Glucagon-like peptide 1 receptor agonists (GLP-1RA) are FDA-approved for treating type 2 diabetes (T2D), and in preclinical and clinical studies, they have also shown beneficial effects on the airway.

Now, a team at Brigham and Women’s Hospital has reported that patients with T2D and chronic obstructive pulmonary disease (COPD) who initiate GLP-1RA have decreased risk of both moderate and severe COPD exacerbations, compared with users of sulfonylureas or dipeptidyl peptidase 4 inhibitors (DPP-4i). Users of GLP-1RA and sodium–glucose cotransporter 2 inhibitors (SGLT2i) had similar exacerbation outcomes.

Dinah Foer, MD, an attending physician in the Division of Allergy and Immunology at the Brigham, Elizabeth W. Karlson, MD, MS, a rheumatologist and epidemiologist in the Division of Rheumatology, Inflammation, and Immunity at the Brigham and vice-president of Personalized Medicine at Mass General Brigham, Zachary Strasser, MD, formerly of Massachusetts General Hospital, and colleagues detail the findings in the American Journal of Respiratory and Critical Care Medicine.

Methods

The study was a retrospective analysis of the electronic health record system for Mass General Brigham. Using natural language processing, a form of artificial intelligence (AI), the researchers extracted key data (e.g., on smoking and pulmonary function testing) that identified 1,642 patients with COPD who received a new prescription for a diabetes drug between January 1, 2012, and May 27, 2022:

• Sulfonylurea users—701 (43% of the cohort)
• SGLT2i users—353 (21%)
• GLP-1RA users—328 (20%)
• DPP-4i users—260 (16%)

Primary Outcome

The primary outcome was the combined number of moderate and severe exacerbations during the six months after drug initiation. A severe exacerbation was defined as an inpatient encounter with a COPD code as the primary and/or principal diagnosis. A moderate exacerbation was defined as a prednisone prescription for COPD during the six-month period.

In a multivariate model that considered demographic and clinical factors (the “clinical model”), exacerbation rates compared with GLP-1RA use were:

• Sulfonylurea use—Incidence rate ratio (IRR), 2.09 (P<0.0001)
• DPP-4i use—IRR, 1.48 (P=0.02)
• SGLT2i use—Rate not significantly elevated

The researchers also used a “metabolic model” that added baseline BMI and baseline hemoglobin A1c to the clinical model. In those analyses, exacerbation rates were elevated only among sulfonylurea users (IRR, 1.97; P<0.0001) compared with GLP-1RA users.

Secondary Outcome

The secondary outcome was exacerbation risk, defined as days to COPD exacerbation from the date of drug initiation.

In the clinical model, the risk of moderate exacerbation compared with GLP-1RA use was:

• Sulfonylurea use—HR, 2.09 (P<0.0001)
• DPP-4i use—HR, 1.52 (P=0.01)
• SGLT2i use—Risk not elevated

The risk of severe exacerbation was:

• Sulfonylurea use—HR, 2.21 (P=0.0004)
• DPP-4i use—HR, 1.85 (P=0.02)
• SGLT2i use—Risk not elevated

In the metabolic model, risk of moderate exacerbation remained increased only for sulfonylurea users (HR, 1.92; P<0.0001).

The risk of severe exacerbation in the metabolic model was:

• DPP-4i use—HR, 2.04 (P=0.005)
• Sulfonylurea use—HR, 2.63 (P<0.0001)
• SGLT2i use—Risk not elevated

Implications for Personalized Medicine

If prospective studies support these findings, they could guide treatment choices for patients with comorbid COPD and T2D, analogous to the selection of GLP-1RA for patients with comorbid atherosclerotic cardiovascular disease or SGLT2i for those with comorbid heart failure.

More broadly, the potential therapeutic relevance of metabolic pathways in COPD is intriguing, and further study is warranted to understand the mechanisms underlying the associations observed here.