Sodium-Glucose Cotransporter 2 Inhibitors and Nephrolithiasis Risk in Patients With Type 2 Diabetes

Abstract

ImportanceType 2 diabetes (T2D) is associated with an increased risk of kidney stones. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) might lower the risk of nephrolithiasis by altering urine composition. However, no studies have investigated the association between SGLT2i use and nephrolithiasis risk in patients receiving routine care in the US.ObjectiveTo investigate the association between SGLT2i use and nephrolithiasis risk in clinical practice.Design, Setting, and ParticipantsThis new-user, active comparator cohort study used data from commercially insured adults (aged ≥18 years) with T2D who initiated treatment with SGLT2is, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or dipeptidyl peptidase 4 inhibitors (DPP4is) between April 1, 2013, and December 31, 2020. The data were analyzed from July 2021 through June 2023.ExposureNew initiation of an SGLT2i, GLP-1RA, or DPP4i.Main Outcomes and MeasuresThe primary outcome was nephrolithiasis diagnosed by International Classification of Diseases codes in the inpatient or outpatient setting. New SGLT2i users were 1:1 propensity score matched to new users of a GLP-1RA or DPP4i in pairwise comparisons. Incidence rates, rate differences (RDs), and estimated hazard ratios (HRs) with 95% CIs were calculated.ResultsAfter 1:1 propensity score matching, a total of 716 406 adults with T2D (358 203 pairs) initiating an SGLT2i or a GLP-1RA (mean [SD] age, 61.4 [9.7] years for both groups; 51.4% vs 51.2% female; 48.6% vs 48.5% male) and 662 056 adults (331 028 pairs) initiating an SGLT2i or a DPP4i (mean [SD] age, 61.8 [9.3] vs 61.7 [10.1] years; 47.4% vs 47.3% female; 52.6% vs 52.7% male) were included. Over a median follow-up of 192 (IQR, 88-409) days, the risk of nephrolithiasis was lower in patients initiating an SGLT2i than among those initiating a GLP-1RA (14.9 vs 21.3 events per 1000 person-years; HR, 0.69 [95% CI, 0.67-0.72]; RD, −6.4 [95% CI, −7.1 to −5.7]) or a DPP4i (14.6 vs 19.9 events per 1000 person-years; HR, 0.74 [95% CI, 0.71-0.77]; RD, −5.3 [95% CI, −6.0 to −4.6]). The association between SGLT2i use and nephrolithiasis risk was similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT2i use was larger among adults aged younger than 70 years vs aged 70 years or older (HR, 0.85 [95% CI, 0.79-0.91]; RD, −3.46 [95% CI, −4.87 to −2.05] per 1000 person-years; P for interaction <.001).Conclusions and RelevanceThese findings suggest that in adults with T2D, SGLT2i use may lower the risk of nephrolithiasis compared with GLP-1RAs or DPP4is and could help to inform decision-making when prescribing glucose-lowering agents for patients who may be at risk for developing nephrolithiasis.

Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Nephrolithiasis in Clinical Practice—Reply

“…We agree that differences may exist in patient characteristics. Nonetheless, new initiators of GLP1-RA and DPP4i, which were also second-line medications for glucose-lowering medications during the study period, showed reasonably similar characteristics to initiators of SGLT2is even before adjustment via propensity score matching (eTable 2 in Supplement 1), suggesting these medications are reasonable comparators. Propensity score matching based on 57 prespecified baseline covariates further mitigated potential confounding.…”

“…Regarding the finding of a greater magnitude of risk reduction in patients younger than 70 years, we conducted sensitivity analyses that excluded the Medicare fee-for-service database and used alternative age cutoffs for subgroups (<50 vs ≥50 years; <60 vs ≥60 years) to evaluate the robustness of our findings. These analyses produced consistent results.…”

“…In Reply We appreciate the interest of Hsiao and Wei in our study that identified a lower risk of nephrolithiasis among adults with type 2 diabetes who were newly prescribed sodium-glucose cotransporter 2 inhibitor (SGLT2i) compared with a newly prescribed a glucagon-like peptide 1 receptor agonist (GLP-1RA) or dipeptidyl peptidase 4 inhibitor (DPP4i). We agree that differences may exist in patient characteristics.…”

Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Nephrolithiasis in Clinical Practice

“…To the Editor We write in response to the recent article by Paik et al on the risk of nephrolithiasis among patients with type 2 diabetes receiving different types of oral antidiabetic drugs. The findings presented in the study are both encouraging and inspiring, suggesting a potential correlation between certain antidiabetic medications and a reduced risk of nephrolithiasis.…”

“…Regarding the selection of oral antidiabetic drugs, it is essential to acknowledge that drug choice is often dictated by individual patient factors, such as blood glucose levels, lifestyle, and comorbidities. The study highlights differences in patient characteristics among those receiving glucagon-like peptide 1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase 4 inhibitors (DPP4is) compared with those prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2is), with notable variations in the prevalence of chronic kidney disease stages 3 to 4 and concomitant use of diuretics and insulin. Although propensity score matching was used to mitigate confounding variables and systemic biases, the potential limitations of this method still exist, particularly if the distribution of propensity scores in the clinical setting significantly deviates from those observed in the study …”