Study to Assess the Efficacy of Liraglutide in Patients With Type 2 Diabetes Mellitus
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): liraglutide; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 7-week subcutaneous liraglutide once daily; 7-week subcutaneous placebo once daily
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: diabetes; liraglutide; lung function