SGLT2i Use Linked to Lower Risk of Nephrolithiasis in Patients With Type 2 Diabetes

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Compared to glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, Use of sodium-glucose cotransporter 2 inhibitors was linked to a decreased risk of nephrolithiasis in patients with type 2 diabetes.

Use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) may lower the risk of nephrolithiasis compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase 4 inhibitors (DPP4is) in patients with type 2 diabetes (T2D), according to findings from a recent study published in JAMA Internal Medicine.1

Results from the new-user, active comparator cohort study leveraging nationwide data from 3 US sources pose significant implications for the use of glucose-lowering agents in this patient population and highlight the importance of considering patients’ individual risk profiles for developing nephrolithiasis when making decisions regarding treatment initiation.1

According to the US Centers for Disease Control and Prevention, about 38 million US adults have diabetes, approximately 90-95% of whom have T2D. Elevated blood sugar and blood pressure associated with T2D can damage blood vessels and nephrons in the kidneys, leading to chronic kidney disease and other kidney-related complications, such as kidney stones. However, data about the impact of glucose-lowering agents on urine composition, volume, and the subsequent risk of nephrolithiasis is limited.2,3

“To our knowledge, this study is the first and largest to assess the association between SGLT2i use and risk of nephrolithiasis in patients with T2D in routine US clinical practice,” wrote Julie Paik, MD, ScD, MPH, associate professor of medicine at Harvard Medical School, and colleagues.1

In this new-user, active comparator cohort study, investigators used deidentified, longitudinal data for adult patients ≥ 18 years of age with T2D, identified using ICD-9 and ICD-10 codes, from 3 US sources: Optum’s deidentified Clinformatics Data Mart Database, IBM MarketScan, and Medicare Fee-for-Service Parts A, B, and D. The study’s exposure was the initiation of an SGLT2i, GLP-1RA, or DPP4i between April 1, 2013, and December 31, 2020.1

Investigators excluded patients with any prior history of kidney or urinary tract stones recorded in the databases, as well as those with insurance enrollment for < 365 days, age < 18 years, missing age or sex, simultaneous use of both the exposure drug and the comparator drug, organ transplant, end-stage kidney disease, or nursing home admission.1

New SGLT2i users were propensity score matched in a 1:1 ratio to new users of a GLP-1RA or DPP4i in pairwise comparisons to mitigate the risk of confounding, accounting for the following covariates measured during the 365 days prior to cohort entry: demographic characteristics, combined comorbidity score, comorbid conditions, history of diabetes-related complications, use of diabetes medications, use of other medication classes, and measures of health care utilization.1

The primary outcome was nephrolithiasis diagnosed by ICD codes in the inpatient or outpatient setting. Follow-up started the day after cohort entry and continued until the outcome event, treatment discontinuation, switching to a comparator drug class, death, end of continuous health plan enrollment, or end of the study period.1

After 1:1 propensity score matching, a total of 716,406 adults with T2D initiating an SGLT2i or a GLP-1RA were included in the study. Among these patients, the mean age was 61.4 (Standard deviation [SD], 9.7) years for both groups and the majority were female (SGLT2i, 51.4% vs GLP-1RA 51.2%). An additional 662,056 adults initiating an SGLT2i or a DPP4i were enrolled in the study, again with similar ages (61.8 years vs 61.7 years) but a greater proportion of male patients (52.6% vs 52.7%).1

Over a median follow-up of 192 (Interquartile range [IQR], 88-409) days, nephrolithiasis occurred in 4670 patients in the SGLT2i group and 6134 patients in the GLP-1RA group, correlating to a decreased risk of nephrolithiasis in patients initiating an SGLT2i than among those initiating a GLP-1RA (Hazard ratio [HR], 0.69; 95% Confidence interval [CI], 0.67 to 0.72; Rate difference [RD], −6.4; 95% CI, −7.1 to −5.7).1

In the SGLT2i vs DPP4i propensity score-matched cohort, nephrolithiasis occurred in 4438 patients in the SGLT2i group and 5769 patients in the DPP4i group. Again, investigators noted a reduced risk of nephrolithiasis in the SGLT2i group compared with the DPP4i group (HR, 0.74; 95% CI, 0.71 to 0.77; RD, −5.3; 95% CI, −6.0 to −4.6).1

Investigators pointed out these findings remained consistent in the intention-to-treat analyses and additionally called attention to similar associations by sex, race and ethnicity, history of chronic kidney disease, and obesity. However, they noted the magnitude of the risk reduction with SGLT2i use was greater among adults < 70 years of age compared to those ≥ 70 years of age (HR, 0.85; 95% CI, 0.79 to 0.91; RD, −3.46; 95% CI, −4.87 to −2.05 per 1000 person-years; P <.001).1

Despite the study’s strengths in its large sample size, active comparator design, and adjustment for multiple confounders, investigators also called attention to several potential limitations. These included, but were not limited to, potential residual confounding, outcome misclassification, investigators’ inability to definitively distinguish incident versus recurrent kidney stones, and the short follow-up duration with no reason for medication discontinuation available in the databases.1

“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,” investigators concluded.1


  1. Paik JM, Tesfaye H, Curhan GC, et al. Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes. Jama Intern Med. doi:10.1001/jamainternmed.2023.7660
  2. Centers for Disease Control and Prevention. Type 2 Diabetes. Diabetes. April 18, 2023. Accessed January 29, 2024.
  3. Centers for Disease Control and Prevention. Diabetes and Chronic Kidney Disease. Diabetes. December 30, 2022. Accessed January 29, 2024.