Obesity in COPD: to treat or not to treat?

KEYWORDS:

• COPD
• obesity
• comorbidity
• respiratory
• management

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a significant chronic disease, particularly in aging populations. Both the prevalence and mortality of COPD are increasing throughout the world [1], at a time when other chronic diseases show a reduction in disease burden. In 2010, COPD became the third leading cause of death worldwide [1]. New and more effective approaches to management of COPD are urgently needed.

Precision medicine is defined as treatments that are targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations [2]. The National Institutes of Health’s Precision Medicine Initiative was launched by President Obama in 2015, as an attempt to advance this area for certain diseases. We believe that precision medicine is also important in COPD. Since COPD is a multisystem illness with systemic consequences and comorbidities [3], it is now recommended that therapy should be precisely tailored to the specific disease components or ‘treatable traits’ that manifest most significantly in each individual [3,4]. In one controlled clinical trial, this approach led to highly significant improvements in health status [3].

Despite this new approach to COPD care, the management of comorbid obesity in COPD remains an important evidence gap. Body composition may be one such lifestyle/psychosocial ‘treatable trait’ that can be targeted using precision medicine. Historically, COPD has been associated with sarcopenia (involuntary loss of skeletal muscle mass that usually occurs with advancing age), and particularly so as the disease progresses. However, obesity is now becoming increasingly common in COPD, and in some populations, obesity is now more prevalent in COPD than in the general population [5–7]. In an Australian cohort of older people with COPD, we found that 42% of participants were obese (BMI ≥ 30 kg/m²) and 35% were overweight (BMI ≥25 and <30 kg/m²) [6].

2. COPD and obesity

COPD without obesity significantly impacts exercise capacity, health status, health-care utilization, and mortality [8]. The burden of COPD with coexisting obesity is amplified, as patients with both conditions may experience increased health-care utilization, have worse dyspnea and poorer health-related quality of life, more marked reduction in functional capacity, and increased physical inactivity [7]. In addition, sarcopenia remains common in obesity and is associated with poor functional outcomes [9].

3. The COPD obesity paradox

Obesity can potentiate many of the known comorbidities associated with COPD, such as cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), skeletal muscle dysfunction, and obstructive sleep apnea [10]. The mechanism may be via chronic low-grade systemic inflammation [7], a key metabolic change in obesity. In mild–moderate COPD, CVD is the leading cause of death.

Paradoxical to the impact of obesity in the general population, overweight and mild obesity in COPD are also reported to be associated with improved survival [11,12] and a slower decline in lung function [10]. This was first described in 1999 using data from The Copenhagen City Heart Study [11], a large prospective study with long-term follow-up. Landbo et al. reported that BMI had an independent effect on all cause and COPD mortality, in severe COPD patients. Not only did they demonstrate that the low BMI population had the highest mortality (risk ratio [RR] 1.63, 95% CI, 1.15–2.31), but they also reported better survival in the overweight (RR 0.66, 95% CI, 0.49–0.87) and obese (RR 0.62, 95% CI, 0.41–0.94) categories, compared to healthy weight COPD patients. Other studies have since reported similar findings and in 2016, Guo et al. [12] reported the results of a meta-analysis of 17 studies evaluating the dose–response relationship between BMI and mortality. Compared to healthy weight individuals with COPD, the RR for death in underweight was 1.40 (95% CI, 1.20–1.63; p = 0.0001), whereas the risk of death was reduced in those in the overweight (RR 0.80, 95% CI, 0.67–0.96; p = 0.0001) and obese categories (RR 0.77, 95% CI, 0.62–0.95; p = 0.0162). There was a significant and nonlinear relationship between mortality and BMI categories. Those with a BMI <21.75 kg/m² had the greatest risk of dying. The lowest risk was in those with a BMI of 30 kg/m²; however, once BMI exceeded 32 kg/m², the protective effect of high BMI was no longer evident, suggesting that the survival benefit associated with increased body weight is evident only in those who are overweight or mildly obese.

Interestingly, this reverse epidemiology or ‘obesity paradox’ is also evident in other chronic diseases including CVD, chronic heart failure, stroke, chronic kidney disease, and T2DM [13].

4. To treat or not to treat?

Because of the ‘obesity paradox,’ the most appropriate therapeutic strategy for the management of obesity in COPD is unknown. Clinicians face the dilemma of whether to recommend weight loss in obese COPD patients, which may improve cardiovascular outcomes but may worsen respiratory outcomes and even increase their risk of death. If weight loss is recommended, what is the ideal intervention? This is especially problematic because weight loss interventions in older people result not only in fat loss but also loss of skeletal muscle mass, which is very detrimental in COPD. At present, there is no level I or II evidence to inform the management of obese COPD patients and international experts have called for research in this area [14]. This is a particularly important issue, as it is likely that the prevalence of coexisting obesity and COPD will continue to increase, placing a major and ongoing burden on the health-care system and on the lives of patients and their caregivers.

