A glucagon-like peptide-1 receptor agonist has been found to prevent pulmonary fibrosis in a mouse model of type 2 diabetes following SARS-CoV-2 infection, according to findings published in the Journal of Virology.
The effect appeared to work independently of glucose lowering, pointing toward an anti-inflammatory mechanism that could eventually matter for patients who develop lung-related postacute sequelae of COVID-19.
For pharmacists managing GLP-1 RA therapy in patients with T2D, the work adds another dimension to a drug class whose nonglycemic effects continue to expand.
The incidence of pulmonary PASC among people with T2D is 4 times higher than among those without T2D, and the immune mechanisms behind that gap have remained poorly characterized.
Researchers at the University of Hong Kong reanalyzed a previously published single-cell RNA sequencing data set from patients hospitalized with COVID-19, comparing those with T2D against those without across 3 timepoints.
Patients with T2D showed significantly upregulated fibrosis-related genes in monocytes that correlated positively with pulmonary fibrosis biomarkers at the convalescent timepoint.
They used db/db mice as a T2D model and found that SARS-CoV-2 infection produced persistent lung fibrosis and long-lasting weight loss not seen in nondiabetic controls.
Depleting pulmonary macrophages with clodronate liposomes significantly reduced collagen deposition and improved weight recovery, establishing proinflammatory macrophages as determinants of the fibrotic response.
Study leader Runhong Zhou, PhD, noted that people with diabetes experience far more severe infection-related disease after COVID-19 than others and that the team wanted to understand the source of those long-term symptoms.
Mice received daily intraperitoneal injections of a GLP-1-Fc construct or control-Fc from day 1 through day 14 postinfection.
Treatment reduced diffuse alveolar damage, decreased α-smooth muscle actin production, and prevented collagen deposition in the lungs at 15 days postinfection.
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Critically, nonfasting blood glucose fell only nonsignificantly, supporting a glucose-independent antifibrotic effect.
Mechanistically, the GLP-1 RA appeared to reprogram bone marrow-derived macrophages, restoring CXCL10 induction that was absent in infected diabetic mice and suppressing the fibrosis genes.
The GLP-1 receptor is highly expressed in lung tissue, which the authors cite as a plausible route for local activity.
It is worth looking at how this finding compares to other situations where antidiabetic agents have shown potential in preventing long-term complications, such as metformin studies that have explored its role in reducing the risk of long COVID.
In the COVID-OUT trial, outpatient metformin reduced long COVID incidence by approximately 41% versus placebo over 300 days.
More recent data reinforced that signal.
Because metformin increases endogenous GLP-1 secretion, the study authors speculate the mechanisms may overlap.
Pharmacists fielding questions about GLP-1 RAs and long COVID should be clear about the evidentiary ceiling here.
Zhou characterized the findings as preliminary proof of concept involving a small number of mice.
Patients with T2D carry an raised risk of restricted pharmacy access and persistent respiratory symptoms after COVID-19, and adherence to existing therapy plus vaccination remains the evidence-based intervention.
The authors also note that the practical takeaway is counseling accuracy.
