Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from absolute or relative insulin deficiency and resistance. The number of individuals with DM is anticipated to increase to 800 million by 2045.1 Diabetic kidney disease (DKD) is a secondary complication of DM and a leading cause of chronic kidney and end-stage renal diseases.2 DKD is characterized by glomerular hyperfiltration in the early stages and gradually progresses to microalbuminuria, overt albuminuria, and nephrotic syndrome.3 Effective DKD treatment remains a challenge worldwide, and the current recommended treatment is careful management of blood pressure and glycemic levels. The implementation of renin-angiotensin system blockade using angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers has been shown to be advantageous in reducing albuminuria and preserving renal function, whereas mineralocorticoid receptor antagonists have been shown to decrease proteinuria4; however, the benefits of these drugs for treating DKD remain unclear. Therefore, novel treatment approaches are required.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a recent addition to the class of oral hypoglycemic agents. This novel class of drugs, which includes empagliflozin, canagliflozin (CANA), and dapagliflozin, was first introduced in 2012.5 SGLT2 inhibitors obstructs sodium-glucose cotransporter 2 in the proximal convoluted tubule of the kidney, increasing renal glucose excretion and decreasing glucose reabsorption ultimately reducing hyperglycemia.6 Three recent large-scale clinical trials demonstrated that SGLT2 inhibitors exhibit renoprotective effects in patients with type 2 diabetes, independent of glucose levels. These trials included the EMPA-REG OUTCOME (empagliflozin), CANVAS Program (CANA), and Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.7., 8., 9.

The precise mechanism by which SGLT2 inhibitors ameliorate DKD remains elusive; however, it is likely multifaceted and indirect, encompassing enhancements to the overall phenotype and reductions in blood pressure and volume.10 Numerous studies using animal models have consistently demonstrated the potential renoprotective properties of SGLT2 inhibitors, such as a reduction in inflammatory responses and oxidative stress and enhanced mitochondrial function.11 Furthermore, some studies have demonstrated that SGLT2 inhibitors have favorable metabolic advantages and significantly impede the progression of chronic kidney disease12; thus, assessing the global footprint of the metabolic status of the kidneys can offer valuable information into the protective mechanisms of SGLT2 inhibitors. Metabolomics analysis provides insight into the metabolites and metabolic processes of a particular organ, and reveals alterations resulting from both endogenous and exogenous stimuli.13 Untargeted metabolomics analyzes all detectable metabolites in a specific sample; this semi-quantitative approach focuses on identifying significant variations in metabolite abundance across various groups.14 In this study, we investigated the metabolic effects of CANA treatment on DKD using nuclear magnetic resonance (NMR)-based metabolomics of the kidney, to provide a better understanding of CANA therapy.

We found that CANA significantly improved glucose metabolism and kidney damage in diabetic mice. Metabolomics analysis showed that CANA increased the levels of essential amino acids within the kidney, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.