Result. We have included a total of 11635698 participants who experienced nephrolithiasis 44 from a total of six clinical studies with nephrolithiasis rates of 1,27% in the SGLT2i group (n 45 = 739197), compared to 1,56% in the control arm (n = 10896501). SGLT-2 inhibitor therapy 46 has been associated with a lower risk for nephrolithiasis compared to placebo (OR 0.61, 95% 47 CI, 0.53-0.70, p < 0.00001) or active therapy such as glucagon-like peptide 1 and dipeptidyl 48 peptidase-IV inhibitors (OR 0.66, 95% CI, 0.47-0.93, p = 0.02).
Conclusion. We have demonstrated a lower risk of nephrolithiasis risk with SGLT-2 inhibitor 50 therapy compared to placebo or active control. Potential underlying mechanisms include 51 osmotic diuresis leading to a reduction in the concentration of lithogenic substances, anti52 inflammatory and anti-fibrotic effects, and an increase in urine pH. There is a clear need for 53 future large-scale randomized clinical trials evaluating such associations for better 54 understanding.
