Glucose-lowering med shows promise for treating kidney stones in nondiabetics

Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin helps improve the urinary lithogenic risk profile of nondiabetic patients with calcium and uric acid stones, as shown in the results of the randomized crossover SWEETSTONE trial.

In patients with calcium stones, empagliflozin yielded a significant reduction in the relative supersaturation ratio of calcium phosphate compared with placebo (relative difference, –36 percent, 95 percent confidence interval [CI], –48 to –21; p<0.001). However, no significant effect was observed for relative supersaturation ratios of calcium oxalate and uric acid. [ERA 2025, abstract 119]

In patients with uric acid stones, empagliflozin resulted in a significant reduction in the relative supersaturation ratio of uric acid (relative difference, –30 percent, 95 percent CI, –44 to –12; p=0.002) but not in those of calcium oxalate and calcium phosphate when compared with placebo.

“This is quite interesting and also relevant, because [calcium phosphate and uric acid] are the most relevant factors for stones in these [respective] patients,” said lead study author Dr Manuel Anderegg from the Bern University Hospital in Bern, Switzerland.

24-h urine parameters

Looking at 24-h urine parameters, Anderegg pointed out that the reduction in the relative supersaturation ratio of calcium phosphate in patients with calcium stones was mediated by a 60-percent increase in urinary citrate excretion (median, 4.9 vs 3.2 mmol per 24 h) and a 4-percent decrease in urine pH (median, 5.6 vs 5.8) with empagliflozin vs placebo.

Net gastrointestinal alkali absorption was higher with empagliflozin vs placebo (median, 49.9 vs 38.1 mEq/24 h; difference, 24 percent), as was net acid excretion (median, 70.7 vs 62.1 mEq/24 h; difference, 26 percent).

In patients with uric acid stones, on the other hand, the reduction in the relative supersaturation ratio of uric acid was mediated by a 40-percent increase in urinary citrate (median, 4.2 vs 3.7 mmol per 24 h) and a 3-percent increase in urine pH (median, 5.6 vs 5.3) with empagliflozin vs placebo, according to Anderegg.

But unlike in calcium-stone formers, net acid excretion was lower with empagliflozin vs placebo (median, 64.8 vs 63.4 mEq/24 h; difference, –9 percent) in uric acid-stone formers. Anderegg explained that this might be due to changes in proximal tubular metabolism of this patient subgroup.

Outcome trial in the works

Overall, the findings suggest that SGLT2 inhibitors are a promising potential treatment option for patients with calcium and uric acid stones, Anderegg said. This is especially important for calcium stone-formers, who have limited available treatment options, he added.

However, he acknowledged that the SGLT2 inhibitors’ efficacy for kidney stone prevention remains uncertain. To address it, an outcome trial, the EMPASTONE, is being planned. Anderegg shared that EMPASTONE will be a multicentre, multinational European trial focusing on patients with recurrent calcium kidney stones and will employ a two-by-two factorial design.

The current single-centre SWEETSTONE study included 53 adult patients (mean age 50.9 years, 75 percent male, mean body index 28.4 kg/m²) with kidney stones who had no diabetes, of which 28 had calcium stones and 25 had uric acid stones. These patients received treatment with empagliflozin 25 mg and placebo for 2 weeks each, in a randomized sequence, with a 2-week washout period in between.