Ghrelin Treatment of Cachectic Patients with Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

BackgroundPulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated.Methodology/Principal FindingsIn a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated.Conclusions/SignificanceIn cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD.Trial RegistrationUMIN Clinical Trial Registry C000000061

Ghrelin: Ghrelin as a Regulatory Peptide in Growth Hormone Secretion

“…However, the morphological characteristics and thorough distribution of ghrelin cells in the gastrointestinal tract has not been defined. Ghrelin is also produced in small amounts by other organs like heart, lung, lymphatic tissue, kidney, adrenal glands, thyroid gland, pancreas, gonads, some neoplastic tissues and cancer-cell lines [15][16][17]. Ghrelin-immunoreactive neurons are present in few regions of the brain like the arcuate and the ventromedial nucleus of the hypothalamus, cerebellum and brainstem [12,[18][19][20].…”

Effect of exacerbation frequency on body composition and serum ghrelin and adiponectin concentrations in patients with chronic obstructive pulmonary disease

“…In our study, we found a higher ghrelin concentration in patients with frequent exacerbations, but the difference was not significant. There have been attempts to treat patients with COPD and cachexia with ghrelin, 41,42 and the results seem quite encouraging. The anti-inflammatory effect of ghrelin was also the subject of studies in the experimental model of colitis, 43 hepatic disorders, 44 sepsis, 45 and rheumatoid arthritis.…”

Ghrelin – Physiological Functions and Regulation

“…104,105 Among the first applications of ghrelin in human chronic illness were studies in congestive heart failure (CHF) 106 and chronic obstructive pulmonary disease (COPD). 107,108 In the field of surgery, ghrelin comprehensively improves the patients' general conditions and quality of life via its pleiotropic physiological functions. This characteristic is unique and different from the existing drugs.…”