Effect of Liraglutide on Intermittent Hypoxia-Induced Metabolic Dysfunction: From Bench to Bedside.

Abstract

Intermittent hypoxia (IH)-mediated adipose tissue inflammation with M1 macrophage polarisation plays a key role in the pathogenesis of metabolic diseases in obstructive sleep apnoea (OSA). Effective treatment strategies are so far lacking. Here, we hypothesised that a glucagon-like peptide (GLP)-1 (Liraglutide)-based weight loss regimen improves IH-induced metabolic perturbations. To test the hypothesis, we employed a comprehensive translational approach consisting of an innovative IH system for cell cultures, a murine IH model of diet-induced obese mice and a proof-of-concept randomised-controlled study in OSA (NCT04186494). Liraglutide significantly attenuated IH-mediated pro-inflammatory polarisation of bone marrow-derived murine macrophages in cell culture. However, this did not translate into improved IH-induced insulin resistance in C57Bl/6 mice fed on a high-fat diet despite significant weight loss. In OSA subjects without diabetes (n = 30, 50 ± 7 years, 80% males, apnoea-hypopnoea index [AHI] 50 ± 19/h, body mass index [BMI] 35.0 ± 3 kg/m²), Liraglutide in contrast to CPAP over 24 weeks led to improvement in insulin sensitivity (mean difference 1.91 ± 1.46 vs. -1.02 ± 2.75, p = 0.03) in correlation with reduction in anthropometric measures and visceral adipose tissue volume. However, in conjunction with its limited effect on OSA parameters, the combination of Liraglutide with CPAP therapy appeared superior to Liraglutide alone for improvement of other glycaemic parameters such as fasting glucose, glucose tolerance, or HbA1c. In summary, while Liraglutide is effective in mediating weight loss, a lack of improvement in IH-triggered metabolic dysfunction does not support its role as monotherapy for metabolic diseases in OSA.