SGLT2 Inhibitor-Associated Changes in Urinary Volatile Organic Compounds in Diabetic Kidney Disease: A Comprehensive...

Originally developed as glucose-lowering agents for type 2 diabetes, sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently attracted attention for their kidney-protective effects in patients with diabetic kidney disease (DKD). However, their underlying metabolic mechanisms remain unclear. We, therefore, hypothesized that non-invasive urinary metabolite profiling could provide novel mechanistic insights.

We comprehensively analysed urinary volatile organic compounds (VOCs) in patients with DKD using gas chromatography-mass spectrometry. A total of 61 patients were enrolled, including those treated with SGLT2 inhibitors and untreated individuals. Overall, 79 urinary VOCs were identified and quantified; clinical variables were examined using appropriate statistical methods.

Among the 61 patients, those treated with SGLT2 inhibitors showed significantly higher urinary levels of acetone and 2-pentanone compared with untreated individuals. These metabolites are derived from ketone bodies, suggesting enhanced ketogenesis in the treated group. The increase in these VOCs was consistent across patients and was not explained by differences in other baseline clinical characteristics.

Our findings indicate that SGLT2 inhibitor therapy is associated with elevated urinary ketone-related VOCs, reflecting a shift in systemic energy metabolism. These observations contribute to a better understanding of the metabolic mechanisms underlying the kidney-protective effects of SGLT2 inhibitors. Considering that urinary VOCs can be measured non-invasively, this approach holds promise for future research and clinical monitoring of treatment effects in DKD.