Clinical trial NCT02889510: Study to Assess the Efficacy of Liraglutide in Patients With Type 2 Diabetes Mellitus
Official title: Multicentre Randomized Double Blind, Crossover, Placebo Controlled Clinical Trial to Evaluate the Effect of Liraglutide on Lung Function in Patients With Type 2 Diabetes Mellitus (LIRALUNG Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Keywords: diabetes
liraglutide
lung function
Lead sponsor: Lecube, Albert, M.D.
Sponsor class: INDIV
Collaborators: name: Dynamic Solutions
name: Novo Nordisk A/S
First posted: 2016-09-05
Enrollment: 76
Sex: ALL
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Type 2 diabetes (T2DM) is related to reduced pulmonary function. As experimental studies with glucagon-like peptide 1 (GLP-1) have shown an increase in pulmonary surfactant secretion, and the GLP-1 receptor has been found in significant amounts in the lung, it could be hypothesized that the treatment with liraglutide (a GL-1 agonist) will improve this reduced pulmonary function

Detailed description: There is growing evidence to suggest an association between type 2 diabetes and impaired pulmonary function. In this regard, several cross-sectional studies have appeared showing decreased indices of forced expiration, lung volume and diffusion capacity as the main lung dysfunctions detected in type 2 diabetic populations. In fact, diabetes is frequently co-morbid with chronic obstructive pulmonary disease, and data from the Atherosclerosis Risk in Communities Study showed a faster pulmonary function decline in type 2 diabetic patients than in other participants. This is important because the reduction of FEV1 has been demonstrated an independent cause of mortality in diabetic patients.

Interestingly, lung function measures start to decrease several years before the diagnosis of diabetes. In this regard an investigation found that insulin resistance is an independent determinant of pulmonary function in non-diabetic morbidly obese women. In addition, the results suggest that the metabolic pathways related to insulin resistance are crucial in initiating lung abnormalities in type 2 diabetic patients.

The reasons for the association between respiratory disease and diabetes are unclear. However, the relationship between type 2 diabetes and muscle strength, the impairment in lung elastic properties, and the presence of a low-grade chronic inflammation state are involved. In supporting these findings, thickening of the alveolar epithelia and pulmonary capillary basal lamina, fibrosis, centrilobular emphysema, and pulmonary microangiopathy have been detected in autopsies of diabetic patients. In addition, defects in the bronchiolar surfactant layer, which is involved in maintaining airway stability and diameter, may also be considered a contributing factor to the impairment of airway calibre regulation in diabetic patients. When the alveolocapillary barrier is damaged, surfactant proteins leak into the bloodstream. A recent population-based random sample study has described how increased circulating levels of surfactant protein A, the major surfactant-associated protein, were associated with altered glucose tolerance and insulin resistance. Therefore, surfactant defects in diabetic individuals may also lead to an increase in airway resistance and to a reduction in ventilatory patterns as observed in our studies. In addition, as experimental studies have shown that glucagon-like peptide 1 plays a role in the stimulation of surfactant production, its underlying deficit in type 2 diabetes could also enhance the airway resistance observed in these patients. However, the beneficial effects on pulmonary function using incretin-based therapies remain to be elucidated.

Clinical trial study hypothesis is that treatment with an incretin mimetic such as liraglutide may ameliorate lung function parameters in type 2 diabetics patients, independently of weight reduction. This hypothesis is based on the following factors:

1. - There is growing evidence to suggest an association between type 2 diabetes and impaired pulmonary function.
2. - In patients with type 2 diabetes, the incretin effect is severely reduced or absent, contributing to the reduced lung function parameters observed in type 2 diabetic patients.
3. - GLP-1 stimulates surfactant production in "in vitro" studies and, in consequence, the increase in surfactant production induced by liraglutide could be the main factor involved in the respiratory improvement.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent.
* Subjects between 40 and 65 years old. Diagnosis of type 2 diabetes mellitus with more than 5 years of evolution of disease.
* Metformin (alone or in combination with sulfonylurea and / or insulin and / or thiazolidinediones) at a stable dose for at least the past 3 months.
* HbA1c ≥ 7,0 y ≤ 9,0 %.
* BMI between 30 and 40 kg / m2.
* No pulmonary disease (COPD, asthma, fibrosis, etc) known.
* Baseline FEV1 decline of equal or greater than 10% in the percentage of the theoretical value.
* Chest radiography without significant changes in the lung parenchyma

Exclusion Criteria:

