Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial
In a randomized phase 2 crossover trial of nondiabetic adults with calcium or uric acid kidney stones, the SGLT2 inhibitor empagliflozin significantly reduced relevant urinary supersaturation ratios, signaling a potential new stone-prevention strategy.
Background
Whether SGLT2 inhibitors prevent kidney stones in nondiabetic patients was previously unknown, despite registry signals suggesting lower urolithiasis rates among users. Urinary relative supersaturation ratios (RSRs) for calcium oxalate, calcium phosphate, and uric acid are validated surrogates for stone recurrence and served as the trial's outcome measures.
Study design
This double-blind, placebo-controlled, single-center crossover phase 2 trial randomized 53 nondiabetic adults (28 with calcium stones, 25 with uric acid stones, all with at least one prior stone event) to once-daily empagliflozin 25 mg followed by placebo or the reverse order, with 2 weeks per treatment period. Randomization and analysis were performed separately for each stone type, with primary analyses in the per-protocol set. The prespecified target was at least a 15% reduction in RSR.
Key findings
Prespecified RSR reductions were met in both stone-former groups. In calcium-stone formers, empagliflozin reduced the calcium phosphate RSR (relative difference versus placebo -36%; 95% CI -48% to -21%; P < 0.001) but not the calcium oxalate or uric acid RSRs. In uric acid-stone formers, it reduced the uric acid RSR (-30%; 95% CI -44% to -12%; P = 0.002) but not the calcium oxalate or calcium phosphate RSRs. No serious or prespecified adverse events occurred (ClinicalTrials.gov NCT04911660).
Clinical implications
Empagliflozin substantially lowered the stone-type-relevant urinary supersaturation ratios in nondiabetic adults with calcium and uric acid stones, supporting SGLT2 inhibition as a promising candidate for kidney-stone prevention. Because the trial used validated surrogate endpoints rather than clinical stone recurrence over a short 2-week treatment period, larger and longer trials with hard clinical outcomes are needed before routine use.
Category
Research
Source
Nature Medicine
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