Research Focuses on GLP-1RAs to Improve COPD

The evidence that glucose-lowering medications can improve symptoms of chronic obstructive pulmonary disease (COPD) in people with diabetes has been growing, but a few studies, including a clinical trial currently underway in the United States, have explored the potential of glucagon-like peptide 1 receptor agonists (GLP-1RAs) specifically to treat advanced pulmonary disease in patients who may not have diabetes.

The latest evidence of the potential of GLP-1RAs to improve COPD comes from a comparative effectiveness research study of almost 400,000 patients with diabetes taking glucose-lowering medications from three major US insurance claims databases. The study found that patients taking GLP-1 RAs as well as sodium-glucose cotransporter-2 inhibitors (SGLT-2is) had a lower risk for moderate or severe COPD exacerbation than patients taking dipeptidyl peptidase-4 inhibitors (DPP-4is).

“SGLT-2is and GLP-1RAs may help reduce COPD exacerbations through anti-inflammatory effects, weight loss, cardiovascular benefits, and potential lung-protective mechanisms, leading to better respiratory health,” lead study author Avik Ray, MD, MS, of Brigham and Women’s Hospital and Harvard Medical School in Boston, told Medscape Medical News.

This follows a Danish clinical trial in patients with obesity and COPD that found that 40 weeks of treatment with the GLP-1RA liraglutide increased forced vital capacity and carbon monoxide diffusion capacity and improved COPD assessment test scores. “Our study suggests that liraglutide at 3 mg may be an appropriate treatment in patients with obesity and COPD,” the study authors wrote.

A ‘Game Changer’ Drug?

Nathan Stall, MD, PhD, an editorial fellow of JAMA Internal Medicine who authored a commentary on Ray’s study and practices internal medicine and geriatrics at Sinai Health System and the University of Toronto, Toronto, Ontario, Canada, said the body of work supporting the use of glucose-lowering medications to treat pulmonary disease, along with other indications, is growing.

“The term ‘game changer’ is far too often used to describe therapeutic advances in medicine,” Stall told Medscape Medical News. “However, in the setting of SGLT2-inhibitors and GLP-1RAs, the term fits. These medications were initially developed as glucose-lowering medications for people with type 2 diabetes, with additional benefits of weight loss. There is now robust and accumulating evidence that these medications have remarkable additional benefits beyond controlling blood sugars, including for patients with heart failure and kidney disease, and sometimes even for patients without diabetes.”

Other studies have found that SGLT-2is prevented COPD exacerbations in patients with diabetes. A 2022 retrospective study of 31,411 patients enrolled in the COPD registry at Carle Foundation Hospital in Urbana, Illinois, found patients on SGLT-2is had about one sixth the incidence of COPD exacerbation vs other patients (3.16% vs 18.3%; P < .05).

“There was reduction in the overall incidence of COPD exacerbation, including the incidence of severe exacerbation needing hospitalization and ICU [intensive care unit] admissions,” Susan Gupta, MD, a pulmonary critical care fellow at the Medical College of Wisconsin, Milwaukee, who led the Illinois study, said, although the reduction in overall ICU admissions didn’t reach statistical significance. The study also found that SGLT-2i drugs were associated with a lower incidence of COPD exacerbation regardless of underlying diabetes control.

Would SGLT-2is Have the Potential to Control COPD Exacerbations in Patients Without Diabetes?

“This is a very interesting realm to be studied more in detail,” Gupta said. “There is data to support that SGLT-2 inhibitors might impact pathways that are not related to glucose and might reduce exacerbations in COPD, so it would be interesting to study to see the impact of SGLT-1 in nondiabetic patients with COPD and whether they have a similar effect in reducing exacerbations.”

Elisabetta Patorno, MD, DrPH, the senior author of the comparative effectiveness research study with Ray at Brigham & Women’s Hospital, said that extrapolating the results of their study to patients with COPD who do not have diabetes would be a stretch. “Further research is needed to confirm whether similar benefits exist in nondiabetic COPD populations,” she said.

