Can SGLT2 Inhibition Also Reduce the Risk of Nephrolithiasis?
Diabetes mellitus (DM) is a risk factor for the development of nephrolithiasis. Recent studies associated with nephrolithiasis suggest a possible beneficial effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i, also known as gliflozins), a significant group of modern antidiabetics. Below we summarize findings from a study that explored this potential in empagliflozin using conducted phase I–IV studies, including EMPA-REG OUTCOME.
Nephrolithiasis in association with diabetes
Nephrolithiasis is a common problem with an estimated global prevalence of up to 15%. In recent decades, its incidence has been increasing, likely as a result of dietary and lifestyle changes. The recurrence rate after the first episode is high, with up to 50% of patients experiencing a second episode. Nephrolithiasis can negatively affect kidney function and has also been associated with an increased risk of chronic kidney disease. Although the links between nephrolithiasis and diabetes are still not fully understood, hyperuricemia and hyperuricosuria in patients with metabolic syndrome are thought to play key roles.
Previous findings
The authors of the work outlined below1 were motivated by a large retrospective observational study by Kristensen et al.2 involving more than 24,000 type 2 diabetics using gliflozins. This study found that the use of SGLT2i was associated with a significant reduction in the risk (by 49%) of developing nephrolithiasis compared to the effect of glucagon-like peptide 1 receptor agonists (GLP-1RA): hazard ratio (HR) 0.51 (95% confidence interval [CI] 0.37–0.71). A reduction in recurrence risk by 32% (HR 0.68; 95% CI 0.48–0.97) was also observed.
The aim of the presented work by Balasubramanian et al. was to explore the association between reducing the risk of nephrolithiasis and SGLT2 inhibition, using existing data from randomized controlled trials evaluating the effects of the SGLT2i agent empagliflozin.
Methodology of the analysis
The study sample represented data from 15,081 patients with type 2 diabetes randomized to receive empagliflozin (n = 10,177) or a placebo (n = 4904) who participated in 20 phase I–IV studies, including the large cardiovascular (CV) assessment EMPA-REG OUTCOME. Nephrolithiasis events were captured using MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, urinary stone, nephrocalcinosis. A sensitivity analysis was also performed using a narrower definition (excluding the terms renal colic and nephrocalcinosis). Incidence rate ratios (IRR) and 95% CI were calculated using a relative risk estimate, stratified by study.
Results
The median exposure to the study drug was 543 days for placebo and 549 days for empagliflozin at doses of 10 or 25 mg. Nearly half of the patients (46.5%; n = 7020) participated in the EMPA-REG OUTCOME study, where the longest median exposure to treatment was 2.6 years.
A total of 9 patients (3 in the placebo arm, 6 among those treated with empagliflozin 10 or 25 mg) had reported a history of kidney stones at study entry, with only 1 experiencing recurrence during follow-up. Overall, 183 patients experienced urolithiasis during follow-up (79 in the placebo arm, 104 among those taking empagliflozin), resulting in an annual incidence rate of 1.01 vs. 0.63 events per 100 patient-years in the placebo vs. empagliflozin arms. The IRR was 0.64 (95% CI 0.48–0.86) in favor of empagliflozin.
Conclusion and discussion
Treatment with empagliflozin was associated with a reduction in the risk of nephrolithiasis by approximately 40% compared to placebo. The results remained similar even when researchers used a stricter definition, excluding renal colic (which is subjective) and nephrocalcinosis (which is a tubulointerstitial disease with a different pathophysiology). These data extend the aforementioned previous observation made by Kristensen et al.
This additional potential benefit of SGLT2 inhibition is identifiable compared to the effect of placebo across a wide range of glucose-lowering therapies used in the included studies (not just compared with GLP-1RA, as focused on by Kristensen et al.).
The fundamental mechanisms of the observed phenomena remain unknown, but according to the authors, they may involve an altered lithogenic profile of the urine. They suggest conducting prospective randomized clinical trials to potentially confirm these initial findings in patients with and without type 2 diabetes, as well as studies of the lithogenic profile of the urine of patients with a history of nephrolithiasis who were treated with SGLT2i.
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Sources:
1. Balasubramanian P., Wanner C., Ferreira J. P. et al. Empagliflozin and decreased risk of nephrolithiasis: a potential new role for SGLT2 inhibition? J Clin Endocrinol Metab 2022; 107 (7): e3003–e3007, doi: 10.1210/clinem/dgac154.
2. Kristensen K. B., Henriksen D. P., Hallas J. et al. Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis. Diabetologia 2021; 64 (7): 1563–1571, doi: 10.1007/s00125-021-05424-4.
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