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

Официальное название

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

Обзор

Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation, obesity-related metabolic dysfunction, skeletal muscle impairment, and progressive decline in lung function. While obesity has historically been viewed as protective in COPD, emerging evidence suggests that excess adiposity and adipokine dysregulation, particularly elevated leptin levels, contribute to chronic inflammation, impaired muscle function, and worse clinical outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated anti-inflammatory, metabolic, and potential muscle-preserving effects beyond weight loss, making them promising therapeutic candidates for COPD. The GLIMR COPD study is a prospective, randomized, controlled pilot trial designed to evaluate the effects of tirzepatide on lung function, skeletal muscle health, inflammation, and body composition in overweight and obese adults with COPD. Thirty participants will be enrolled at the Cleveland Clinic COPD Center, including 20 participants receiving tirzepatide and 10 age- and sex-matched control participants. Study participants will be followed for 12 months with assessments performed at screening, baseline, 6 months, and 12 months. Tirzepatide-treated participants will undergo standard dose escalation to a maintenance dose of 2.4 mg weekly. The primary objective is to determine the effect of GLP-1 receptor agonist therapy on skeletal muscle function and physiology over 12 months. Secondary objectives include evaluating changes in body composition, systemic inflammation, adipokine signaling, immune function, pulmonary physiology, physical performance, and treatment tolerability. The study is built around three mechanistic aims. First, we will characterize the effects of GLP-1 therapy on systemic inflammation and immune dysregulation using longitudinal blood-based proteomic analyses and adipokine measurements, including leptin and adiponectin. Second, we will investigate the impact of GLP-1 therapy on skeletal muscle mitochondrial function and fatty acid oxidation using muscle biopsies obtained at baseline and 12 months, combined with high-resolution respirometry, transcriptomics, metabolomics, and proteomics. Third, we will assess changes in clinical outcomes including lung function, body composition, muscle strength, and physical performance. Participants will undergo comprehensive phenotyping that includes spirometry, respiratory muscle strength testing, six-minute walk testing, handgrip strength, sit-to-stand testing, body composition assessment, diaphragm ultrasound, and non-contrast CT imaging of the lungs and thighs. Blood samples will be collected for biomarker, proteomic, metabolomic, genomic, and immunologic analyses. Vastus lateralis muscle biopsies will be performed at baseline and study completion to evaluate mitochondrial bioenergetics and molecular pathways associated with muscle remodeling. Eligible participants will be adults aged 40-80 years with COPD, a smoking history of at least 10 pack-years, and overweight or obesity. Individuals with diabetes, active malignancy, recent COPD exacerbations, contraindications to tirzepatide, or conditions that could interfere with study participation will be excluded. This pilot study is designed to generate critical mechanistic and clinical data regarding the role of GLP-1 receptor agonists in COPD. Findings will help define the relationships among obesity, adipokine signaling, systemic inflammation, skeletal muscle dysfunction, and lung disease progression, while providing preliminary efficacy estimates to support the design of a future multicenter randomized clinical trial evaluating GLP-1 therapy as a novel treatment strategy for COPD.

Подробное описание

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.

Вмешательства

• Препарат Tirzepatide
  Tirzepatide is a once-weekly subcutaneous dual GIP/GLP-1 receptor agonist administered for 52 weeks using standard dose escalation as tolerated in addition to standard clinical care.

Первичные конечные точки

• Change in FEV1 [Срок оценки: 12 months]

Вторичные конечные точки (6)

• Change in Hand Grip Strength [Срок оценки: 6 months and 12 months]
• Change in Six-Minute Walk Distance (6MWD) [Срок оценки: 6 months and 12 months]
• Change in Five Sit-to-Stand Performance [Срок оценки: 6 months and 12 months]
• Change in Lean Muscle Mass [Срок оценки: 12 months]
• Change in Serum Leptin Concentration [Срок оценки: 6 months and 12 months]
• Change in Skeletal Muscle Mitochondrial function [Срок оценки: 12 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Cleveland Clinic — Cleveland

Публикации

• Hong Y, Lee JH, Jeong KW, Choi CS, Jun HS. Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. J Cachexia Sarcopenia Muscle. 2019 Aug;10(4):903-918. doi: 10.1002/jcsm.12434. Epub 2019 Apr 24. PMID 31020810
• Foer D, Strasser ZH, Cui J, Cahill KN, Boyce JA, Murphy SN, Karlson EW. Association of GLP-1 Receptor Agonists with Chronic Obstructive Pulmonary Disease Exacerbations among Patients with Type 2 Diabetes. Am J Respir Crit Care Med. 2023 Nov 15;208(10):1088-1100. doi: 10.1164/rccm.202303-0491OC. PMID 37647574

Идентификаторы

NCT: NCT07747805 · IRB 25-1092 · Mandel MAG0024

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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