Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial
Research Design and Methods: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin qd or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.
Results: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated empagliflozin-induced decrease in fasting glucose and liver fat.
Conclusions: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.