SGLT2 inhibitors in polycystic kidney disease (PKD): current evidence and future perspectives

Abstract

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary nephropathy and an important cause of chronic kidney failure worldwide. Beyond tolvaptan, the only disease-modifying drug currently available, new therapies are urgently needed. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated consistent renoprotective effects across diverse chronic kidney disease (CKD) populations, but ADPKD patients were excluded from pivotal trials.
Methods: We reviewed the rationale, preclinical data, early clinical evidence, and ongoing randomized trials
of SGLT2i in ADPKD. Particular attention was given to their potential synergism with tolvaptan and their unique
protective role against nephrolithiasis, a common complication in ADPKD. Other metabolic interventions (metformin, 2-deoxy-D-glucose, mTOR inhibitors) were also examined to underline the relevance of glucose metabolism as a therapeutic target.
Results and conclusion: SGLT2i combine robust renoprotective mechanisms, a favorable safety profile, and the
potential to reduce nephrolithiasis. For the first time, dedicated randomized trials (EMPA-PKD, DAPA-PKD, STOPPKD) are ongoing, and their findings may define a new era of combination therapy in ADPKD.