Role of Empagliflozin (Jardiance) in CKD Patients
For Patients with eGFR 45-90 mL/min/1.73 m² and ACR >22.6 mg/g
Empagliflozin 10 mg once daily should be initiated in these patients for cardiovascular and renal protection, regardless of diabetes status, as it reduces kidney disease progression by 39% and cardiovascular death or heart failure hospitalization by 29%. 1, 2
Evidence-Based Rationale
The 2024 American Diabetes Association guidelines provide a Class I, Level A recommendation for SGLT2 inhibitors in patients with CKD and eGFR ≥20 mL/min/1.73 m², emphasizing that these agents slow CKD progression and reduce heart failure risk independent of glucose management. 1
The EMPA-KIDNEY trial demonstrated that empagliflozin reduced the primary composite outcome (kidney disease progression or cardiovascular death) by 28% (HR 0.72,95% CI 0.64-0.82) in patients with eGFR 45-90 mL/min/1.73 m² and albuminuria ≥200 mg/g. 2
For patients with ACR >22.6 mg/g (which converts to approximately 20-30 mg/g), empagliflozin provides significant renoprotection even at this lower level of albuminuria, though the strongest evidence exists for ACR ≥200 mg/g. 1, 2
Dosing and Initiation Algorithm
Start empagliflozin 10 mg once daily in the morning, with or without food—this is the standard dose for cardiovascular and renal protection. 3
No dose adjustment is needed for eGFR ≥45 mL/min/1.73 m², and the dose may be increased to 25 mg if additional glycemic control is required in patients with diabetes. 3
Assess volume status before initiation and correct any volume depletion, particularly in elderly patients (≥75 years) or those on concurrent diuretics. 3
Cardiovascular and Renal Benefits
Empagliflozin reduces the risk of incident or worsening nephropathy by 39%, including progression to macroalbuminuria, doubling of serum creatinine, ESKD, or renal death. 1
The medication reduces the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73 m² by 44%. 1
Empagliflozin slows the annual eGFR decline by approximately 1-2 mL/min/1.73 m²/year compared to placebo, representing long-term preservation of kidney function. 4, 5
Hospitalization from any cause is reduced by 14% (HR 0.86,95% CI 0.78-0.95). 2
For Patients with eGFR 20-45 mL/min/1.73 m²
Empagliflozin 10 mg once daily should be initiated for cardiovascular and renal protection in patients with eGFR 20-45 mL/min/1.73 m², but NOT for glycemic control, as glucose-lowering efficacy is minimal at this level of kidney function. 1, 2
Critical FDA Labeling Consideration vs. Clinical Trial Evidence
Important discrepancy exists: The current FDA label states that empagliflozin should not be initiated if eGFR <45 mL/min/1.73 m² and should be discontinued if eGFR falls persistently below 45 mL/min/1.73 m². 3
However, the EMPA-KIDNEY trial (2023) specifically enrolled patients with eGFR 20-45 mL/min/1.73 m² and demonstrated significant benefit, with 432 vs. 558 primary outcomes (HR 0.72,95% CI 0.64-0.82, P<0.001). 2
The 2024 American Diabetes Association guidelines now recommend SGLT2 inhibitors for patients with eGFR ≥20 mL/min/1.73 m², representing an evolution beyond the FDA label based on newer evidence. 1
Evidence-Based Rationale for eGFR 20-45 mL/min/1.73 m²
The EMPA-KIDNEY trial enrolled 6,609 patients, with a substantial proportion having eGFR 20-45 mL/min/1.73 m², and demonstrated consistent benefit across the entire eGFR spectrum down to 20 mL/min/1.73 m². 2
Empagliflozin reduced the composite kidney outcome (sustained profound decline in eGFR, chronic dialysis, or transplant) by 47% (HR 0.53,95% CI 0.31-0.91) in patients with baseline CKD. 4
The EMPEROR-Reduced trial showed that empagliflozin slowed eGFR decline by 1.11 mL/min/1.73 m²/year in patients with CKD, with benefits extending to patients with eGFR as low as 20 mL/min/1.73 m². 4
Japanese subgroup analysis from EMPA-KIDNEY confirmed consistent effects, with 33 vs. 64 primary outcomes (HR 0.49,95% CI 0.32-0.75) in patients from Japan. 6
Dosing Algorithm for eGFR 20-45 mL/min/1.73 m²
Initiate empagliflozin 10 mg once daily for cardiovascular and renal protection—this is a fixed dose with no titration required. 2, 4
Do not use empagliflozin for glycemic control at this eGFR level, as glucose-lowering efficacy is significantly reduced due to the mechanism of action (reduced filtered glucose load). 3
If eGFR falls below 20 mL/min/1.73 m² during treatment, empagliflozin may be continued until dialysis is initiated, though initiation is not recommended below 20 mL/min/1.73 m². 1
Monitoring and Safety Considerations
Expect an initial eGFR dip of 3-5 mL/min/1.73 m² within the first 4 weeks, which is hemodynamic, reversible, and actually predicts better long-term renal outcomes. 5
Recheck eGFR within 1-2 weeks after initiation to assess for the expected transient decline, then monitor every 3-6 months. 1
Assess volume status carefully before initiation, as patients with eGFR 20-45 mL/min/1.73 m² are at higher risk for volume depletion, particularly if elderly (≥75 years) or on concurrent diuretics. 3
Consider reducing loop diuretic doses by 50% in patients on high-dose diuretics to prevent symptomatic hypotension when initiating empagliflozin. 1
Critical Safety Precautions
Withhold empagliflozin during acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake, to prevent euglycemic diabetic ketoacidosis and volume depletion. 1
Educate patients to stop empagliflozin immediately when sick and contact their healthcare provider, as the risk of ketoacidosis increases during intercurrent illness. 1
Monitor for genital mycotic infections (occur in approximately 6% of patients vs. 1% on placebo) and urinary tract infections, which are more common in elderly patients (15.7% in those ≥75 years). 3
Maintain at least low-dose insulin in insulin-requiring patients even when empagliflozin is held during illness, as complete insulin cessation increases DKA risk. 1
Common Pitfalls to Avoid
Do not discontinue empagliflozin solely because eGFR falls below 45 mL/min/1.73 m²—the cardiovascular and renal protective benefits persist even when glycemic efficacy is lost. 1, 4
Do not withhold ACE inhibitors/ARBs when starting empagliflozin, as the combination provides additive renoprotection, though use clinical judgment if simultaneously up-titrating both agents. 1
Do not reduce empagliflozin dose to 5 mg for renal protection—the 10 mg dose is the evidence-based dose for cardiovascular and renal outcomes across all eGFR levels. 2, 4
Do not delay initiation waiting for "optimal" glycemic control—empagliflozin should be initiated early as foundational therapy for cardiorenal protection, independent of HbA1c level. 1