What is the role of empagliflozin (Empagliflozin) in managing Chronic Kidney Disease (CKD)?

Empagliflozin in Chronic Kidney Disease: Key Findings from EMPA-KIDNEY

Primary Trial Results and Indications

Empagliflozin 10 mg once daily reduces the risk of kidney disease progression or cardiovascular death by 28% in patients with chronic kidney disease, regardless of diabetes status. 1

The EMPA-KIDNEY trial enrolled 6,609 patients with CKD at risk of progression, including those with eGFR 20-44 mL/min/1.73 m² or eGFR 45-89 mL/min/1.73 m² with albuminuria ≥200 mg/g. 1 Over a median follow-up of 2.0 years, the primary composite outcome (sustained ≥40% eGFR decline, end-stage kidney disease, sustained eGFR <10 mL/min/1.73 m², or death from kidney failure) occurred in 13.1% of empagliflozin patients versus 16.9% of placebo patients (HR 0.72,95% CI 0.64-0.82; P<0.0001). 1

Kidney-Specific Benefits

Rate of eGFR Decline

• Empagliflozin slowed chronic eGFR decline by 1.37 mL/min/1.73 m²/year, representing a 50% reduction in the rate of kidney function loss. 1
• After an initial transient decrease in eGFR (expected hemodynamic effect), kidney function stabilized with empagliflozin but continued to decline progressively with placebo. 2
• This protective effect was consistent across all baseline eGFR levels, including patients with eGFR as low as 20 mL/min/1.73 m². 3

Albuminuria Reduction

• Empagliflozin reduced progression to macroalbuminuria by 50% (HR 0.50,95% CI 0.33-0.75) in patients with heart failure. 2
• The American Diabetes Association reports that in EMPA-REG OUTCOME, empagliflozin reduced progression of albuminuria by 27% and reduced the risk of doubling of serum creatinine accompanied by eGFR ≤45 mL/min/1.73 m² by 44%. 4

Cardiovascular Benefits in CKD Population

Empagliflozin reduced cardiovascular death or heart failure hospitalization by 22-28% across the spectrum of kidney function. 3

• In patients with CKD (eGFR <60 mL/min/1.73 m² or albuminuria >300 mg/g), empagliflozin reduced the primary cardiovascular outcome with HR 0.78 (95% CI 0.65-0.93). 3
• In patients without baseline CKD, the benefit was similar with HR 0.72 (95% CI 0.58-0.90), with no heterogeneity between groups (P=0.63). 3
• Total heart failure hospitalizations were reduced consistently regardless of CKD status. 3

Efficacy Across Different Primary Kidney Diseases

The relative benefit of empagliflozin was broadly similar irrespective of the underlying cause of kidney disease. 1

The trial included diverse etiologies:

• Diabetic kidney disease: 31.1% of participants 1
• Glomerular disease: 25.3% 1
• Hypertensive or renovascular disease: 21.9% 1
• Other or unknown causes: 21.8% 1

There was no evidence that the relative effect size varied significantly by primary kidney disease (P for heterogeneity = 0.62). 1 The chronic eGFR slope benefit was similar across all subgroups, including different types of glomerular disease and presence or absence of diabetes (all P values for heterogeneity >0.1). 1

Dosing and Initiation Criteria

Initiate empagliflozin 10 mg once daily in patients with eGFR ≥20 mL/min/1.73 m² who have CKD at risk of progression. 1

• The FDA label indicates empagliflozin is not expected to be effective for glycemic control in severe renal impairment, ESRD, or dialysis patients. 5
• However, for cardiovascular and renal protection (not glycemic control), empagliflozin can be initiated down to eGFR 20 mL/min/1.73 m². 1
• SGLT2 inhibitors are recommended for people with stage 3 CKD or higher and type 2 diabetes, as they slow CKD progression and reduce heart failure risk independent of glucose management. 4

Interaction with Background Medications

Empagliflozin's kidney benefits are maintained regardless of concurrent use of medications that alter intrarenal hemodynamics. 6

• Risk reductions in incident or worsening nephropathy with empagliflozin were consistent across subgroups using ACE inhibitors/ARBs, calcium channel blockers, diuretics, and NSAIDs. 6
• Over 99% of CREDENCE trial patients were on background ACE inhibitor or ARB therapy, demonstrating additive benefit. 4
• Acute renal failure rates were numerically lower with empagliflozin even in patients using ACE inhibitors/ARBs, despite these medications increasing baseline risk. 6

Safety Profile in CKD Population

Empagliflozin was well tolerated across the spectrum of kidney function, with no increase in serious adverse events. 3

• The incidence of kidney-related adverse events was comparable between empagliflozin and placebo groups. 2
• In patients with eGFR below 60 mL/min/1.73 m², cardiovascular death findings were consistent with overall trial results. 5
• The FDA label notes that risks of renal impairment, volume depletion, and urinary tract infections increased with worsening renal function in all groups (including placebo), but this did not negate the overall benefit. 5

Mechanism of Renal Protection

Empagliflozin reduces intraglomerular pressure and oxidative stress through SGLT2 inhibition, providing direct renal protection independent of glycemic effects. 4

• SGLT2 inhibitors reduce renal tubular glucose reabsorption, systemic blood pressure, intraglomerular pressure, and albuminuria through mechanisms independent of glycemia. 4
• Recent data support that SGLT2 inhibitors reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen while reducing NLRP3 inflammasome activity. 4
• The apparent terminal elimination half-life of empagliflozin is 12.4 hours with oral clearance of 10 L/h. 5

Clinical Implications and Recommendations

Empagliflozin should be part of standard care to minimize risk of kidney failure in patients with CKD at risk of progression, regardless of diabetes status or underlying kidney disease etiology. 1

• The American Diabetes Association recommends SGLT2 inhibitors for patients with stage 3 CKD or higher to slow CKD progression and reduce heart failure risk. 4
• The 2022 Diabetes Care guidelines indicate empagliflozin received FDA approval to reduce the risk of major adverse cardiovascular death in adults with type 2 diabetes and cardiovascular disease. 4
• Benefits extend to patients with heart failure across the spectrum of kidney function, with consistent effects in those with eGFR as low as 20 mL/min/1.73 m². 3

Japanese Population Subanalysis

Among 612 Japanese participants in EMPA-KIDNEY, empagliflozin reduced the primary outcome by 51%, with even greater relative benefit than the overall population. 7

• Japanese participants had higher baseline albuminuria and eGFR than non-Japan regions. 7
• Primary outcomes occurred in 33 empagliflozin patients versus 64 placebo patients (HR 0.49,95% CI 0.32-0.75). 7
• Safety outcomes were comparable between Japanese and non-Japanese participants. 7
• The heterogeneity P-value was 0.06, suggesting possible greater benefit in Japanese patients, though this may reflect baseline characteristic differences. 7