Obesity Paradox: Does Fat Alter Outcomes in Chronic Obstructive Pulmonary Disease?

Abstract

The role of obesity and its influence on mortality in the general population has been well established. However, over the last decade, there has been substantial focus on the paradox that exists among the obese with various chronic diseases, where overweight and at least mild-moderately obese with these chronic diseases appear to have a better prognosis than do their leaner counterparts. Among them, congestive heart failure and coronary heart disease have received considerable attention. However, the influence of the obesity paradox on outcomes among patients with chronic obstructive pulmonary disease (COPD), including those requiring long-term oxygen therapy, has not been elucidated. This paper highlights the current research in this area and brings to light the lacunae that exists with regard to this paradox in COPD.

Keywords:

• body mass index
• cardiorespiratory fitness
• mortality
• physical activity

Abbreviations
BMI = body mass index	=
COPD = chronic obstructive pulmonary disease	=
CHD = cardiovascular heart disease	=
CRF = cardiorespiratory fitness	=
CVD = cardiovascular disease	=
DM = diabetes mellitus	=
FFM = fat free mass	=
HF = heart failure	=
LMI = lower lean mass index	=
PA = physical activity	=
PAD = peripheral arterial disease	=

Introduction

Being overweight and obese has been shown to be associated with an increased risk for cardiovascular disease (CVD) and all-cause mortality (1, 2). Contrary to this finding seen in a healthy population, being overweight or obese has been associated with a better prognosis in those suffering from various chronic diseases, such chronic heart failure (HF) and coronary heart disease(CHD) (3, 4). In fact recent studies have found an inverse relationship between body mass index (BMI) and mortality in CHD (5, 6), HF (7), stroke (8), chronic kidney disease (9), hypertension (10), type 2 diabetes mellitus (DM) (11), and pulmonary hypertension (12).

Noteworthy is that the obesity paradox among chronic obstructive pulmonary disease (COPD) has not been well elucidated, despite the poor prognosis seen among those with low BMI and co-existing COPD. Because the obesity paradox appears to have a role to influence outcomes in those with various chronic diseases, it is only logical that similar findings could potentially be seen among those with COPD. This paper will elucidate the influence of obesity paradox in COPD by summarizing the existing literature available in this area.

The term “obesity paradox” was coined by Gruberg et al. in 2002, following their observations on the higher risk of complications and mortality among patients who were underweight and with normal BMI compared with their overweight and obese counterparts with CHD (13). Following his observation, there have been numerous studies assessing the impact of obesity on outcomes in various chronic diseases (Table 1) (14).

Table 1.   Conditions associated with the obesity paradox

Heart failure

Coronary heart disease

Percutaneous coronary intervention

Hypertension

Stroke

Atrial fibrillation

Pulmonary hypertension

Diabetes

Transcatheter aortic valve replacement

Hemodialysis

Referral population for stress testing

Current evidence on obesity paradox

A recent meta-analysis by Flegal et al. (15), reported lower all-cause mortality in overweight and moderately obese individuals, though individuals with BMI ≥ 35 kg/m² had greater mortality. The hazard ratios were 0.95 (95% CI, 0.88–1.01) for grade 1 obesity, 0.94 (95% CI, 0.91–0.96) for overweight and 1.18 (95% CI, 1.12–1.25) for all grades of obesity combined, with significantly increased mortality in those with BMI > 35 kg/m². It was observed by Shah et al. (16) that having a low BMI placed the individual at a higher risk of mortality in acutely decompensated HF, whereas the obesity paradox was limited to a population who were > 75 years (HR: 0.82; p = 0.006), with an ejection fraction < 50% (HR: 0.85; p < 0.001), lesser cardiometabolic diseases (HR: 0.86, p < 0.001) and had new onset of HF (HR: 0.89; p = 0.004).

BMI was associated with higher mortality for every 5 kg/m² increase in BMI (HR: 0.89, 95% CI: 0.80–0.98) at 30 days and 0.91 (95% CI: 0.87–0.96) for every 5 kg/m² increase in BMI at 1 year. This phenomenon of having a lower mortality rate with higher BMI was observed globally with Asia (HR: 0.53; 95% CI: 0.39–0.72), Western Europe (HR: 0.71; 95% CI: 0.64–0.78), Central Europe (HR: 0.80; 95% CI: 0.74–0.87) and North America (HR: 0.85; 95% CI: 0.76–0.94). Similarly in patients with DM, overweight and moderately obese had lowest mortality in comparison to adults with BMI < 25 kg/m² (RR = 0.94; 95% CI: 0.91–0.96 and RR = 0.95; 95% CI: 0.88–1.01 respectively) (17). Similar findings were observed by Oreopoulos et al. (18), wherein they found that overweight and obese HF individuals had better prognosis than their leaner counterparts. That being said, it is important to realize that BMI does not differentiate between fat and lean mass.

