SGLT-2 inhibitors associated with lower risk of kidney stones vs. other new diabetes drugs

Possible mechanisms to explain the association include increased urinary citrate excretion, increased urinary bicarbonate excretion that raises urine pH, or anti-inflammatory effects.

Patients taking sodium-glucose cotransporter-2 (SGLT-2) inhibitors had a reduced risk of kidney stones compared with those taking glucagon-like peptide 1 (GLP-1) receptor agonists or dipeptidyl peptidase 4 (DPP-4) inhibitors, a study found.

The cohort study included 1,378,462 commercially insured adults with type 2 diabetes newly prescribed one of the three drug classes between April 2013 and December 2020. New SGLT-2 inhibitor users were propensity-score matched 1:1 to new users of a GLP-1 receptor agonist or a DPP-4 inhibitor in pairwise comparisons. Results were published Jan. 29 by JAMA Internal Medicine.

There were 358,203 pairs who started an SGLT-2 inhibitor and a GLP-1 receptor agonist and 331,028 pairs who started an SGLT-2 inhibitor and a DPP-4 inhibitor. Over a median follow-up of 192 days, the risk of kidney stones was lower in patients taking an SGLT-2 inhibitor than among those taking a GLP-1 receptor agonist (14.9 vs. 21.3 events per 1,000 person-years; hazard ratio [HR], 0.69 [95% CI, 0.67 to 0.72]; risk difference [RD], −6.4 [95% CI, −7.1 to −5.7]) and those taking a DPP-4 inhibitor (14.6 vs. 19.9 events per 1,000 person-years; HR, 0.74 [95% CI, 0.71 to 0.77]; RD, −5.3 [95% CI, −6.0 to −4.6]).

The associations were similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT-2 inhibitor use was larger among adults younger than age 70 years versus those ages 70 years or older (HR, 0.85 [95% CI, 0.79 to 0.91]; RD, −3.46 [95% CI, −4.87 to −2.05] per 1,000 person-years; P<0.001).

Mechanisms that might explain the association include increased urinary citrate excretion with SGLT-2 inhibitor use, increased urinary bicarbonate excretion that raises urine pH, anti-inflammatory effects caused by suppressing the expression of a stone core matrix protein, or increased urine flow due to osmotic diuresis from glucosuria and natriuresis, the study authors wrote. Among potential limitations, the authors could not rule out potential confounding but the study did adjust for many clinically relevant confounders. They also pointed out that prescribers currently do not consider baseline kidney stone risk when prescribing SGLT-2 inhibitors.

"Our results suggest that for patients with T2D, the individual risk profile for developing nephrolithiasis could be a consideration when deciding which glucose-lowering agent patients should initiate," they concluded.