Effects of Ghrelin Treatment on Exercise Capacity in Underweight COPD Patients: a substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment

Chronic obstructive pulmonary disease (COPD) is a major health issue, especially in its advanced stages. It is characterized by a significant systemic deterioration, so-called pulmonary cachexia, that affects exercise capacity, quality of life, and survival in such patients [1‐6]. Treatment strategies targeting pulmonary cachexia have been attempted and have provided insight into the pathogenetic mechanisms of pulmonary cachexia [2, 7].

Pulmonary rehabilitation (PR) is recommended as a therapeutic strategy in many diseases, including cachectic COPD [8]. However, it has been important to determine whether cachectic COPD patients are capable of adaptive responses to PR, because PR may partially disturb anabolic and catabolic balance in such patients [2, 9].

Ghrelin is an endogenous ligand for growth hormone (GH) secretagogue receptor (GHSR), originally isolated from the stomach [10]. Given that ghrelin has GH-releasing activity, ghrelin may have beneficial effects in COPD patients through a GH-dependent mechanism. Meanwhile, as a GH-independent mechanism, ghrelin induces a positive energy balance by decreasing fat utilization [11], stimulating food intake and adiposity [12], increasing cardiac output in healthy humans [13], and inhibiting sympathetic nerve activity [13, 14]. In an open-label pilot study, we previously demonstrated that ghrelin may improve walking distance and inhibit sympathetic nerve activity in underweight COPD patients [15]. More recently, a multicenter, randomized, double-blind, placebo-controlled trial was conducted to investigate the efficacy and safety of adding ghrelin to PR in underweight COPD patients, and it showed that ghrelin administration improved symptoms and respiratory muscle strength. While the results were considered most likely to have been due to ghrelin treatment, the precise mechanism that underlies the improvement of exercise performance or symptoms remains unclear. This study was simultaneously conducted in a single center as part of a multicenter, randomized, double-blind, placebo-controlled study of underweight COPD patients [16]. The primary objective was to investigate whether ghrelin-PR combination treatment would improve exercise capacity. A secondary objective was to determine whether the underlying mechanisms of the improvements in response to ghrelin would be associated with improvement of exertional cardio-respiratory functions and attenuation of exertional sympathetic nervous system activity. Some results of this trial have been reported in abstract form [17].

The protocol for this trial and Supplementary Results are available as supporting information; see Additional file 1 (Protocol) and Additional file 2 (Supplementary Results).

A total of 20 underweight patients (mean BMI (SD), 18.3 (2.3) kg/m²) was randomized to ghrelin treatment with PR (ghrelin group; n = 10) or placebo treatment with PR (placebo group; n = 10), and all patients completed the study protocol. There were no significant differences in baseline characteristics between the two groups (Table 1). No significant difference in the total work performed during 3-week PR (mean ± SD: ghrelin group, 6970 ± 6169 watt·min versus placebo group, 7167 ± 4310 watt·min, between-group p = 0.935) was observed. Next, the effects of ghrelin administration on exercise capacity, as well as the underlying mechanisms were examined once (Week 3) using two measurement points: iso-time and the peak exercise point.

This substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment in underweight COPD patients was designed and powered to investigate the effects of repeated ghrelin administration and the underlying mechanisms using cardiopulmonary exercise testing. The main findings were as follows. 1) With incremental exercise, in the ghrelin group, the mean change from pre-treatment i) in peak V • o 2 was significantly increased compared with the placebo group, and ii) that in dyspnea intensity showed a significant within-group decrease at the iso-time point. Furthermore, iii) the mean changes from pre-treatment in V • E / V • c o 2, V • E / V • o 2, and V_D/V_T were significantly improved compared with the placebo group at peak exercise; iv) the mean change from pre-treatment in V_T showed a significant within-group increase at peak exercise; and v) that in O₂-pulse was increased compared with the placebo group at peak exercise. 2) With constant-load exercise, in the ghrelin group, the mean change from pre-treatment in IC showed a significant within-group increase throughout exercise.

Many approaches to treating cachectic COPD have been attempted [2, 7]. In the present study, exercise training alone did not show significant improvements in exertional capacity and cardio-ventilatory parameters, except for endurance time. In the placebo group, V • o 2 (mean difference: -0.8 mL/kg/min, within-group: p = 0.051) and O₂-pulse were not improved at the iso-time point (Table 3). The plasma norepinephrine levels seemed to be inhibited at the iso-time point (Table 3). Given the reported negative connotations of sympathetic activation in cardiac as well as respiratory disease patients [22‐26], sympathetic inhibition may have positive consequences in COPD. These findings suggest that underweight patients with COPD who undergo exercise training can only increase their endurance time, efficiently decreasing V • o 2 and plasma norepinephrine levels. In contrast, repeated ghrelin administration was associated with a significant increase from pre-treatment in the peak V • o 2 by an average of 1.4 mL/kg/min (between-group p = 0.025, Table 2 and Figure 2A). Endurance time was not increased after ghrelin-PR combination treatment (Table 2). These findings suggest that patients treated with ghrelin had a high exercise capacity with instantaneous force, though the pedal revolutions per minute on the electrically braked-cycle ergometer were not monitored. We considered the following potential mechanisms for the increase in exercise capacity that was induced by ghrelin treatment: i) improved ventilatory efficiency and ventilatory volume; and ii) increased cardiac function.

