What is the latest effect of Empagliflozin (Empagliflozin) on chronic kidney disease (CKD) in patients with type 2 diabetes?

Latest Effect of Empagliflozin on Chronic Kidney Disease

Empagliflozin reduces the risk of kidney disease progression or cardiovascular death by 28% in patients with chronic kidney disease, with consistent benefits across the full spectrum of kidney function down to eGFR 20 mL/min/1.73 m², regardless of diabetes status. 1, 2

Primary Renal Protection Benefits

The EMPA-KIDNEY trial, the most recent and definitive study, demonstrated that empagliflozin provides substantial renal protection in patients with CKD 1:

• 24% reduction in major renal events, including sustained eGFR decline >50%, progression to dialysis, transplantation, or renal/cardiovascular death 2
• 44% reduction in doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73 m² 3
• 27% reduction in progression of albuminuria 3
• Slows the rate of eGFR decline by preventing the typical annual decline seen with placebo 4

Approximately one-half of the 6,609 participants in EMPA-KIDNEY had diabetes, demonstrating that the renal protective effects extend beyond glycemic control mechanisms 1.

Cardiovascular Benefits in CKD Patients

Beyond renal protection, empagliflozin provides significant cardiovascular benefits in patients with CKD 1, 2:

• 28% reduction in cardiovascular death or kidney disease progression (HR 0.72 [95% CI 0.64-0.82]; P<0.001) 1
• 31% reduction in cardiovascular death or heart failure hospitalization in advanced CKD populations 1
• 20% reduction in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke 1

These cardiovascular benefits were consistent in patients with prevalent kidney disease at baseline, including those with eGFR <60 mL/min/1.73 m² 5.

Mechanisms of Renal Protection

Empagliflozin protects kidneys through multiple mechanisms that are independent of glycemic control 2, 3:

• Restores tubuloglomerular feedback and reduces intraglomerular pressure by increasing afferent arteriolar tone 1, 4
• Reduces oxidative stress in the kidney by >50% 3
• Decreases systemic blood pressure and albuminuria 2, 3
• Reduces NLRP3 inflammasome activity 2, 3
• Blunts increases in angiotensinogen 3

The hemodynamic effects, particularly the reduction in intraglomerular pressure, contribute to long-term preservation of kidney function 4.

Clinical Application Algorithm by eGFR

For eGFR ≥45 mL/min/1.73 m²:

• Initiate empagliflozin 10 mg once daily for both renal/cardiovascular protection and glycemic control (if diabetic) 2
• No dose adjustment needed based on renal function 2

For eGFR 20-44 mL/min/1.73 m²:

• Initiate empagliflozin 10 mg once daily for renal/cardiovascular protection only 2
• Glucose-lowering efficacy is significantly reduced in this range, but cardiovascular and renal benefits are fully preserved 2, 6

For eGFR <20 mL/min/1.73 m²:

• Empagliflozin is not expected to be effective and should not be initiated 6
• Contraindicated in patients with ESRD or receiving dialysis 6

Expected eGFR Changes and Monitoring

An initial transient decrease in eGFR occurs within the first 4 weeks of treatment 4:

• Adjusted mean slope decreases by -0.77 mL/min per 1.73 m² per week during treatment initiation (weeks 0-4) 4
• Annual mean slope stabilizes at 0.23 mL/min per 1.73 m² per year during chronic maintenance treatment (after week 4), compared to -1.46 mL/min per 1.73 m² per year with placebo 4
• After drug cessation, eGFR returns toward baseline level, confirming the hemodynamic nature of the initial decline 4

Check eGFR and creatinine within 1-2 weeks after initiation to assess the expected transient decrease 2.

Consistency Across Background Medications

The renal benefits of empagliflozin are consistent regardless of common background medications that alter intrarenal hemodynamics 7:

• ACE inhibitors/ARBs: Risk reductions maintained without increasing acute renal adverse events 7
• Calcium channel blockers: No heterogeneity of treatment effect 7
• Diuretics: Benefits preserved, though volume status should be assessed before initiation 7
• NSAIDs: Renal protection consistent across subgroups 7

Over 99% of participants in the CREDENCE trial were on background ACE inhibitor or ARB therapy, demonstrating that empagliflozin provides additive renal protection 1.

Critical Safety Precautions

Volume depletion risk:

• Assess volume status before starting empagliflozin 2
• Monitor for signs of volume depletion in the first few weeks, particularly in elderly patients or those on diuretics 2

During acute illness:

• Stop empagliflozin during acute illness with reduced food/fluid intake, fever, vomiting, or diarrhea 2
• Maintain at least low-dose insulin in insulin-requiring patients even when empagliflozin is held 2

Euglycemic diabetic ketoacidosis:

• Risk exists particularly in insulin-requiring patients 2
• Educate patients to recognize symptoms even with normal blood glucose levels 2

Genital mycotic infections:

• Daily hygienic measures recommended to reduce risk 2
• More common in patients taking SGLT2 inhibitors 2

Dosing and Administration

The recommended dose is empagliflozin 10 mg once daily in the morning 2:

• No titration required 2
• No dose adjustment needed based on renal function at initiation (as long as eGFR ≥20 mL/min/1.73 m²) 2
• May be administered with or without food 6

Guideline Recommendations

The American Diabetes Association provides Class A, Level 1 recommendations for empagliflozin in patients with type 2 diabetes and CKD 1, 2. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines support the use of empagliflozin for renal and cardiovascular protection in patients with eGFR ≥20 mL/min/1.73 m², regardless of diabetes status 2.