SGLT-2 inhibitors stop kidney stone recurrence in T2D patients with nephrolithiasis, gout

Use of an SGLT-2 inhibitor, compared with a GLP-1 receptor agonist or a DPP-4 inhibitor, helps to prevent nephrolithiasis from recurring in patients with type 2 diabetes (T2D) and pre-existing nephrolithiasis or gout, as shown in target trial emulation studies. 

“The benefits associated with SGLT-2 inhibitor for patients with nephrolithiasis in these target trial emulations suggest they may be a useful addition to current treatments to simultaneously manage nephrolithiasis recurrence and comorbidities, including gout,” the investigators said. 

A total of 20,146 patients with T2D and nephrolithiasis, including those with concomitant gout at baseline, were included in these target trial emulation studies that utilized the Canadian population database from January 2014 to June 2022. 

The participants initiated an SGLT-2 inhibitor or a GLP-1 receptor agonist, with DPP-4 inhibitors as an alternative comparator. The investigators then used Poisson and Cox proportional hazards regression models, as well as overlap weighting, to assess outcomes, including recurrent nephrolithiasis and hospital admission or emergency department visits, among others. 

After inverse probability of treatment weighting, 14,456 patients treated with an SGLT-2 inhibitor had a total of 1,924 recurrent nephrolithiasis events (105.3 per 1,000 person-years) compared with 853 events among the 5,877 patients who used a GLP-1 receptor agonist (156.4 per 1,000 person-years). [BMJ 2024;387:e080035] 

The adjusted rate ratio (RR) was 0.67 (95 percent confidence interval [CI], 0.57–0.79) while the rate difference (RD) was –51 (95 percent CI, –63 to –40) per 1,000 person-years, with a number needed to treat (NNT) of 20. The absolute RD among patients with recently active nephrolithiasis was 219 per 1,000 person-years, with an NNT of 5. 

The protective benefits derived from initiating an SGLT-2 inhibitor persisted for nephrolithiasis events requiring an ED visit, hospital admissions, or procedures when compared with a DPP-4 inhibitor (RR, 0.73, 95 percent CI, 0.68–0.78; RD, –38, 95 percent CI, –46 to –29; NNT of 26). 

These protective associations were also observed among nephrolithiasis patients with gout, with RR of 0.67 (95 percent CI, 0.57–0.79) and RD of –53 (95 percent CI, –0.78 to –0.27) versus a GLP-1 receptor agonist (NNT of 19) and with RR of 0.63 (95 percent CI, 0.55–0.72 and RD of –62 (95 percent CI, –81 to –42 relative to a DPP-4 inhibitor (NNT of 16). 

Osmotic diuresis 

“The mechanism underlying the lower risk of recurrent nephrolithiasis with SGLT-2 inhibitor use could partly be attributed to increased urinary output from osmotic diuresis,” the investigators said. [Clin J Am Soc Nephrol 2017;12:700-710; Clin Ther 2016;38:2265-2276; Diabetes Ther 2018;9:863-871] 

In addition, use of SGLT-2 inhibitors resulted in a reduced rate of gout flare-up versus GLP-1 receptor agonists (RR, 0.72, 95 percent CI, 0.54–0.95; RD, –16, 95 percent CI, –31 to –1) and DPP-4 inhibitors (RR, 0.65, 95 percent CI, 0.52–0.82; RD, –21, 95 percent CI, –33 to –9). 

However, patients treated with an SGLT-2 inhibitor were at greater risk of genital infection (hazard ratio [HR], 2.21, 95 percent CI, 1.68–2.90; RD, 13), with no altered risk of osteoarthritis encounter (HR, 0.87, 95 percent CI, 0.68–1.1; RD, –2) or appendicitis (HR, 1.07, 95 percent CI, 0.69–1.67; RD, 1). Similar results were noted after applying propensity score overlap weighting. 

“Together with the multiple cardiometabolic-kidney benefits associated with SGLT-2 inhibitors, for patients with an existing indication (eg, T2D, heart failure, chronic kidney disease), this class of drugs may be a useful addition to the current treatments for nephrolithiasis to simultaneously tackle the high burden of kidney stones and comorbidities, including gout,” the investigators said.