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
Highlights
Pulmonary cachexia is common in the advanced stage of chronic obstructive pulmonary disease (COPD), and it is an independent risk factor for death in such patients [1,2]
Plasma ghrelin levels were elevated in cachectic COPD patients and were associated with the cachectic state and pulmonary function abnormalities, suggesting that endogenous ghrelin increased to compensate for the cachectic state and may provide important clues to improve the catabolic-anabolic imbalance in such patients[12]
Because i) it is difficult to prolong hospitalization considering the current status of health care insurance in Japan, and ii) what constituted a clinically important change in 6-min walk distance (6-MWD) after ghrelin treatment with pulmonary rehabilitation (PR) was not known before the study ended; the sample size calculation was re-performed on the estimated effect of only ghrelin treatment for improving 6-MWD, which was based on information from the pilot study [13]
Summary
Pulmonary cachexia is common in the advanced stage of chronic obstructive pulmonary disease (COPD), and it is an independent risk factor for death in such patients [1,2]. Based on the notion that advanced COPD affects the whole body and causes wasting syndromes, many different therapeutic approaches have been attempted to improve this syndrome [1,3]. Plasma ghrelin levels were elevated in cachectic COPD patients and were associated with the cachectic state and pulmonary function abnormalities, suggesting that endogenous ghrelin increased to compensate for the cachectic state and may provide important clues to improve the catabolic-anabolic imbalance in such patients[12]. In an open-label pilot study, we showed that ghrelin treatment increased walking distance in cachectic COPD patients [13]. Based on the above available evidence, a multicenter, randomized, double-blind, placebo-controlled study was conducted to test the hypothesis that the addition of ghrelin treatment to PR might benefit cachectic COPD patients. The objectives were to investigate the efficacy and safety of adding ghrelin to PR in cachectic COPD patients
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