The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment

Abstract Delaying kidney senescence process will benefit renal physiologic conditions, and prompt the kidney recovering from different pathological states. The renal anti‐senescence effects of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and metformin have been proven in diabetic settings, but the roles of each one and combination of two drugs in natural kidney aging process remain undefined and deserve further research. Senescence‐accelerated mouse prone 8 (SAMP8) were orally administered dapagliflozin, metformin, and a combination of them for 16 weeks. Dapagliflozin exhibits better effects than metformin in lowering senescence related markers, and the combination therapy shows the best results. In vitro experiments demonstrate the same results that the combination of dapagliflozin and metformin can exert a better anti‐senescence effect. Blood metabolites detection in vivo shows dapagliflozin mainly leads to the change of blood metabolites enriched in choline metabolism, and metformin tends to induce change of blood metabolites enriched in purine metabolism. In conclusion, the results suggest dapagliflozin may have a better renal anti‐senescence effect than metformin in non‐diabetes environment, and the combination of the two drugs can strengthen the effect. The two drugs can lead to different blood metabolites alteration, which may lead to different systemic effects.