Glucagon-Like Peptide-1 Receptor Agonists in Obesity-Induced Respiratory Pathophysiology

The days of glucagon-like peptide 1 receptors (GLP1R) agonists (GLP1RAs) serving as niche treatments for type 2 diabetes mellitus (TD2M) and obesity are long gone. These agents have evolved into a major class of therapeutics with wide-reaching clinical impact. One in eight US adults use a GLP1RA, reflecting their efficacy and expanding indications [1]. The therapeutic reach of GLP1RAs is expected to expand even further, with studies investigating potential applications in Alzheimer’s disease [2] and polycystic ovary syndrome. Here we outline the role of GLP1RAs in respiratory physiology and indicate mechanisms of GLP1RAs in treating respiratory disorders.

GLP1RAs received FDA approval for obstructive sleep apnea (OSA) [3], a prevalent respiratory condition characterized by total or partial closure of the upper airway during sleep, leading to intermittent hypoxia and hypercapnia. OSA is associated with higher cardiovascular mortality. Several OSA patients also have obesity hypoventilation syndrome (OHS), defined by diurnal hypercapnia in obese individuals without other causes of hypoventilation. Positive airway pressure (PAP) is the first-line treatment for OSA and OHS. However, alternative therapies are needed due to low treatment adherence.

OSA is strongly related to obesity. Surgically induced, conventional weight loss, and lifestyle interventions based on diet and physical activity decrease apnea-hypopnea index (AHI), with benefits that can persist even after the intervention ends. Given the increase in interest in GLP1RAs in controlling body weight and TD2M, one may argue that the activation of GLP1R may be beneficial in the control of breathing and upper airway patency. Several GLP1RAs have been tested in clinical trials. Liraglutide, a GLP1RA, reduces mean AHI in patients with obesity and moderate/severe OSA [4]. Tirzepatide, (Zepbound) a dual receptor long-acting agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP1R, is an effective treatment of OSA in obese adult individuals. However, the effect of liraglutide and tirzepatide in improving the AHI was secondary to body weight reduction, and it is still unclear whether they have direct effects on the respiratory neurons [3]. The potential of GLP1RAs to enhance the hypercapnic ventilatory response, increase breathing during sleep, and reduce AHI and oxyhemoglobin desaturations suggests a promising role in the treatment of OSA in obesity. Investigating the mechanisms of direct activation of GLP1R in respiratory neurons in the brainstem, with minimal effects on metabolism or body weight, could open new avenues not only for the treatment OSA and OHS, but also for hypoventilation syndromes unrelated to obesity, such as opioid-induced respiratory depression or congenital central hypoventilation syndrome.

Tirzepatide was approved by the FDA for OSA in overweight individuals in conjunction with calorie restriction and increased physical activity, showing benefits in respiratory function. Tirzepatide has been evaluated in individuals with a BMI above 30kg/m² and OSA. Patients on PAP combined with tirzepatide had a greater decrease in AHI compared to placebo and tirzepatide alone [3]. It also remains critical to find treatments that alleviate upper airway obstruction for individuals with normal BMI and for patients who may not adhere to PAP. These previous studies place tirzepatide in the center of the discussion about the dual agonist regulation not only in glycemia and body weight, but also as a potential pleiotropic role in the treatment of respiratory disorders. Lastly, there is an emerging new class of GLP1RA, triple-hormone receptor agonist (retatrutide), which acts as a GLP1, GIP, and glucagon receptor agonist and has a long half-life. This agonist is undergoing clinical trials for the treatment of obesity and was able to reduce BMI compared to placebo.

Diet-induced obese (DIO) mice reveal a typical phenotype of OSA and OHS with daytime hypercapnia and hypoventilation with recurrent hypopneas and apneas during sleep. Leptin, an adipocyte-produced hormone, and the melanocortin system, a downstream pathway of leptin, stimulate breathing during sleep in polygenic/environmental mouse models of OHS and OSA [5].

Leptin stimulates GLP1 secretion from enteroendocrine L cells through activation of the leptin receptor. DIO mice exhibit lower basal and glucose–induced plasma GLP1 levels. These findings provide a proof of concept that leptin promotes GLP1 secretion and suggest that leptin resistance may contribute to the reduced GLP1 levels observed in obesity [6]. GLP1RAs can reverse obesity-induced leptin resistance in mice [7], which is consistent with clinical trials showing that GLP1RAs decrease circulating leptin levels [8]. These findings suggest that the beneficial effects of GLP1RAs in OSA may be not only mechanical, through weight loss, but also functional, by reducing leptin resistance.

