(C-002) SGLT2 Inhibitors and Nephrolithiasis Risk in Patients with Type 2 Diabetes: A Cohort Study and Meta-analysis

Background: Type 2 diabetes (T2D) is a significant risk factor for nephrolithiasis. Some studies have suggested that sodium-glucose cotransporter 2 inhibitors (SGLT2is) may reduce the risk of nephrolithiasis. However, current evidence remains inconsistent and inconclusive, warranting further investigation.

Objectives: To evaluate the relationship between SGLT2i use and nephrolithiasis risk in patients with T2D through a real-world cohort study and meta-analysis.

Methods: This study utilized electronic health records from the TriNetX Analytics Network, encompassing 64 healthcare organizations in the United States. Adult patients with T2D who initiated treatment with SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), or glucagon-like peptide-1 receptor agonists (GLP-1RAs) between January 2015 and December 2023 were included. DPP4is and GLP-1RAs were used as active comparators. A target trial emulation framework was applied to design the study. Propensity score matching was performed to balance baseline characteristics between treatment groups for two comparisons: SGLT2is vs. DPP4is and SGLT2is vs. GLP-1RAs, including age, sex, race, comorbidities, baseline medications, and relevant laboratory test results. Patients were followed up for up to 5 years or until July 1, 2024. Cox regression models were used to estimate hazard ratios (HRs) for nephrolithiasis. Additionally, a meta-analysis was performed using random-effects models to synthesize the findings from currently available real-world evidence.

Results: The cohort study included 500,000 patients (250,000 matched pairs) for the SGLT2is vs. DPP4is comparison and 482,284 patients (241,142 matched pairs) for the SGLT2is vs. GLP-1RAs comparison. The risk of nephrolithiasis was significantly lower in patients using SGLT2is compared to those using DPP4is (HR: 0.86; 95% CI: 0.83–0.90) and GLP-1RAs (HR: 0.90; 95% CI: 0.86–0.94). The meta-analysis included two studies comparing SGLT2is with DPP4is and four studies comparing SGLT2is with GLP-1RAs. It revealed a significant reduction in nephrolithiasis risk with SGLT2is compared to DPP4is (pooled RR: 0.77; 95% CI: 0.69–0.86). Similarly, SGLT2is were associated with a lower risk of nephrolithiasis compared to GLP-1RAs (pooled RR: 0.70; 95% CI: 0.61–0.81).

Conclusions: This study suggests that SGLT2is may reduce the risk of nephrolithiasis in patients with T2D, offering a potential benefit beyond glycemic control when selecting glucose-lowering therapies.