Is Farxiga (dapagliflozin) nephrotoxic?

Is Farxiga (Dapagliflozin) Nephrotoxic?

Farxiga (dapagliflozin) is not nephrotoxic but rather nephroprotective, demonstrating significant benefits in reducing kidney disease progression and providing renal protection in patients with chronic kidney disease. 1, 2

Mechanism of Action and Renal Effects

Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor that works by:

• Inhibiting SGLT2 in the proximal renal tubules, reducing glucose reabsorption and promoting urinary glucose excretion 2
• Reducing sodium reabsorption and increasing sodium delivery to the distal tubule 2
• Decreasing intraglomerular pressure through tubuloglomerular feedback mechanisms 2

These mechanisms contribute to its renoprotective effects rather than causing nephrotoxicity.

Evidence of Renoprotective Effects

DAPA-CKD Trial Results

The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial provided strong evidence of dapagliflozin's renoprotective effects:

• Primary composite outcome (≥50% sustained decline in eGFR, ESKD, or CV/renal death) was reduced by 39% (HR 0.61 [95% CI 0.51-0.72]; p<0.001) 1, 2
• Renal composite outcome (sustained decline in eGFR ≥50%, ESKD, or death from renal causes) was reduced by 44% (HR 0.56 [95% CI 0.45-0.68]; p<0.001) 1, 2
• Benefits were observed regardless of diabetes status (67.5% of participants had type 2 diabetes) 1
• Benefits were maintained across different eGFR ranges (25-75 mL/min/1.73 m²) 2

Other Supporting Evidence

• CREDENCE trial showed canagliflozin (another SGLT2 inhibitor) reduced the risk of ESKD, doubling of serum creatinine, or renal death by 30% 1
• EMPA-KIDNEY trial demonstrated empagliflozin reduced the risk of kidney disease progression 1
• KDIGO 2022 guidelines recommend SGLT2 inhibitors for patients with T2D and CKD to reduce CKD progression 1

Initial eGFR Changes and Long-term Effects

An important clinical consideration is that dapagliflozin may cause:

• Small, transient reductions in eGFR initially (within first week of treatment) 3
• Return to near baseline values by 24 weeks 3
• Stable eGFR over long-term follow-up (up to 102 weeks) 3

This initial dip in eGFR is hemodynamic in nature and does not represent nephrotoxicity.

Recommendations for Use in Renal Impairment

• Can be initiated when eGFR ≥20 mL/min/1.73 m² 1
• Should be continued as long as tolerated, even if eGFR falls below 20 mL/min/1.73 m², until kidney replacement therapy is initiated 1
• Glucose-lowering effect is minimal at eGFR <45 mL/min/1.73 m², but cardiovascular and kidney benefits persist 1
• Contraindicated in patients on dialysis 1

Safety Considerations

While not nephrotoxic, certain safety considerations should be kept in mind:

• Risk of volume depletion: Monitor volume status and blood pressure, particularly in patients who are ill or fasting 1
• Diabetic ketoacidosis (DKA): Rare but serious risk, especially in insulin-deficient patients 1
• Genital mycotic infections: Most common adverse effect, particularly in women 1
• Urinary tract infections: More common than with placebo 2

Conclusion

Farxiga (dapagliflozin) is not nephrotoxic. On the contrary, it has demonstrated significant renoprotective effects in multiple large clinical trials, reducing the risk of kidney disease progression and kidney failure. The initial, transient decrease in eGFR observed with treatment initiation represents a hemodynamic effect that is part of its mechanism of action rather than nephrotoxicity.