GLP1R are embedded throughout multiple physiological regulatory networks, including the neuroendocrine, cardiovascular, and respiratory systems, making them attractive targets for a broad spectrum of diseases. An escalating prevalence of respiratory complications coincides with a growing body of research utilizing GLP1RAs treatment for their conditions. GLP1RAs improve OSA, but it remains unclear whether this benefit is mediated by weight loss or by direct GLP1 effect on the central nervous system (CNS). GLP1R are expressed in several respiratory regions, including the parabrachial nuclei (PBN) in the pons, which shape post-inspiratory motor output, and the nucleus of solitary tract (NTS) [9]. NTS is composed of several populations of neurons that integrate visceral afferent signals, serve as a key gateway for neural control of breathing, and establish synaptic contacts to several CNS regions.

Upper airway muscle tone is regulated mainly by the hypoglossal nerve (XII), which innervates the genioglossus muscle, the main tongue protruder. Targeting hypoglossal motoneurons that may express GLP1R or GLP1R+ neurons projecting to the hypoglossal nucleus may serve as a drug target in OSA by improving upper airway patency.

Systemic administration of GLP1RAs increases NTS neural activity [10]. Locus coeruleus (LC), a key noradrenergic nucleus involved in arousal, respiratory, and cardiovascular functions, expresses GLP1R [11], indicating a potential role of GLP1 signaling in modulating respiratory function via NTS and/or LC (Figure 1). Catecholaminergic A1/C1 neurons that participate in respiratory pattern generation also express GLP1R [12]. However, the effects of GLP1R activation in CNS regions that control breathing and upper airway patency in health and disease remain poorly understood. GLP1R in the pre-Bötzinger complex, a bilateral structure in the ventrolateral medulla responsible for respiratory rhythm generation, and in the retrotrapezoid nucleus (RTN), a central chemoreceptor detecting CO₂ and H⁺, has not been investigated. The lack of comprehensive studies examining GLP1R expression in respiratory neurons and their colocalization with specific neuronal markers limits translational research in respiratory diseases.

FIGURE 1 |.

Glucagon-like peptide-1 receptors (GLP1R) and its pleiotropic mechanisms controlling respiratory functions in health and disease. GLP1R are expressed in respiratory regions of the brainstem. GLP1R are located in respiratory nuclei including the parabrachial nucleus (PBN), locus coeruleus (LC), and nucleus tractus solitarius (NTS). These regions contribute to the control of breathing, carbon dioxide (CO₂) sensitivity, and upper airway patency through circuits involving the Kölliker-Fuse nucleus (KF), pre-Bötzinger complex (pre-BotC), Bötzinger complex (BotC), retrotrapezoid nucleus (RTN), rostral ventral respiratory group (rVRG), caudal ventral respiratory group (cVRG), and XII (hypoglossal). Facial nucleus (VII). GLP1R are also found in carotid bodies, composed of Type I (glomus) and Type II (sustentacular) cells. Created with BioRender.com.

Another potential site of GLP1-mediated respiratory effects is the carotid bodies (CBs), peripheral chemoreceptors located at the bifurcation of the common carotid arteries that detect changes in arterial oxygen. CBs are composed of type I (glomus cells), type II cells, progenitor cells, and neural afferents. Glomus cells’ activation stimulates afferent fibers of the carotid sinus nerve and its projections to the NTS. CBs-mediated input to the NTS neurons enhances respiratory motor output. No changes in respiratory rate or phrenic nerve activity were observed when GLP1RAs were applied directly to the CBs [13].

Besides the eventual effects of GLP1R signaling on CNS respiratory regions and CBs, previous studies have shown that GLP1RAs reduce mortality and improve lung function in mice with obstructive lung disease [14]. A cohort study documented that GLP1RAs significantly improved lung function of the TD2M population without co-existing chronic obstructive respiratory disorders [15] supporting the hypothesis that GLP1RAs have beneficial effects in respiratory diseases.

In summary, GLP1RAs are primarily used to manage TD2M and weight loss, but offer several additional benefits, including improvements in respiratory diseases, which can positively impact conditions such as OSA and OHS independent of weight loss.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.