SGLT-2 inhibitors for the prevention of recurrent nephrolithiasis
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj.q2447 (Published 07 November 2024) Cite this as: BMJ 2024;387:q2447Linked Research
Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for recurrent nephrolithiasis among patients with pre-existing nephrolithiasis or gout
- Khashayar Sakhaee, professor
- Department of Internal Medicine, UT Southwestern Medical Center, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Dallas, TX, USA
- khashayar.sakhaee{at}utsouthwestern.edu
Kidney stones and the systemic conditions associated with them have a major impact on health and the economy in the US and worldwide.12 In recent years, the prevalence of kidney stones has increased in parallel with the epidemics of obesity and metabolic syndrome, as well as cardiorenal disease. Since 1988, when the US Food and Drug Administration approved potassium citrate to prevent recurrent nephrolithiasis, no other drug has been introduced for the secondary prevention of this chronic illness. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are an accepted treatment for type 2 diabetes and have also emerged as a novel therapeutic class with beneficial cardiorenal effects.3
In a linked paper, McCormick and colleagues (doi:10.1136/bmj-2024-080035) report a target trial emulation study evaluating SGLT-2 inhibitors in adults with recurrent nephrolithiasis and type 2 diabetes using the general Canadian population database.4 After inverse probability weighting or propensity score overlap weighting to balance the study groups, the authors compared treatment with SGLT-2 inhibitors versus competitor agents, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in patients with recurrent nephrolithiasis and type 2 diabetes, with and without gout.
The primary outcome was diagnosis of recurrent nephrolithiasis documented by diagnostic codes from the emergency department, hospital admissions, and outpatient visits. Secondary endpoints included nephrolithiasis resulting in hospital admission or emergency department visits, hospital admission or emergency department visits requiring urological procedures, and gout flare ups. Genital infection was a positive control outcome (an association with SGLT-2 inhibitors was expected) and osteoarthritis and appendicitis were negative control outcomes (associations were not expected).4
The rate of recurrent nephrolithiasis was significantly lower, by about 30%, among patients initiating SGLT-2 inhibitors compared with those treated with GLP-1 receptor agonists (105.3 and 156.4 events per 1000 person years, respectively (adjusted rate ratio 0.67, 95% confidence interval 0.57 to 0.79)). Among patients with combined nephrolithiasis and gout flare ups, treatment with SGLT-2 inhibitors was associated with a lower rate of both recurrent nephrolithiasis and gout flare ups than treatment with GLP-1 receptor agonists or DPP-4 inhibitors.
McCormick and colleagues’ novel study confirmed that treatment with SGLT-2 inhibitors can be an additional treatment strategy for patients with nephrolithiasis and type 2 diabetes, adding extra benefits to those already documented on the heart and kidney. Their findings are consistent with another large study of claims data from the US, showing that among people with type 2 diabetes, those taking SGLT-2 inhibitors had a significantly lower risk of nephrolithiasis than those taking GLP-1 receptor agonists or DPP-4 inhibitors, over a median follow-up of 192 days.5 Finally, an observational study comparing SGLT-2 inhibitors with GLP-1 receptor agonists in patients with type 2 diabetes showed a noticeable decrease in risk of incident and recurrent nephrolithiasis among those treated with SGLT-2 inhibitors.6
Two previous meta-analyses of clinic trials evaluating SGLT-2 inhibitors in patients with type 2 diabetes reported mixed findings. One reported no difference in risk of nephrolithiasis, relative to placebo or active comparators,7 whereas the other reported a statistically significant reduction in risk of nephrolithiasis relative to placebo.8
Mechanism of action
Although good evidence now suggests that SGLT-2 inhibitors may help prevent recurrent formation of kidney stones, the underlying mechanisms have not been fully explored. Several mechanisms are possibilities. First, osmotic diuresis and dilution of urine would reduce the urinary super saturation that underlies urinary crystallization of stone-forming salts. Second, increased urinary citrate excretion—as shown previously in healthy volunteers treated with empagliflozin compared with placebo—may have a beneficial effect in patients with calcium related nephrolithiasis.9 Finally, the protective effect against kidney stones could be explained by the anti-inflammatory actions of SGLT-2 inhibitors influencing the balance between pro-inflammatory and anti-inflammatory cytokines that could facilitate kidney stone formation.10
To answer these questions, a short term proof of concept study followed by long term prospective clinical trials would be of value to patients, clinicians, and researchers. These studies could explore the underlying metabolic factors influencing the formation of kidney stones and inform the development of more targeted treatments. Future studies should also recruit patients with nephrolithiasis but no concurrent diabetes to test whether SGLT-2 inhibitors could be beneficial for them.
A recent trial of hydrochlorothiazide, a commonly used treatment for hypercalciuric nephrolithiasis, failed to show its hypothesized effect in reducing the formation of kidney stones.11 However, one reason to consider SGLT-2 inhibitors instead of hydrochlorothiazide for patients prone to kidney stones is that new onset diabetes and gout were both more common among trial participants receiving hydrochlorothiazide compared with placebo.
McCormick and colleagues’ study strengthens the evidence supporting use of SGLT-2 inhibitors for patients with recurrent nephrolithiasis, type 2 diabetes, and comorbidities such as gout. Further research to identify underlying mechanisms of action, and to evaluate use for patients without type 2 diabetes, would help strengthen the evidence still further.
Footnotes
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The author declares the following other interests: None.
Provenance and peer review: Commissioned; not externally peer reviewed.
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