GLP-1 Agonists for Lung Function Improvement and Muscle Restoration in COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is increasingly recognized as a systemic disease that affects far more than the lungs. In addition to airflow limitation, many individuals with COPD experience chronic inflammation, loss of skeletal muscle function, reduced exercise capacity, and metabolic abnormalities that contribute substantially to disability, hospitalizations, and reduced quality of life. Obesity, which is highly prevalent among patients with COPD, further worsens these systemic manifestations through complex interactions involving inflammation, altered hormone signaling, and impaired energy metabolism. Despite the significant burden imposed by these metabolic and musculoskeletal complications, few therapies specifically target the underlying biological pathways that connect obesity, inflammation, muscle dysfunction, and lung disease.

The GLIMR COPD study is a randomized, controlled pilot clinical trial designed to investigate whether treatment with the GLP-1/GIP receptor agonist tirzepatide can improve lung function, skeletal muscle health, physical performance, and systemic inflammation in overweight and obese individuals with COPD. Beyond its established effects on weight reduction and glucose regulation, tirzepatide has demonstrated potent anti-inflammatory and metabolic benefits that may favorably influence multiple biological pathways involved in COPD progression. Emerging evidence suggests that GLP-1-based therapies can reduce inflammatory signaling, improve mitochondrial function, enhance skeletal muscle metabolism, and alter adipokine profiles, including reductions in circulating leptin, a hormone that has been strongly associated with worse COPD outcomes.

The study will enroll 30 participants with COPD, including 20 individuals receiving tirzepatide and 10 age- and sex-matched control participants. Participants will undergo detailed evaluations at baseline, six months, and twelve months. These assessments will include pulmonary function testing, exercise capacity measurements, muscle strength testing, body composition analysis, imaging studies, blood biomarker analyses, and skeletal muscle biopsies. By combining clinical assessments with advanced molecular analyses, the study seeks to understand not only whether tirzepatide improves health outcomes, but also the biological mechanisms responsible for those improvements.

The first objective of the study is to determine how tirzepatide influences systemic inflammation and immune dysfunction in COPD. Blood samples collected throughout the study will undergo comprehensive proteomic and biomarker analyses to identify changes in inflammatory pathways and circulating mediators associated with treatment. Particular attention will be given to adipokines such as leptin and adiponectin, which may serve as important links between obesity and COPD progression.

The second objective is to investigate the effects of tirzepatide on skeletal muscle health. Skeletal muscle dysfunction is a major contributor to exercise intolerance and reduced quality of life in COPD. Muscle biopsies obtained before and after treatment will be used to evaluate mitochondrial function, fatty acid oxidation, gene expression, protein signaling, and metabolic pathways that regulate muscle performance and adaptation. These studies will provide important insights into whether tirzepatide directly improves muscle bioenergetics and cellular health.

The third objective is to quantify the effects of tirzepatide on clinically meaningful outcomes. Investigators will assess changes in lung function, respiratory muscle strength, exercise capacity, muscle strength, physical performance, and body composition. Advanced CT imaging will be used to measure changes in skeletal muscle mass, visceral fat, and other body composition characteristics. These measurements will help determine whether improvements in metabolic health translate into better physical function and pulmonary outcomes.

Participants eligible for enrollment will be adults aged 40-80 years with COPD and overweight or obesity. The study is being conducted through the Cleveland Clinic COPD Center, which follows more than 2,500 patients and has extensive experience in COPD clinical research and translational investigations.

The long-term goal of this project is to establish a scientific foundation for larger multicenter clinical trials evaluating incretin-based therapies as novel treatment strategies for COPD. By examining the interconnected relationships among obesity, inflammation, skeletal muscle dysfunction, and lung disease, this study has the potential to identify new therapeutic approaches that address both pulmonary and systemic manifestations of COPD. The findings may ultimately help improve physical function, quality of life, and long-term outcomes for millions of individuals living with COPD.

Inclusion criteria

• Age 40-80 years
• Diagnosis of chronic obstructive pulmonary disease (COPD) with post-bronchodilator FEV₁/FVC < 0.70
• GOLD stage 1-3 COPD (FEV₁ >30% predicted)
• Former smoker with a smoking history of at least 10 pack-years
• Body mass index (BMI) ≥27 kg/m² with at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) or BMI 30-40 kg/m²
• Able and willing to provide written informed consent
• Able to comply with study procedures and follow-up visits

Exclusion criteria

• Type 2 diabetes mellitus (HbA1c > 6.5%)
• Pregnancy or breastfeeding
• Coagulopathy, defined as INR > 1.4 or platelet count <80,000/μL
• Active malignancy, including lung cancer
• Use of medications known to significantly alter muscle protein metabolism within 6 weeks of enrollment (e.g., oral corticosteroids, tamoxifen, high-dose estrogen, testosterone)
• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2 (MEN2)
• Known hypersensitivity or contraindication to tirzepatide or its components
• History of pancreatitis
• Severe gastrointestinal disease that, in the opinion of the investigator, would increase risk from study participation
• Significant diabetic retinopathy
• Clinically significant renal impairment
• Clinically significant gallbladder disease
• Current treatment with a DPP-4 inhibitor
• COPD exacerbation within 60 days prior to enrollment
• Participation in pulmonary rehabilitation within 2 weeks prior to enrollment
• Any medical, psychiatric, or social condition that, in the opinion of the investigators, may interfere with study participation, adherence to study procedures, or participant safety