Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

Abstract

Objective: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.

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 every day 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 the 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.

Trial registration: ClinicalTrials.gov NCT03227484.

© 2022 by the American Diabetes Association.

Figures

Figure 1

Primary outcome: impact of empagliflozin treatment on insulin action in the brain. A: Interaction of treatment × time on insulin responsiveness of the brain. Whole-brain analysis revealed a significant cluster in the hypothalamus, as indicated by the color-coded F map (PFWE < 0.05, small-volume corrected). B: Insulin response in regional CBF of the hypothalamus was extracted. Presented are box plots with whiskers indicating 1.5 interquartile range. P value is for treatment × time interaction that was tested by repeated-measures ANOVA. Model of treatment group (empagliflozin vs. placebo) as a predictor of fasting glucose (C) and liver fat content (D) after 8 weeks of treatment mediated by improved hypothalamic insulin responsiveness. Path coefficients and corresponding P values are shown next to arrows; path a indicates the relationship between treatment and hypothalamic insulin action after treatment; path b indicates the relationship between the hypothalamic insulin response and fasting glucose levels or liver fat content at the end of treatment; path ab indicates the indirect effect of treatment on fasting glucose or liver fat via hypothalamic insulin response; and path c’ indicates the direct effect of treatment on fasting glucose or liver fat.

Figure 2

Impact of empagliflozin vs. placebo on key secondary outcomes. A: The course of fasting plasma glucose was different between the two treatment groups. No significant interaction between treatment × time was detected for 2 h glucose during the OGTT (B) or BMI (C). The course of total adipose tissue content (D) and liver fat content (E) was significantly different between treatment groups. Caloric energy intake did not change during the study (F). Presented are box plots with whiskers indicating 1.5 interquartile range. P values are for treatment × time interactions that were tested by repeated-measures ANOVA.