A recent study by the present authors reported a novel intervention for obese COPD. This study evaluated the feasibility of a weight loss intervention in obese COPD participants and the effect on COPD outcomes [15]. The pilot study enrolled 28 obese COPD patients who underwent dietary counseling and calorie restriction using meal replacements and resistance exercise training. Weight loss was achieved (mean (SD) loss 6.4 (3.6) kg; p < 0.0001) and important clinical outcomes improved. There was a 2.4 (1.1)-kg/m² (p < 0.0001) reduction in BMI, but, importantly, skeletal muscle mass was maintained. Furthermore, there were clinically and statistically significant improvements in exercise capacity; the mean 6MWD increased by 32.1 (44.0) m; p = 0.0006. Health status also improved; the mean (SD) change in the St George Respiratory Questionnaire total score was 9.6 (12.7) units, which is greater than two times the minimally important difference of four units, p = 0.0005. This improvement in health status despite only a moderate weight loss is consistent with results reported in an obese asthma population, where between 5% and 10% loss of body weight resulted in clinically significant improvements in health status and asthma control [16]. Interestingly, the mean baseline BMI was 36.1 kg/m² and 75% of participants remained obese following the intervention, with no participants achieving a BMI < 25 kg/m². These data suggest that a treatment strategy that includes targeted interventions to reduce body weight and maintain skeletal mass over a 3-month period leads to improved outcomes, with the majority remaining in the BMI category associated with reduced mortality risk. However, a definitive randomized controlled trial of such an intervention with longer term follow-up is now needed. At present, there is only one weight loss trial registered on clinicaltrials.gov (NCT02634268) that is targeting obese COPD individuals. This study encourages weight loss through a series of sessions delivered by digital video disks. The sessions’ focus of attention is on healthy eating and physical activity, and participants are encouraged to monitor their weight, diet, and physical activity for 2 years. The co-primary outcomes are weight loss and 6-min walk distance. It will be very important to assess whether this intervention leads to behavioral change or has any positive or deleterious impact on skeletal muscle.

Pulmonary rehabilitation could be a vehicle for obesity management, as it is an effective multidisciplinary treatment intervention for people with COPD which improves exercise capacity, health-related quality of life, dyspnea, and health-care utilization [17]. The current goals of pulmonary rehabilitation, however, do not include weight loss per se, and there are few data to suggest that this occurs, although data from one study report that it is achievable [18]. Interventions for obesity could potentially be incorporated into such programs. Targeting treatable traits within pulmonary rehabilitation, such as has been done with anxiety, is an area that requires further investigation.

The limited evidence in this field clearly indicates that this is an area that requires further investigation. In particular, how can obesity management be incorporated into models of pulmonary rehabilitation and can tailoring treatment to target obesity as a treatable trait be achieved? Furthermore, understanding the effect of treating one comorbidity on others is an interesting question; for example, if obesity is targeted, what effect does this have on not only COPD outcomes, but also on the connected comorbidities such as anxiety, depression, skeletal muscle dysfunction, and cardiovascular and metabolic markers? Do these comorbidities work in partnership with each other? Moreover, whilst resistance exercise training and a very low calorie diet leads to improved outcomes in a proof of concept study [15], the most appropriate model of intervention requires further investigation. Understanding the mechanisms for the obesity paradox is also important.

5. Summary

Obesity in COPD is becoming increasingly common; it is associated with decreased exercise capacity, increased CVD risk, and reduced health status. However, the obesity paradox shows that it is also associated with improved survival. Should we treat obesity in COPD? The current data suggest that a BMI around 30 kg/m² is associated with the greatest survival, but as weight continues to increase, this effect is diminished. The few studies that have examined the effect of a weight loss intervention in obese COPD suggest that when coupled with resistance exercise training, weight loss leads to improved outcomes. This is clearly an area where more research and funding must be directed; definitive studies to inform treatment guidelines are urgently needed. However, in the mean time, it would appear that obesity in COPD is a ‘treatable trait,’ and the targeted intervention could include dietary counseling, calorie restriction, and resistance exercise training to achieve a BMI close to 30 kg/m².

Declaration of interest

VM. McDonald is supported by an NHMRC TRIP fellowship. She has participated in educational symposia funded by GlaxoSmithKline, AstraZeneca, Menarini, Boehringer Ingelhiem and Novartis. She has participated in studies funded by GlaxoSmithKline and advisory boards for GlaxoSmithKline, Novartis, AstraZeneca and Menarini. PG. Gibson holds an NHMRC Practitioner Fellowship. He has participated in educational symposia funded by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis, and has participated in studies funded by GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.