Empagliflozin and decreased risk of nephrolithiasis: a potential new role

for SGLT2 inhibition?

https://doi.org/10.1210/clinem/dgac154

Priyadarshini Balasubramanian, Christoph Wanner, João Pedro Ferreira, Anne Pernille Ofstad, Amelie Elsaesser, Bernard Zinman, Silvio E Inzucchi

Abstract

Context.Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists.
Objective. We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials.

Methods. We pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study.

Results. The median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104), yielding annual incidence rates of 1.01 vs 0.63 events/100 patient-years in the 2 respective groups. The IRR was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin. In the sensitivity analysis, the results were similar (IRR, 0.62 [95% CI, 0.45-0.85]). Conclusion. Compared with placebo, empagliflozin therapy was associated with an approximate 40% reduced risk of urinary tract stone events in T2D patients. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine. Dedicated randomized prospective clinical trials are warranted to confirm these initial observations in patients with and without T2D.

Keywords: nephrolithiasis, SGLT2 inhibitors, empagliflozin, type 2 diabetes mellitus.

References

1. Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Primers. 2016;2:16008.
2. Geraghty RM, Cook P, Walker V, Somani BK. Evaluation of the economic burden of kidney stone disease in the UK: a retrospective cohort study with a mean follow-up of 19 years. BJU Int. 2020;125[4]:586-594.
3. Antonelli JA, Maalouf NM, Pearle MS, Lotan Y. Use of the National Health and Nutrition Examination Survey to calcu- late the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. Eur Urol. 2014;66[4]:724-729.
4. Kristensen KB, Henriksen DP, Hallas J, Pottegard A, Lund LC. Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis. Diabetologia. 2021;64[7]:1563-1571.
5. Kinduryte Schorling O, Clark D, Zwiener I, Kaspers S, Lee J, Iliev H. Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus. Adv Ther. 2020;37[8]3463-3484.
6. Ferrannini E. Sodium-glucose transporter-2 inhibition as an antidiabetic therapy. Nephrol Dial Transplant. 2010;25[7]: 2041-2043.
7. YeY,ZhaoC,LiangJ,YangY,YuM,QuX.Effectof sodium- glucose co-transporter 2 inhibitors on bone metabolism and fracture risk. Front Pharmacol. 2018;9:1517.
8. Novikov A, Fu Y, Huang W, et al. НЗКТГ-2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Renal Physiol. 2019;316[1]:F173- F185.
9. Wiederkehr MR, Moe OW. Uric acid nephrolithiasis: a systemic metabolic disorder. Clin Rev Bone Miner Metab. 2011;9[3-4]:207-217.
10. Onishi A, Fu Y, Patel R, et al. A role for tubular Na(+)/H(+) exchanger NHE3 in the natriuretic effect of the НЗКТГ-2 inhibitor empagliflozin. Am J Physiol Renal Physiol. 2020;319[4]:F712-F728.
11. Bletsa E, Filippas-Dekouan S, Kostara C, et al. Effect of dapa- gliflozin on urine metabolome in patients with type 2 diabetes. J Clin Endocrinol Metab. 2021;106[5]: 1269-1283.