Dr Priyadarshini Balasubramanian

Patients with type 2 diabetes who received empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, were almost 40% less likely to have a kidney stone than patients who received placebo during a median 1.5 years of treatment.

These findings are from an analysis of pooled data from phase 1-4 clinical trials of empagliflozin for blood glucose control in 15,081 patients with type 2 diabetes.  

Priyadarshini Balasubramanian, MD, presented the study as a poster at ENDO 2022: The Endocrine Society Annual Meeting, which was also published online in the Journal of Clinical Endocrinology & Metabolism.

The researchers acknowledge this was a retrospective, post-hoc analysis and that urolithiasis — a stone in the urinary tract, which includes nephrolithiasis, a kidney stone — was an adverse event, not a primary or secondary outcome.

Also, the stone composition, which might help explain how the drug may affect stone formation, is unknown.

Therefore, “dedicated randomized prospective clinical trials are needed to confirm these initial observations in patients both with and without type 2 diabetes,” said Balasubramanian, a clinical fellow in the section of endocrinology & metabolism, department of internal medicine, Yale School of Medicine in New Haven, Connecticut.

However, “if this association is proven, empagliflozin may be used to decrease the risk of kidney stones at least in those with type 2 diabetes, but maybe also in those without diabetes,” Balasubramanian told Medscape Medical News.

Further trials are also needed to determine if this is a class effect, which is likely, she speculated, and to unravel the potential mechanism.

This is important because of the prevalence of kidney stones, which affect up to 15% of the general population and 15% to 20% of patients with diabetes, she explained.

“Provocative” Earlier Findings

The current study was prompted by a recent observational study by Kasper B. Kristensen, MD, PhD, and colleagues.

Because SGLT2 inhibitors increase urinary glucose excretion through reduced renal reabsorption of glucose leading to osmotic diuresis and increased urinary flow, they hypothesized that these therapies “may reduce the risk of upper urinary tract stones (nephrolithiasis) by reducing the concentration of lithogenic substances in urine.” 

Using data from Danish Health registries, they matched 12,325 individuals newly initiated taking an SGLT2 inhibitor 1:1 with patients newly prescribed a glucagon-like peptide-1 (GLP1) agonist, another new class of drugs for treating type 2 diabetes.

They found a hazard ratio of 0.51 (95% CI, 0.37- 0.71) for incident nephrolithiasis and a hazard ratio of 0.68 (95% CI, 0.48 – 0.97) for recurrent nephrolithiasis for patients taking SGLT2 inhibitors versus GLP-1 agonists.

These findings are “striking,” according to Balasubramanian and colleagues. However, “these data, while provocative, were entirely retrospective and therefore possibly prone to bias,” they add.

Pooled Data From 20 Trials

The current study analyzed data from 20 randomized controlled trials of glycemic control in type 2 diabetes, in which 10,177 patients had received empagliflozin 10 mg or 25 mg and 4904 patients had received placebo.

Most patients (46.5%) had participated in the EMPA-REG OUTCOMES trial, which also had the longest follow-up (2.6 years).

The researchers identified patients with a new stone from the urinary tract (including the kidney, ureter, and urethra). Patients had received either the study drug for a median of 543 days or placebo for a median of 549 days.

During treatment, 104 of 10,177 patients in the pooled empagliflozin groups and 79 of 4904 patients in the pooled placebo groups developed a stone in the urinary tract.

This was equivalent to 0.63 new urinary-tract stones per 100 patient-years in the pooled empagliflozin groups versus 1.01 new urinary-tract stones per 100 patient-years in the pooled placebo groups.

The incidence rate ratio (IRR) was 0.64 (95% CI, 0.48 – 0.86), in favor of empagliflozin.

When the analysis was restricted to new kidney stones, the results were similar: 75 of 10,177 patients in the pooled empagliflozin groups and 57 of 4904 patients in the pooled placebo groups developed a kidney stone.

This was equivalent to 0.45 new kidney stones per 100 patient-years in the pooled empagliflozin groups versus 0.72 new kidney stones per 100 patient-years in the pooled placebo groups.

The IRR was 0.65 (95% CI, 0.46 – 0.92), in favor of empagliflozin.

Upcoming Small RCT in Adults Without Diabetes

Invited to comment on the new study, Kristensen said: “The reduced risk of SGLT2 inhibitors towards nephrolithiasis is now reported in at least two studies with different methodology, different populations, and different exposure and outcome definitions.”

“I agree that randomized clinical trials designed specifically to confirm these findings appear warranted,” added Kristensen, from the Institute of Public Health, Clinical Pharmacology, Pharmacy, and Environmental Medicine, University of Southern Denmark in Odense.

There is a need for studies in patients with and without diabetes, he added, especially ones that focus on prevention of nephrolithiasis in patients with kidney stone disease.

A new trial should shed further light on this.

Results are expected by the end of 2022 for SWEETSTONE (Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers), a randomized, double-blind crossover exploratory study in 46 patients without diabetes.

This should provide preliminary data to “establish the relevance for larger trials assessing the prophylactic potential of empagliflozin in kidney stone disease,” according to an article on the trial protocol recently published in BMJ Open.

The trials included in the pooled dataset were funded by Boehringer Ingelheim or the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. Balasubramanian has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

J Clin Endocrinol Metab. 2022;107:e3003-e3007. Full text

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