Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a vital therapeutic class for patients with type 2 diabetes mellitus (T2DM), providing glycemic control alongside cardiometabolic benefits. A new randomized controlled trial has highlighted enavogliflozin’s impact on adipokine modulation, particularly leptin reduction, offering insights into weight-independent metabolic effects. Researchers evaluated the effects of enavogliflozin over a 24-week period in adults with T2DM. The study demonstrated that enavogliflozin significantly reduced circulating leptin levels independent of body weight change. Elevated leptin is often associated with insulin resistance, chronic inflammation, and impaired metabolic regulation. By lowering leptin, enavogliflozin may contribute to improved insulin sensitivity and better energy balance regulation. Notably, the reduction in leptin correlated with improvements in the homeostatic model assessment of insulin resistance (HOMA-IR) and with higher serum ketone body concentrations. These findings suggest that enavogliflozin not only enhances glycemic control but also induces favorable shifts in energy metabolism and substrate utilization. The rise in ketone levels aligns with previous evidence that SGLT2 inhibitors promote a mild, physiologic ketosis that supports metabolic flexibility and cardiovascular protection. The trial underscores that the benefits of enavogliflozin extend beyond simple glucose lowering or weight reduction. By targeting adipokine dysregulation, enavogliflozin may help address the underlying pathophysiology of insulin resistance and metabolic syndrome. This is particularly important given the high burden of cardiovascular disease and chronic kidney disease in individuals with T2DM. Clinically, these results may position enavogliflozin as a promising therapeutic option for patients struggling with metabolic dysregulation despite standard care. Future research should explore long-term outcomes, including cardiovascular events, renal endpoints, and durability of adipokine modulation. Overall, the study provides evidence that enavogliflozin’s metabolic benefits extend to improving adipokine profiles and reducing insulin resistance, independent of body weight. This highlights its potential role as a comprehensive strategy for managing T2DM and its associated complications. Kim MK, Kim MK, Kim HS, et al. Effects of enavogliflozin on adipokine levels and metabolic health in patients with type 2 diabetes: a randomized controlled trial. Cardiovascular Diabetology. 2025;24(1):25. doi:10.1186/s12933-025-02917-z