RCT: Empagliflozin Lowers Urinary Supersaturation in Nondiabetic Adults With Calcium and Uric Acid Kidney Stones
15 Jan, 2025 | 12:03h | UTCBackground: Kidney stones represent a major health challenge worldwide, with calcium-based (calcium oxalate or phosphate) and uric acid (UA) stones accounting for most cases. Despite multiple preventive measures—including hydration, dietary modification, and, in certain cases, pharmacotherapy—recurrence rates remain high. Recent retrospective analyses suggest sodium-glucose cotransporter 2 (SGLT2) inhibitors may reduce stone episodes in patients with type 2 diabetes. These agents could theoretically lower stone risk by promoting urinary citrate excretion, altering urine pH, and enhancing UA clearance. However, prospective data are lacking in nondiabetic individuals. This phase 2, single-center, double-blind, placebo-controlled, crossover study (SWEETSTONE) explored whether empagliflozin (25 mg daily) modifies urinary relative supersaturation ratios (RSRs)—a validated surrogate of stone risk—in adults without diabetes who have a history of either calcium or UA stones.
Objective: To determine if empagliflozin significantly reduces RSRs for calcium oxalate (CaOx), calcium phosphate (CaP), and UA in nondiabetic adults with recurrent kidney stones and to assess short-term safety.
Methods: A total of 53 participants (28 calcium stone formers, 25 UA stone formers) were randomized to empagliflozin 25 mg once daily or placebo for two weeks, followed by a 2–6-week washout, then crossed over to the alternative treatment. Primary outcomes were changes in RSR CaOx, RSR CaP, and RSR UA. Secondary measures included 24-hour urine pH, citrate, calcium, and UA, as well as key blood parameters. Analyses were performed separately for calcium and UA stone groups using a generalized linear mixed effects model. The per protocol set was used for the main analysis, with additional intention-to-treat assessments for confirmation.
Results: In calcium stone formers, empagliflozin lowered RSR CaP by 36% (95% CI −48% to −21%; p<0.001) compared with placebo but did not significantly change RSR CaOx. Uric acid supersaturation rose modestly, yet nonsignificantly. Among UA stone formers, empagliflozin reduced RSR UA by 30% (95% CI −44% to −12%; p=0.002), with no significant effect on RSR CaOx or RSR CaP. Both groups showed substantial increases in 24-hour urine citrate (60% for calcium stones, 40% for UA stones) and marked reductions in plasma UA levels. Urine calcium rose in some calcium stone formers, but no severe adverse events were reported during the study.
Conclusions: Short-term treatment with empagliflozin produced meaningful decreases in key urinary supersaturation indices among nondiabetic adults with calcium or UA stones, while exhibiting an acceptable safety profile. These favorable laboratory changes offer mechanistic promise but do not establish definitive evidence that long-term stone recurrence is reduced.
Implications for Practice: Although the pronounced improvement in urinary lithogenic profiles is encouraging, it remains unclear whether these shifts will translate into sustained reductions in actual stone formation. Consequently, clinicians should be cautious about recommending off-label SGLT2 inhibition for stone prevention solely on the basis of these short-term biochemical improvements. Larger, longer-duration trials with clinical endpoints (i.e., stone recurrence) are warranted before SGLT2 inhibitors can be broadly endorsed for this indication. In addition, practical considerations—such as cost, insurance coverage, and potential off-target effects—must be weighed in individualized clinical decisions.
Study Strengths and Limitations: Strengths include the randomized crossover design and distinct analyses for calcium and UA stone phenotypes. Nevertheless, the sample size was modest, and the treatment duration too brief to capture definitive impacts on stone recurrence. The predominance of white male participants also limits generalizability to more diverse populations.
Future Research: Extended follow-up is crucial to determine the long-term clinical effectiveness of empagliflozin in preventing stone events. Future work should also explore potential mechanisms in larger cohorts, assess cost-effectiveness in real-world settings, and evaluate whether other SGLT2 inhibitors elicit comparable effects.
Reference: Anderegg MA, Schietzel S, Bargagli M, et al. Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial. Nature Medicine (2025). DOI: https://doi.org/10.1038/s41591-024-03330-x