eGFR as low as 20 mL/min/1.73 m² 1, 2. KDIGO and other major guideline societies now recommend initiation at eGFR ≥20 mL/min/1.73 m² 1.
Evidence Supporting Renal and Cardiovascular Protection
EMPA-KIDNEY Trial Results (2023)
The most recent and highest-quality evidence comes from EMPA-KIDNEY, which enrolled 6,609 patients with CKD (with or without diabetes) 2:
Primary outcome: 28% reduction in kidney disease progression or cardiovascular death (HR 0.72; 95% CI 0.64-0.82; P<0.001) 2
Kidney-specific benefits: 44% reduction in doubling of serum creatinine, 55% reduction in need for renal replacement therapy 5
Hospitalization: 14% reduction in all-cause hospitalization (HR 0.86; 95% CI 0.78-0.95; P=0.003) 2
Consistency: Benefits were present regardless of diabetes status and across all eGFR ranges studied 2
Mechanism of Renal Protection
Empagliflozin protects kidneys through multiple pathways independent of glucose lowering 1:
- Restores tubuloglomerular feedback, reducing intraglomerular pressure 6
- Decreases systemic blood pressure and albuminuria 1
- Reduces oxidative stress and NLRP3 inflammasome activity 1
The initial eGFR dip of 3-5 mL/min/1.73 m² within the first 4 weeks is hemodynamic, reversible, and actually predicts better long-term renal outcomes 6.
Monitoring Requirements
Initial Assessment
- Check eGFR and creatinine before initiation 1, 4
- Assess volume status, particularly in elderly patients or those on diuretics 1, 7
- Correct volume depletion if present before starting 1
Follow-Up Monitoring
- Recheck eGFR and creatinine within 1-2 weeks after initiation to assess the expected transient decrease 1
- Monitor eGFR at least annually if ≥60 mL/min/1.73 m², or every 3-6 months if 45-59 mL/min/1.73 m² 7
- Do not discontinue empagliflozin if eGFR falls below 45 mL/min/1.73 m² during treatment, as cardiovascular and renal protective benefits persist even when glycemic efficacy is lost 1, 7
Critical Safety Precautions
Sick Day Management
Temporarily discontinue empagliflozin during any acute illness with reduced food/fluid intake, fever, vomiting, or diarrhea 1:
- Risk of euglycemic diabetic ketoacidosis (DKA), which can occur even with normal blood glucose levels 1
- Maintain at least low-dose insulin in insulin-requiring patients even when empagliflozin is held 1
- Resume empagliflozin only after recovery and normal oral intake is re-established 1
Volume Depletion Risk
- Higher risk in elderly patients, those on concurrent diuretics, or with low systolic blood pressure 1
- Consider reducing diuretic doses when initiating empagliflozin 1
- Monitor for signs of intravascular volume contraction in the first few weeks 1
Genital Mycotic Infections
- Occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo 1, 7
- Daily hygienic measures may reduce risk 1
- Monitor and treat appropriately if infections occur 4
Hypoglycemia Prevention
- If patient is on insulin with well-controlled HbA1c, reduce total daily insulin dose by approximately 20% when initiating empagliflozin 7
- Consider weaning or stopping sulfonylureas or glinides to prevent hypoglycemia 7
Common Pitfalls to Avoid
Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m² during treatment, as the cardiovascular and renal protective benefits remain even when glucose-lowering efficacy is reduced 1, 7. This is a critical distinction from the older FDA guidance that was based on glycemic efficacy rather than cardiorenal outcomes 4.
Do not withhold empagliflozin for at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis 1.
Do not ignore the initial eGFR dip of 3-5 mL/min/1.73 m² in the first 4 weeks—this is expected, hemodynamic, and reversible 6. However, if eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering empagliflozin adjustment 1.