Could GLP-1 RAs Improve COVID-19-Induced Pulmonary Arterial Hypertension?

Recent studies show that glucagon-like peptide-1 receptor agonists have anti-inflammatory effects in human and rodent pathological models, making them a potential therapeutic strategy for treating pulmonary arterial hypertension after COVID-19 infection.

Glucagon-like peptide-1 (GLP-1) is a hormone well-known for regulating blood sugar, and GLP-1 receptor agonists (GLP-1RAs) have been used in treatment for type 2 diabetes. But recent research shows that GLP-1RAs have anti-inflammatory effects in human and rodent models that might make them a novel therapeutic strategy for treating pulmonary arterial hypertension (PAH) after COVID-19 infection.

In many cases, patients with COVID-19 experience a cytokine storm — a systemic inflammatory syndrome caused by elevated levels of circulating cytokines. It is a leading cause of inflammatory lung damage, pneumonia, and death in COVID-19 patients. A recent article published in Medical Hypotheses noted that even in patients who recover from COVID-19, some studies show evidence of lung damage present after inflammatory biomarkers return to normal.

An autopsy of lung tissue from a COVID-19 patient revealed a thickened pulmonary vascular wall, which is a key characteristic of PAH. Therefore, author Jong Han Lee, of the Department of Marine Bio and Medical Science at Hanseo University in South Korea, presented the hypothesis that GLP-1RAs have the potential to play a role in combating COVID-19 in patients with characteristics of PAH.

Aside from the glycemic control that lends GLP-1RAs to diabetes treatment, the treatment has been shown to reduce circulating inflammatory biomarkers in patients with diabetes and obesity. In mouse and rat studies, GLP-1RAs have proven effective in reducing pulmonary inflammation, reducing cytokine production, and preserving lung function in those with lung injury. These studies suggest a potential role for GLP-1RAs in treating systemic inflammation and as a therapy for COVID-19 patients showing signs of PAH.

However, there is controversy around the use of GLP-1RAs in the COVID-19 treatment setting, “mainly because of its unstable therapeutic effects and the angiotensin-converting enzyme 2 (ACE2) upregulation induced by GLP-1RAs,” Lee noted. ACE2 allows virus entry into host target cells, but it may improve lung injury during COVID-19, and ACE2 overproduction may counteract the ACE2 decline typically seen as infections progress.

The leading cause of COVID-19 deaths is pulmonary insufficiency, and Lee cites reports that autopsies have shown thickened pulmonary vascular walls in patients who died from COVID-19. In lung injury rodent models, studies have shown GLP-1RAsreduce inflammation, cytokine production, and mucus secretion. Reports also show that GLP-1RAs improve lung function in patients with diabetes regardless of glucose levels, and therefore may directly affect lung tissue.

Further studies showed GLP-1 receptor overexpression can suppress cytokine release in chronic obstructive respiratory diseases, and preclinical studies suggest they reduce both cytokine production and lung inflammation. A study of 60-day mortality after a positive SARS-CoV-2 (the virus that causes COVID-19) polymerase chain reaction test showed GLP-1RAs reduce the rate of mortality. Another study found that GLP-1RAs did not increase respiratory tract infection and pneumonia risks in patients with cardiovascular comorbidities or type 2 diabetes.

If further clinical evidence supports the use of GLP-1RAs in alleviating PAH and inflammatory response in patients with COVID-19, it may hold promise in this treatment setting.

“Since signs of lung damage last longer, people with a history of SARS-CoV-2 infection are more likely to develop PAH in their future,” Lee wrote. “Therefore, apart from their lowering blood glucose effects, GLP-1RAs will be a new clinical option for the treatment of PAH at least due to its anti-inflammatory effects targeting lung tissue.”

Reference

Lee JH. Potential therapeutic effect of glucagon-like peptide-1 receptor agonists on COVID-19-induced pulmonary arterial hypertension. Med Hypotheses. Published online December 9, 2021. doi:10.1016/j.mehy.2021.110739