Stall noted that the results from the study by Patorno and Ray should be interpreted with caution. The patients taking DPP-4is “were notably different” from those treated with SGLT-2is or GLP-1RAs before propensity matching, he said. “Those initiating treatment with DPP-4is were older and more likely to be men, have frailty, and have more advanced COPD,” he said. “This makes it likely that they may have differed on crucial unmeasured characteristics as well; thus, the groups may not be fully comparable.”

Stall also noted the study had limited data on baseline A1c levels and no data on A1c levels after the patients started taking the drugs. “Glycemic control is well known to be associated with the progression and prognosis of COPD,” he said. The study also did not include information on patient weight; SGLT-2is and GLP-1RAs are known to be associated with weight loss, while DPP-4is are generally weight neutral, he added.

What Other Studies Have Found

A 2023 retrospective observational study out of Massachusetts General Hospital also found that GLP-1RA users had about a 50% lower rate of COPD exacerbation than patients on DPP-4is and almost half the rate of patients taking sulfonylurea. A 2022 population-based cohort study using a United Kingdom database found a 30% lower risk for severe COPD exacerbations in GLP-1RA users than in DPP-4is users and a 38% lower risk for SGLT-1is. Both studies enrolled patients with type 2 diabetes.

Michaela Anderson, MD, MS, an assistant professor of pulmonology, allergy, and critical care at the University of Pennsylvania, Philadelphia, noted the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) trial last year showed the potential of GLP-1RA treatment for obesity to decrease the rate of infection-related acute respiratory failure in patients with COVID-19; patients on GLP-1RAs who had COVID-19 were less likely to have a COVID-related serious adverse event or die of COVID-19. 

Further supporting this finding, Anderson noted a study this year of more than 2 million patients in Veterans Affairs databases found that patients on GLP-1RAs had a reduced risk for a host of comorbidities, including several respiratory diseases.

GLP-1RAs and Advanced Lung Disease

Anderson is leading a phase 1/2 clinical trial of semaglutide in patients with advanced lung disease that is currently recruiting patients. An impetus for the study is that a large percentage of patients with interstitial lung disease or COPD, the two most frequent indications for lung transplantation, are obese, she said. “Right now, these patients are excluded from life-saving lung transplantation at many centers,” Anderson said.

Lung transplant candidate selection guidelines state that a body mass index (BMI) > 35 is a high risk, and a BMI of 30-35 is considered an increased risk for poor outcomes, Anderson noted. Her research team surveyed transplant providers and found that more than half required candidates to have a BMI of ≤ 32 and 25% required a BMI of ≤ 30.

“These guidelines are because lung transplant recipients with obesity, defined by BMI of 30 or greater, are more than twice as likely to develop early lung injury — primary graft dysfunction — and are at significantly increased risk for death after lung transplantation,” she said.

“My big picture question is whether treatment of obesity in advanced lung disease can increase access to lung transplantation and improve lung transplant outcomes,” Anderson said. She noted the potential concerns with GLP-1RA use in patients with chronic respiratory disease: They increase the risk for gastroparesis, gastroesophageal reflux, and muscle mass loss, “all potential drivers of poor outcomes in chronic respiratory disease.”

The goal of the study is threefold, Anderson said: To evaluate if patients can tolerate semaglutide when they are using it with medications to treat advanced lung diseases; to understand how these medications alter both adipose tissue and muscle mass in a population at high risk for frailty and low muscle mass; and to develop a preliminary assessment of effectiveness in patients who also frequently use medications that lead to weight gain, such as prednisone.

Patorno reported a financial relationship with Boehringer Ingelheim. Ray, Stall, Gupta, and Anderson reported no relevant financial relationships.

Richard Mark Kirkner is a medical journalist based in Philadelphia.