Kidney Compass: Testing SGLT2 Inhibition in Rapidly Progressing ADPKD

Welcome back to Kidney Compass!

Recording from ASN Kidney Week 2026 in Denver, Colorado, cohosts Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, welcomed Stephen Seliger, MD, of the University of Maryland School of Medicine, and Michel Chonchol, MD, of the University of Colorado Anschutz Medical Campus. The investigators discussed their pilot randomized trial of empagliflozin in autosomal dominant polycystic kidney disease (ADPKD), published simultaneously in the Journal of the American Society of Nephrology.¹

Results showed the drug was safe and well tolerated, but an unexpected increase in kidney volume raised new questions for SGLT2 inhibitor research in this population.

Why Test Empagliflozin in Rapidly Progressing ADPKD?

Seliger noted tolvaptan remains the only FDA-approved therapy to slow ADPKD progression in the US, but aquaretic adverse effects and a risk of liver injury limit its use. Chonchol added patients with ADPKD were excluded from the landmark SGLT2 inhibitor trials, leaving a gap the team set out to address.¹

Seliger explained risk in ADPKD is typically stratified by imaging using the Mayo classification, with classes 1C through 1E identifying rapid progressors. He clarified the FDA considers total kidney volume a likely surrogate end point, acceptable for accelerated approval only when accompanied by longer-term evidence of slower kidney function decline.

The investigators randomly assigned 50 adults aged 18 to 55 years with ADPKD at high risk of rapid progression, defined as Mayo imaging class 1C to 1E, to empagliflozin or placebo for 12 months.¹ Participants had an eGFR of 30 to 90 mL/min/1.73 m² and were not receiving tolvaptan. Seliger said concurrent tolvaptan was excluded because of concern about volume depletion.

Empagliflozin was started at 10 mg daily and increased to 25 mg after 1 month if tolerated.¹ The co-primary end points were safety and tolerability, with tolerability defined as taking the full dose at 12 months and reporting the ability to tolerate it lifelong. Chonchol explained the age cap was chosen to enrich for rapid progressors.

Did Empagliflozin Increase Kidney Volume in ADPKD?

All participants completed follow-up, and 96% in each group tolerated the full study drug dose at 12 months.¹ Adverse events were similar between groups, with 2 urinary tract infections and 1 genital infection in the empagliflozin group and 1 acute kidney injury event in the placebo group.

“The empagliflozin at 25 milligrams was very well tolerated,” Seliger said.

For the exploratory endpoints, height-adjusted total kidney volume increased by 10.5% per year with empagliflozin compared with 5.1% per year with placebo (P = .001).¹ Empagliflozin produced the expected acute eGFR dip of 6.2 mL/min/1.73 m² at 1 month, but the chronic eGFR slope did not differ between groups, nor did aortic pulse wave velocity, copeptin, urinary KIM-1, or patient-reported outcomes.

Participants receiving empagliflozin were modestly more likely to be Mayo class 1E (32% vs 20%), though adjustment for imaging class did not materially change the kidney volume findings.

“At this point, it really does remain uncertain whether our finding of greater cyst enlargement and kidney volume enlargement over time is a true biologic finding or a chance finding,” Seliger said.

He noted some preclinical models suggest SGLT2 inhibitors can promote cyst growth, and future trials should weigh the possible safety signal. Although increased vasopressin release has been proposed as a mechanism, copeptin levels did not rise in the trial.¹ The team is now analyzing biomarkers of glucose metabolism and advanced imaging features of cyst growth.

Chonchol noted the 2025 KDIGO ADPKD guideline does not recommend SGLT2 inhibitors to slow disease progression.² He pointed to a German trial of 44 patients, including 10 receiving tolvaptan, expected to report in March, and a planned French trial of more than 400 patients. Neuen added the RENAL LIFECYCLE trial of dapagliflozin in advanced CKD permitted enrollment of patients with ADPKD.

Editors’ note: Disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Disclosures for Seliger include Estuary, Vertex, Astra Zeneca, and Novartis. Disclosures for Chonchol include Estuary, Calico, Lonestar, and GindolaBIo.

References

1. Seliger SL, Gitomer B, You Z, et al. Empagliflozin therapy in autosomal dominant polycystic kidney disease: a feasibility randomized controlled trial. J Am Soc Nephrol. Published online October 24, 2026. doi:10.1681/ASN.0000001271

2. Torres VE, Ahn C, Barten TRM, et al. KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary. Kidney Int. 2025;107(2):234-254. doi:10.1016/j.kint.2024.07.010