The two major contributing factors leading to exercise limitation in COPD may be the increased ventilatory requirement and the decreased ventilatory capacity [27]. In the ghrelin group, V_D/V_T, V • E / V • c o 2, and V • E / V • o 2, which are useful to estimate wasted ventilation, were significantly decreased at peak exercise (Table 2, Figure 2B and C), resulting in a decreased ventilatory requirement. These findings suggest that ghrelin treatment was associated with an improvement of ventilatory efficiency at peak exercise. V_T during incremental exercise (Tables 2 and 3) and IC during constant-load exercise were increased after ghrelin-PR combination treatment, though the difference compared with placebo was not significant. Additionally, increased peak V • o 2 after ghrelin treatment was positively correlated with the change in V • E from pre-treatment. In the present study, 4 weeks after the completion of ghrelin and PR treatment, MEP was better in the ghrelin group than in the placebo group (Table 4). These findings suggest that these improvements in ventilatory parameters may occur through the mechanism by which ghrelin improved respiratory muscle strength [16]. On the other hand, ghrelin may have additional beneficial effects within the cardiovascular system in underweight COPD patients. Earlier studies showed that ghrelin improved cardiac function in normal subjects and in patients/animals with heart failure [13, 28, 29]. In the ghrelin group, the O₂-pulse after treatment increased significantly compared with placebo at peak incremental exercise. Furthermore, a recent study demonstrated that ghrelin acts on the central nervous system to attenuate sympathetic nervous activity [14], though in the present study, as well as in the main study, ghrelin treatment did not show significant sympathetic inhibition compared with placebo. Further studies are needed to confirm the clinical significance such as regulating exertional dyspnea. Nevertheless, we believe that these improvements in cardio-ventilatory parameters could represent the effect of ghrelin.

It should be noted that individuals in this study had different reactions to PR or ghrelin therapy. Of note, in the present study, the exercise capacity improvement by exogenous ghrelin was negatively correlated with the increase in the plasma acyl-ghrelin level after treatment (r = -0.684). Since the half-life of exogenous ghrelin, which was administered on the day before blood sampling, was about 20 min [30], it is highly possible that the measured plasma acyl-ghrelin level was unaffected by the administered exogenous ghrelin, and reflected the endogenous acyl-ghrelin. These correlations may stand to reason, given that ghrelin administration is considered as replacement therapy for underweight COPD patients who may be unable to compensate for the anabolic-catabolic imbalance, resulting in increasing the endogenous plasma acyl-ghrelin levels, thought repeated exogenous ghrelin might inhibit ghrelin production [31]. Meanwhile, as an effective adjunctive therapy, we used exercise training as a part of PR, which is well accepted to improve exercise performance [8, 32]. However, it is important to determine whether PR improves or worsens it, especially in underweight patients in the severe disease stage.

This study had some limitations. First, the number of participants was small, and few women were included in this trial. Given the exploratory nature of the present study, a formal power calculation was not possible. Many statistical comparisons under exercise conditions might increase the chance of type I error. As a consequence, the present findings should be considered preliminary and need to be confirmed in a future large study. Second, ghrelin did not show any effects on whole lean body mass and weight. The training work rate remained at the initial setting in 4 patients (40%) in each group during this trial, because they found the initial training work rate intolerable. The lack of response to exercise training or ghrelin treatment in weight and whole lean body mass may be related to the inability to tolerate the type, the intensity, and/or the duration of the exercise training. Third, there was a significant difference between the ghrelin and placebo groups in the peak V • o 2 measured by the protocol of 2-min increments to 10 W in the present study. However, in the main multicenter trial at Week 3, outcome measurements measured with a continuous ramp rate of 5 W/min showed no improvements with ghrelin compared to placebo [16]. In the present study, in the ghrelin group, the mean change from pre-treatment in the peak V • o 2 measured by the protocol of 2-min increments to 10 W was larger than that measured by the protocol with the ramp rate of 5 W/min (mean difference: by 2-min increments to 10 W, 1.4 mL/kg/min versus with a ramp rate of 5 W/min, 1.1 mL/kg/min). See Table E1 in Additional file 2 (Supplementary Results) for other details. Several investigators have suggested the desirability of adjusting the work rate increment in exercise testing according to the patient’s cardiopulmonary condition [33, 34]. Tests in which the work rate increased too rapidly may not allow sufficient data for the evaluation to be accumulated. A more suitable exercise testing protocol, considering the patient’s cardiopulmonary condition, should have been conducted in the main multicenter trial. Also, in the present study, at Week 7, i.e., 4 weeks after the completion of the treatment, CPET should have been conducted to evaluate the sustained effects of ghrelin treatment, as shown in the multicenter trial [16].

Given the short-term nature of the study and the discrepancy between the physiological findings and the measures of direct patients benefit, the present findings need to be confirmed by further study. However, in the present substudy, ghrelin administration was associated with improved exertional capacity and improvements in cardio-ventilatory parameters, although the main multicenter study showed no significant difference between the ghrelin and placebo group in exercise capacity. Development of ghrelin administration as a novel cachexia-targeted therapy capable of improving exercise performance may be helpful in COPD treatment.