Summary: In a secondary analysis of a phase-3 placebo-controlled trial in type 2 diabetes, the SGLT2 inhibitor enavogliflozin lowered leptin over 24 weeks and this persisted after adjusting for weight change, whereas the rise in adiponectin was no longer significant once weight change was accounted for.
PICO Summary
| Element | Detail |
|---|---|
| Population | Patients with type 2 diabetes; secondary analysis of a phase-3 randomised, double-blind, placebo-controlled trial, South Korea. |
| Intervention | Enavogliflozin over 24 weeks, with serum adiponectin and leptin as the focus. |
| Comparison | Placebo; analysis of covariance adjusting for baseline values and weight change. |
| Outcome | Versus placebo, adiponectin rose (LS mean difference +0.98 mg/L) and leptin fell (-2.99 µg/L). After adjusting for weight change, the leptin reduction remained significant but the adiponectin change did not. Leptin change correlated positively with HOMA-IR and HOMA-beta and negatively with serum ketone and urinary glucose. |
Enavogliflozin and adipokines in type 2 diabetes
Phase III RCT · post-hoc analysis · 24 weeks
Leptin reduction held after weight adjustment, a genuine drug signal. Adiponectin gain vanished once weight was accounted for, so read that as a weight effect. Post-hoc surrogate data; not a reason to change drug choice.
Expert Commentary
This is a worthwhile mechanistic analysis whose nuance the earlier write-up partly lost, and the distinction matters. Drawing on a properly controlled phase-3 trial rather than a single-arm cohort, it asks whether enavogliflozin improves the adipokine profile beyond what weight loss alone would explain. The honest answer is split: the fall in leptin survived adjustment for weight change, suggesting a genuine weight-independent effect on this inflammatory adipokine, but the increase in adiponectin did not survive that adjustment, meaning it was largely attributable to weight loss rather than a direct drug action. That is a more careful conclusion than a blanket claim that the whole adipokine profile improves independent of weight. The correlations of leptin change with insulin-resistance indices and with ketone and glucosuria markers fit the expected SGLT2 physiology. Limitations remain: adipokines are surrogates, this agent has thinner outcome data than empagliflozin or dapagliflozin, and 24 weeks is short. Can I use this with my patients? Supportively and precisely. It reinforces that SGLT2 inhibitors offer metabolic benefits beyond glucose and the scale, with at least the leptin effect appearing weight-independent, while I avoid overstating adiponectin, and rely on outcome trials for the cardiovascular case.
References
Lyu YS, Lee H, Kim KS, Hong S, Park CY. Weight-independent amelioration of adipokine profile by enavogliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes. Cardiovasc Diabetol. 2025;24(1):355. doi:10.1186/s12933-025-02917-z