Obesity and lung disease in the era of GLP-1 agonists

February 6, 2024 | CHEST Physician

Kiefer Mespelt, DO ; Kimberly Fabyan, MD

GLP-1 receptor agonists

In the past year, glucagon-like peptide receptor agonists (GLP-1RAs) have garnered attention in the medical literature and popular news outlets. GLP-1RAs, including semaglutide, liraglutide, and tirzepatide, are currently FDA approved for the treatment of obesity in patients with a body mass index (BMI) greater than or equal to 30 or a BMI greater than or equal to 27 in the setting of an obesity-related comorbidity, including asthma.

This class of medications acts by increasing the physiologic insulin response to a glucose load, delaying gastric emptying, and reducing production of glucagon. In a phase III study, semaglutide resulted in greater than 15% weight reduction from baseline (Wadden et al. JAMA. 2021;1403-13). In clinical trials, these medications have not only resulted in significant, sustained weight loss but also improved lipid profiles, decreased A1c, and reduced major cardiovascular events (Lincoff et al. N Engl J Med. 2023;389[23]:2221-32) (Verma et al. Circulation. 2018;138[25]:2884-94).

GLP-1RAs and lung disease

GLP-1RAs are associated with ranges of weight loss that lead to symptom improvement. Beyond the anticipated benefits for pulmonary health, there is interest in whether GLP-1RAs may improve specific lung diseases. GLP-1 receptors are found throughout the body (eg, gastrointestinal tract, kidneys, and heart) with the largest proportion located in the lungs (Wu AY and Peebles RS. Expert Rev Clin Immunol. 2021;1053-7). In addition to their known effect on insulin response, GLP-1RAs are hypothesized to reduce proinflammatory cytokine signaling and alter surfactant production potentially improving both airway resistance and lung compliance (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Animal models suggest an antifibrotic effect with delay in the endothelial-mesenchymal transition. If further substantiated, this could impact both acute and chronic lung injury.

Early clinical studies of GLP-1RAs in patients with respiratory diseases have demonstrated improved symptoms and pulmonary function (Kanwar et al. Cureus. 2022 Oct 28. doi: 10.7759/cureus.30812). Even modest weight loss (2.5 kg in a year) with GLP-1RAs leads to improved symptoms and a reduction in asthma exacerbations. Other asthma literature shows GLP-1RAs improve symptoms and reduce exacerbations independent of changes in weight, supporting the hypothesis that the benefit of GLP-1RAs may be more than biomechanical improvement from weight loss alone (Foer et al. Am J Respir Crit Care Med. 2021;831-40).

GLP-1RAs reduce the proinflammatory cytokine signaling in both TH2-high and TH2-low asthma phenotypes and alter surfactant production, airway resistance, and perhaps even pulmonary vascular resistance (Altintas Dogan et al. Int J Chron Obstruct Pulmon Dis. 2022,405-14). GATA-3 is an ongoing clinical trial examining whether GLP-1RAs reduce airway inflammation via direct effects on of the respiratory tract (NCT05254314).

Drugs developed to treat one condition are often found to impact others during validation studies or postmarketing observation. Some examples are aspirin, sildenafil, minoxidil, hydroxychloroquine, and SGLT-2 inhibitors. Will GLP-1RAs be the latest medication to affect a broad array of physiologic process and end up improving not just metabolic but also lung health?