Dapagliflozin (Farxiga) in Polycystic Kidney Disease (PKD)
Dapagliflozin is not recommended for the treatment of Polycystic Kidney Disease (PKD) based on current evidence, and may potentially worsen disease progression by increasing kidney volume. 1, 2
Current Evidence on SGLT2 Inhibitors in PKD
- Recent case reports show that dapagliflozin administration in ADPKD patients resulted in increased total kidney volume (TKV) - from 1641 mL to 2297 mL after 340 days in one patient, with concurrent decline in estimated glomerular filtration rate (eGFR) 1
- A retrospective observational study of seven ADPKD patients treated with dapagliflozin found that annual height-corrected total kidney volume increased in all patients 2
- While dapagliflozin may improve eGFR slope in some ADPKD patients when used with renin-angiotensin system (RAS) inhibitors, the kidney volume increase is concerning as increased TKV correlates with disease progression 2, 3
Established Treatments for ADPKD
- Vasopressin V2 receptor antagonists (tolvaptan) are currently the cornerstone of treatment for ADPKD patients at risk of rapid kidney disease progression 3
- Tolvaptan has demonstrated a net difference in eGFR decline of 1.3 ml/min per 1.73 m² per year and reduced total kidney volume growth by 2.7% compared to placebo 3
- ACE inhibitors and ARBs are the first-line treatments for hypertension in ADPKD, with the largest evidence base for efficacy and safety in patients with renal hypertension 3
Potential Mechanisms of Harm in ADPKD
- SGLT2 inhibitors may promote ADPKD disease progression through several mechanisms:
- Increased intratubular urinary osmotic pressure
- Compensatory glucose reabsorption by sodium-glucose cotransporter-1 in the late proximal tubule
- Hypertrophy in collected cells caused by increased vasopressin 1
- Diuretics (including SGLT2 inhibitors) should be used with caution in ADPKD as they may increase vasopressin levels and have deleterious effects on eGFR compared to ACE inhibitors 3
SGLT2 Inhibitors in Other Kidney Diseases
- While dapagliflozin has shown renoprotective effects in chronic kidney disease (CKD) patients with and without diabetes in the DAPA-CKD trial, ADPKD patients were specifically excluded from this study 4, 5
- Dapagliflozin reduced the risk of kidney failure, cardiovascular death, and heart failure hospitalization in CKD patients in the DAPA-CKD trial 5, 6
- SGLT2 inhibitors are recommended for CKD patients to lower the risk of heart failure hospitalization and slow kidney disease progression in non-ADPKD populations 3
Clinical Implications
- For ADPKD patients, the first-line treatments for hypertension and proteinuria remain ACE inhibitors and ARBs 3
- Tolvaptan should be considered for ADPKD patients at risk of rapid progression 3
- Monitoring of proteinuria/albuminuria should be considered standard care for patients with ADPKD, with ACR measurement in a laboratory rather than dipstick testing 3
- Regular monitoring of total kidney volume through imaging is important in ADPKD patients receiving any treatment to assess disease progression 3
Conclusion
Based on the available evidence, dapagliflozin and other SGLT2 inhibitors should not be used in ADPKD patients due to the risk of increased kidney volume and potential disease acceleration. Established treatments like tolvaptan, ACE inhibitors, and ARBs remain the standard of care for ADPKD management.