* Type 1 diabetes mellitus
* Treatment with inhibitors of dipeptidyl peptidase 4 glitazones and / or
* SGLT2 inhibitors.
* Active and former smokers for less than five years ago smoking.
* Chronic obstructive pulmonary disease.
* Respiratory sleep disorders that require treatment with continuous positive pressure in the airway.
* Asthma treatment with bronchodilators.
* Previous bariatric surgery.
* Cardiovascular disease, heart failure and / or stroke.
* Pathology of the chest wall.
* Serum creatinine\> 1.7 mg / dl.
* Abnormal results in liver function test (Alanine transaminase/ Aspartate Aminotransferase greater than twice the upper limit of normal).
* History of acute or chronic pancreatitis.
* Personal or family history of medullary thyroid cancer or Multiple
* Endocrine Neoplasia (MEN ) type 2.
* Active neoplasms or neoplastic patients considered disease-free history from less than 5 years ago.
* Women of childbearing age who are pregnant (positive pregnancy test within 14 days before the start of treatment) or intend to get pregnant.
* Lactating women.
* Women of childbearing potential not using adequate contraception (such as oral contraceptives, intrauterine device or barrier method of birth control along with spermicide or surgical sterilization) or unwilling to use during the study (as required by local laws or practices).

Primary outcomes:
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: 7 weeks
Secondary outcomes:
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Forced Vital Capacity (FVC)
timeFrame: 7 weeks
measure: Changes From Baseline in Serum Levels of Surfactant A and D Protein
timeFrame: 7 weeks
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Maximum Mid-expiratory Flow (FEF25-75)
timeFrame: 7 weeks
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second/Forced Vital Capacity (FEV1/FVC)
timeFrame: 7 weeks
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Residual Volume (RV)
timeFrame: 7 weeks
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Total Lung Capacity (TLC)
timeFrame: 7 weeks
measure: Changes From Baseline on Measurements of Respiratory Function Defined by Residual Functional Capacity (RFC)
timeFrame: 7 weeks
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d´Hebrón
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
Study officials:
affiliation: Hospital Universitari Arnau de Vilanova de Lleida
name: Albert Lecube, PhD
role: STUDY_DIRECTOR
References:
citation: Davis TM, Knuiman M, Kendall P, Vu H, Davis WA. Reduced pulmonary function and its associations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract. 2000 Oct;50(2):153-9. doi: 10.1016/s0168-8227(00)00166-2.
citation: Yeh HC, Punjabi NM, Wang NY, Pankow JS, Duncan BB, Cox CE, Selvin E, Brancati FL. Cross-sectional and prospective study of lung function in adults with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2008 Apr;31(4):741-6. doi: 10.2337/dc07-1464. Epub 2007 Dec 4.
citation: Vara E, Arias-Diaz J, Garcia C, Balibrea JL, Blazquez E. Glucagon-like peptide-1(7-36) amide stimulates surfactant secretion in human type II pneumocytes. Am J Respir Crit Care Med. 2001 Mar;163(4):840-6. doi: 10.1164/ajrccm.163.4.9912132.
citation: Lecube A, Sampol G, Munoz X, Lloberes P, Hernandez C, Simo R. Insulin resistance is related to impaired lung function in morbidly obese women: a case-control study. Diabetes Metab Res Rev. 2010 Nov;26(8):639-45. doi: 10.1002/dmrr.1131. Epub 2010 Sep 29.
citation: Lecube A, Sampol G, Munoz X, Hernandez C, Mesa J, Simo R. Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study. Diabetologia. 2010 Jun;53(6):1210-6. doi: 10.1007/s00125-010-1700-5. Epub 2010 Mar 9.
citation: Lecube A, Sampol G, Lloberes P, Romero O, Mesa J, Hernandez C, Simo R. Diabetes is an independent risk factor for severe nocturnal hypoxemia in obese patients. A case-control study. PLoS One. 2009;4(3):e4692. doi: 10.1371/journal.pone.0004692. Epub 2009 Mar 5.
citation: Fernandez-Real JM, Chico B, Shiratori M, Nara Y, Takahashi H, Ricart W. Circulating surfactant protein A (SP-A), a marker of lung injury, is associated with insulin resistance. Diabetes Care. 2008 May;31(5):958-63. doi: 10.2337/dc07-2173. Epub 2008 Feb 19.
citation: Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008 Oct;32(4):962-9. doi: 10.1183/09031936.00012408. Epub 2008 Jun 25.
citation: Davis WA, Knuiman M, Kendall P, Grange V, Davis TM; Fremantle Diabetes Study. Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. 2004 Mar;27(3):752-7. doi: 10.2337/diacare.27.3.752.
citation: Nicolaie T, Zavoianu C, Nuta P. Pulmonary involvement in diabetes mellitus. Rom J Intern Med. 2003;41(4):365-74.
citation: Lopez-Cano C, Ciudin A, Sanchez E, Tinahones FJ, Barbe F, Dalmases M, Garcia-Ramirez M, Soto A, Gaeta AM, Pellitero S, Marti R, Hernandez C, Simo R, Lecube A. Liraglutide Improves Forced Vital Capacity in Individuals With Type 2 Diabetes: Data From the Randomized Crossover LIRALUNG Study. Diabetes. 2022 Feb 1;71(2):315-320. doi: 10.2337/db21-0688.