Study to Assess the Efficacy of Liraglutide in Patients With Type 2 Diabetes Mellitus
Primary Purpose
Type 2 Diabetes
Status
Completed
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
liraglutide
placebo
Sponsored by

About this trial
This is an interventional treatment trial for Type 2 Diabetes focused on measuring diabetes, liraglutide, lung function
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).
Sites / Locations
- Hospital Universitari Germans Trias i Pujol
- Clínica Universidad de Navarra
- Hospital Universitari Vall d´Hebrón
- Hospital Universitari Arnau de Vilanova de Lleida
- Hospital Universitario Virgen de la Victoria
- Hospital Universitario Virgen del Rocío
Arms of the Study
Arm 1
Arm 2
Arm Type
Other
Other
Arm Label
liraglutide
placebo
Arm Description
7-week subcutaneous liraglutide treatment once daily
7-week subcutaneous placebo treatment once daily.
Outcomes
Primary Outcome Measures
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second (FEV1)
Changes from baseline on measurements of respiratory function defined by forced expiratory volume in 1 second (FEV1).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Secondary Outcome Measures
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Vital Capacity (FVC)
Changes from baseline on measurements of respiratory function defined by forced vital capacity (FVC).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Changes From Baseline in Serum Levels of Surfactant A and D Protein
Changes from baseline in serum levels of surfactant A and D protein. Values for surfactant A or D protein after 7 treatment weeks (liraglutide or placebo) are registered.
Changes From Baseline on Measurements of Respiratory Function Defined by Maximum Mid-expiratory Flow (FEF25-75)
Changes from baseline on measurements of respiratory function defined by Maximum mid-expiratory flow (FEF25-75).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second/Forced Vital Capacity (FEV1/FVC)
Changes from baseline on measurements of respiratory function defined by forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Changes From Baseline on Measurements of Respiratory Function Defined by Residual Volume (RV)
Changes from baseline on measurements of respiratory function defined by residual volume (RV).
Changes From Baseline on Measurements of Respiratory Function Defined by Total Lung Capacity (TLC)
Changes from baseline on measurements of respiratory function defined by Total lung capacity (TLC).
Changes From Baseline on Measurements of Respiratory Function Defined by Residual Functional Capacity (RFC)
Changes from baseline on measurements of respiratory function defined by Residual functional capacity (RFC) are registered.
However, this parameter was not determined in patients due to an error in the programm used.
Full Information
NCT ID
NCT02889510
First Posted
August 25, 2016
Last Updated
February 9, 2021
Sponsor
Lecube, Albert, M.D.
Collaborators
Dynamic Solutions, Novo Nordisk A/S
1. Study Identification
Unique Protocol Identification Number
NCT02889510
Brief Title
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
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
October 4, 2016 (Actual)
Primary Completion Date
November 18, 2019 (Actual)
Study Completion Date
December 16, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Lecube, Albert, M.D.
Collaborators
Dynamic Solutions, Novo Nordisk A/S
4. Oversight
Data Monitoring Committee
No
5. Study Description
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:
- There is growing evidence to suggest an association between type 2 diabetes and impaired pulmonary function.
- 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.
- 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
Keywords
diabetes, liraglutide, lung function
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
76 (Actual)
8. Arms, Groups, and Interventions
Arm Title
liraglutide
Arm Type
Other
Arm Description
7-week subcutaneous liraglutide treatment once daily
Arm Title
placebo
Arm Type
Other
Arm Description
7-week subcutaneous placebo treatment once daily.
Intervention Type
Drug
Intervention Name(s)
liraglutide
Intervention Description
7-week subcutaneous liraglutide once daily
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
7-week subcutaneous placebo once daily
Primary Outcome Measure Information:
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second (FEV1)
Description
Changes from baseline on measurements of respiratory function defined by forced expiratory volume in 1 second (FEV1).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Time Frame
7 weeks
Secondary Outcome Measure Information:
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Vital Capacity (FVC)
Description
Changes from baseline on measurements of respiratory function defined by forced vital capacity (FVC).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Time Frame
7 weeks
Title
Changes From Baseline in Serum Levels of Surfactant A and D Protein
Description
Changes from baseline in serum levels of surfactant A and D protein. Values for surfactant A or D protein after 7 treatment weeks (liraglutide or placebo) are registered.
Time Frame
7 weeks
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Maximum Mid-expiratory Flow (FEF25-75)
Description
Changes from baseline on measurements of respiratory function defined by Maximum mid-expiratory flow (FEF25-75).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Time Frame
7 weeks
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Forced Expiratory Volume in 1 Second/Forced Vital Capacity (FEV1/FVC)
Description
Changes from baseline on measurements of respiratory function defined by forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC).
Mean difference between 7 weeks after treatment visit and baseline visit is registered.
Time Frame
7 weeks
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Residual Volume (RV)
Description
Changes from baseline on measurements of respiratory function defined by residual volume (RV).
Time Frame
7 weeks
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Total Lung Capacity (TLC)
Description
Changes from baseline on measurements of respiratory function defined by Total lung capacity (TLC).
Time Frame
7 weeks
Title
Changes From Baseline on Measurements of Respiratory Function Defined by Residual Functional Capacity (RFC)
Description
Changes from baseline on measurements of respiratory function defined by Residual functional capacity (RFC) are registered.
However, this parameter was not determined in patients due to an error in the programm used.
Time Frame
7 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Albert Lecube, PhD
Organizational Affiliation
Hospital Universitari Arnau de Vilanova de Lleida
Official's Role
Study Director
Facility Information:
Facility Name
Hospital Universitari Germans Trias i Pujol
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Clínica Universidad de Navarra
City
Pamplona
State/Province
Navarra
ZIP/Postal Code
31008
Country
Spain
Facility Name
Hospital Universitari Vall d´Hebrón
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Universitari Arnau de Vilanova de Lleida
City
Lleida
ZIP/Postal Code
25198
Country
Spain
Facility Name
Hospital Universitario Virgen de la Victoria
City
Málaga
ZIP/Postal Code
29010
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocío
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
10960726
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.
Results Reference
background
PubMed Identifier
18056886
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.
Results Reference
background
PubMed Identifier
11282754
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.
Results Reference
background
PubMed Identifier
20882512
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.
Results Reference
background
PubMed Identifier
20217039
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.
Results Reference
background
PubMed Identifier
19262746
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.
Results Reference
background
PubMed Identifier
18285549
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.
Results Reference
background
PubMed Identifier
18579551
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.
Results Reference
background
PubMed Identifier
14988297
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.
Results Reference
background
PubMed Identifier
15526520
Citation
Nicolaie T, Zavoianu C, Nuta P. Pulmonary involvement in diabetes mellitus. Rom J Intern Med. 2003;41(4):365-74.
Results Reference
background
PubMed Identifier
34737187
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.
Results Reference
derived
Learn more about this trial
Study to Assess the Efficacy of Liraglutide in Patients With Type 2 Diabetes Mellitus
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