SGLT2i: The New Wonder Drugs for Kidney Stone Prevention?

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Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are cardio- and renal-protective in patients with heart failure and proteinuric kidney disease. However, Paik and colleagues’ newest work (1) suggests that SGLT2i may also help prevent kidney stones (or nephrolithiasis). In their retrospective analysis of over 700,000 adults with type 2 diabetes, new users of SGLT2i had a lower incidence of kidney stones compared with new users of glucagon-like peptide-1 receptor antagonists (GLP-1RA) or dipeptidyl peptidase 4 inhibitors (DPP4i). Kidney stone events were 14.9 events per 1000 person-years in the patients treated with SGLT2i compared with 21.3 events per 1000 person-years in patients treated with GLP-1RA or DPP4i at an average of 192 days. Paik and colleagues’ findings (1) are similar to other studies, which also found reduced odds and reduced incidence of kidney stones in patients treated with SGLT2i (2–4). However, these studies are all retrospective, in which glucose-lowering therapy was initiated for the usual indications and not for stone prevention.

Paik and colleagues’ findings (1), although exciting, present more questions than answers. It is unclear whether SGLT2i are protective against all kidney stone types, if the effects are transferrable to stone formers who are nondiabetic, and what the underlying mechanisms might be. Interestingly, there was initial concern that SGLT2i could increase urinary stone formation. In healthy adults and rats treated with SGLT2i, urinary calcium increased (5). However, urine calcium excretion was not increased in healthy volunteers treated with empagliflozin (6). Urinary citrate increased by up to 18% in both healthy volunteers and patients with type 2 diabetes treated with SGLT2i, which may or may not have mitigated against any increase in urinary calcium (6, 7). Healthy volunteers treated with empagliflozin did have a reduced relative supersaturation rate (calculated by the EQUIL2 algorithm) of calcium phosphate, specifically brushite and hydroxyapatite, with no change in that of calcium oxalate. The role of urine citrate and reduced brushite saturation may be important, as brushite crystals are considered to be the nidus of most calcium kidney stones (8). Increases in urinary citrate are the most widely suggested mechanism for stone prevention in patients treated with SGLT2i, but the mechanism by which this effect occurs remains uncertain.

SGLT2i may be more important in the prevention of uric acid kidney stones given that uric acid stones are more common in stone formers who are diabetic (9). Increases in urine bicarbonate and urine pH occurred in mice treated with empagliflozin due to reduced sodium-hydrogen exchanger 3 activity and increased glutamine-mediated ammoniagenesis (10). Although SGLT2i are also uricosuric, uric acid stone formation is more dependent on low urine pH than on high urine uric acid levels (11). Yet, in healthy adults treated with empagliflozin, there was a trend toward lower urine pH with a higher relative supersaturation rate for uric acid (6). This effect was surprising and unexplained given that treatment was also associated with an increase in citrate excretion, a circumstance usually accompanied by increased urine pH.

Other possible mechanisms for stone prevention in individuals treated with SGLT2i include other unmeasured effects in the urine such as reduced inflammatory markers and kidney stone matrix proteins like osteopontin and albumin (1, 2). What is not accounted for are changes in patients’ metabolic profile and weight, which can affect urine pH (7, 9). A final suggested mechanism is increased urinary flow, reducing kidney stone risk, but these effects are transient (2, 3). At this time, the findings from Paik et al. (1) are more thought-provoking than anything else, and we eagerly anticipate further studies to better identify target patient populations, large studies examining changes in urinary profiles, and comparisons of SGLT2i with standard preventative therapies.