Weight-independent amelioration of adipokine profile by enavogliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes

Background and objective: The metabolic benefits of sodium-glucose co-transporter 2 inhibitors in clinical application are well established; however, there is dearth of knowledge on their impact on adipokine regulation. This study investigated the effect of enavogliflozin on adiponectin and leptin in patients with type 2 diabetes. Methods: This secondary analysis of a phase III randomized, double-blind, placebo-controlled trial evaluated changes in serum adiponectin and leptin over 24 weeks. Analysis of covariance was used with baseline values and weight change as covariates to examine whether the effects of enavogliflozin persisted after adjusting for weight change. Correlations between adipokine changes and key metabolic parameters were also assessed. Results: Over the 24 weeks, the enavogliflozin group showed increased adiponectin levels with a least squares (LS) mean difference of 0.98 mg/L compared with the placebo group, while leptin levels showed a significant decrease with an LS mean difference of −2.99 µg/L. Enavogliflozin significantly reduced leptin levels over 24 weeks after adjusting for weight change; however, adiponectin changes were not significant after adjusting for weight change. Adiponectin levels significantly increased across weight loss categories, but leptin showed no significant differences. Leptin changes over 24 weeks significantly were positively correlated with changes in homeostasis model assessment of insulin resistance and homeostasis model assessment of β-cell function but significantly negatively correlated with changes in serum ketone and urinary glucose-to-creatinine ratio. Conclusions: Enavogliflozin treatment decreased leptin over 24 weeks in patients with type 2 diabetes, and this effect remained significant after adjusting for weight change, suggesting an improved adipokine profile. Reductions in leptin were also associated with improvements in insulin resistance and increases in serum ketone levels. These results highlight enavogliflozin as a potential treatment beyond glycemic control, offering additional benefits in managing metabolic dysregulation associated with type 2 diabetes. Trial registration: Not applicable (post hoc analysis).