Heterogeneous effects of sodium-glucose cotransporter-2 inhibitors compared to dipeptidyl peptidase-4 inhibitors on nephrolithiasis in older adults with type 2 diabetes.

Background: Type 2 diabetes (T2D) is associated with an increased risk of nephrolithiasis. Emerging evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may reduce this risk; however, data remain inconclusive.

Objective: To examine the risk of nephrolithiasis among users of SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world population of older adults with T2D.

Methods: A retrospective cohort study was conducted using claims data from a sample of national Medicare beneficiaries. Individuals with T2D who initiated SGLT2i or DPP4i therapy between January 1, 2016, and December 31, 2018, were identified. The index date was defined as the date of the first prescription for either SGLT2i or DPP4i, with no prior use of either drug in the preceding year. Patients were followed from the index date until the earliest occurrence of a medical encounter with a primary diagnosis of nephrolithiasis, death, or December 31, 2018. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates, including sociodemographic characteristics, comorbidities, and comedication use. Cox proportional hazards regression models were applied to compare the risk of nephrolithiasis between SGLT2i and DPP4i users. Additional analyses were conducted within subgroups defined by sex, race, and baseline nephrolithiasis status.

Results: Of 116,506 included Medicare beneficiaries with T2D (mean age 72 ± 10 years, 53% women), 0.96% developed nephrolithiasis over a median follow-up of 360 days (interquartile range [IQR] 200-467 days). The incidence rate of nephrolithiasis was 9.89 (95% confidence interval [CI] 8.49-11.52) and 11.02 (95% CI 10.34-11.73) events per 1000 person-years in the SGLT2i and DPP4i groups, respectively. After applying IPTW, baseline characteristics were well balanced between the two groups. SGLT2i use was associated with a significantly lower risk of nephrolithiasis compared to DPP4i use (hazard ratio [HR], 0.81; 95% CI 0.66-0.99; p = 0.04). In subgroup analyses, SGLT2i use compared to DPP4i was associated with a significantly lower risk of nephrolithiasis among males (HR 0.75; 95% CI 0.58-0.98; p = 0.04), non-Hispanic Black (NHB) individuals (HR 0.22; 95% CI 0.07-0.64; p < 0.01), and those without baseline nephrolithiasis (HR 0.68; 95% CI 0.53-0.88; p < 0.01).

Conclusions: In older adults with T2D, SGLT2i use was associated with a lower risk of nephrolithiasis compared to DPP4i, particularly among men, NHB individuals, and those without baseline nephrolithiasis. Although causality cannot be established, these findings provide real-world evidence supporting a potential benefit of SGLT2is in reducing nephrolithiasis risk, offering valuable insights to guide the selection of glucose-lowering drugs in older adults with T2D.