With this setting, it became necessary to consider central obesity and not only BMI and fat free mass (FFM). Coutinho et al. (19) found that using waist circumference and waist-hip ratio improved risk stratification of CHD patients rather than only depending on BMI. However, similar relationships have not been established among those with COPD. Central obesity was seen to have higher overall mortality (HR: 1.70; 95% CI: 1.58–1.83) as well as in the subset of subjects with normal BMI (HR: 1.70, 95% CI: 1.52–1.89) and BMI ≥ 30 kg/m² (HR: 1.93; 95% CI: 1.61–2.32), whereas BMI was inversely associated with mortality (HR: 0.64; 95% CI: 0.59–0.69).

Obesity paradox in COPD

Patients with COPD are at an increased risk of developing obesity as they have decreased physical activity and due to long term use administration of systemic glucocorticoids (20). Systemic inflammation contributes to loss of FFM, especially muscle mass, accompanied by an increase in fat mass. Muscle weakness and decrease in exercise capacity due to loss of FFM is seen in moderate to severe COPD patients, thus making the FFM index a potentially better prognostic factor as compared to BMI in COPD (21). Along with FFM, weight loss has also been shown to impact prognosis of patients with COPD (22).

Landbo et al. (23), found mortality to be lowest in obese patients with severe COPD. Similar findings were seen from a population study by Jee et al. (24), wherein lower mortality risk from respiratory causes was seen among those with higher BMI. Cao et al. (25), found higher risks for mortality in underweight patients with (HR: 1.48; 95% CI: 1.26–1.75) when compared with those with a normal BMI. Patients who were overweight and obese had lower mortality than did their leaner counterparts (HR: 0.78; 95% CI: 0.65–0.94 and HR: 0.69; 95% CI: 0.54–0.89, respectively). Similar findings were also seen among those COPD patients requiring long-term oxygen therapy (26). Blum et al. (27) found that those with COPD and peripheral arterial disease (PAD) had lesser abdominal obesity with accompanying worsening of the lung disease. The risk of mortality was higher in those without PAD and was similar in symptomatic and asymptomatic patients with PAD; possibly due to impaired endothelial function. This study is the only one to assess the obesity paradox among those with COPD.

Obesity paradox in CHD and COPD

Recently, one of us has assessed the role of COPD to influence the obesity paradox in patients with CHD (28,29) (Table 2). We have demonstrated in these studies that lower BMI, lower body fat percentage, and lower lean mass index (LMI or FFM) was associated with higher mortality. In an analysis of 567 CHD patients who participated on cardiac rehabilitation after major CHD events, including 540 who coded no for COPD and 27 who coded yes for COPD, those with COPD trended lower for% body fat but had lower BMI and LMI or FFM than did those without COPD.

Table 2.   Impact of COPD on Mortality in the Coronary Cohort (29)

	Non-COPD (n = 540)	COPD (n = 27)	p value
BMI, kg/m^2	28.7 ± 5.1	25.4 ± 5.2	0.001
% BF	29.5 ± 7.9	27.3 ± 9.0	NS
LMI, kg/m^2	20.0 ± 2.8	18.1 ± 2.5	0.0005
Age, yrs	63.7 ± 10.6	71.6 ± 6.4	0.0001
Systolic BP, mm Hg	125.6 ± 19.4	124.0 ± 5.3	NS
Diastolic BP, mm Hg	73.7 ± 10.6	72.0 ± 7.2	NS
EF,%	54.5 ± 11.4	55.3 ± 9.0	NS
Peak flow O2, ml/kg/min	16.9 ± 5.2	11.8 ± 3.1	0.0001
Total cholesterol, mg/dl	166.1 ± 37.0	200.7 ± 37.5	0.0001
HDL, mg/dl	40.5 ± 11.5	63.1 ± 22.8	0.0001
LDL, mg/dl	96.5 ± 32.8	112.5 ± 34.6	0.029
Triglycerides, mg/dl	150.0 ± 84.0	125.7 ± 60.3	NS
C-reactive protein, mg/l	5.6 ± 9.3	4.1 ± 4.8	NS
Fasting glucose, mg/dl	110.9 ± 30.1	96.2 ± 10.3	0.03
% Female subjects	25.6% (138/540)	51.9% (14/27)	0.003
% Smokers	34.4% (171/497)	65.4% (17/26)	0.001
% Hypertensive subjects	1.2% (5/407)	3.9% (1/26)	NS
% Diabetic subjects	25.2% (55/218)	0% (0/24)	0.005
% Mortality	3.9% (21/540)	18.5% (5/27)	0.0004

Values are mean ± SD or% (n/N).

COPD = chronic obstructive pulmonary disease; BF = body fat; EF = ejection fraction; BMI = body mass index; BP = blood pressure; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LMI = lean mass index, as per American Medical Association (AMA) guidelines.

Reproduced with permission from reference (29).

Those with COPD were considerably older and had higher levels of total and low-density lipoprotein cholesterol but also had considerably higher levels of high-density lipoprotein cholesterol and considerably lower blood sugar values and prevalence of DM. During 3-year follow-up, mortality was increased by 4- to 5-fold in those with COPD. Nevertheless, COPD in multivariable models was not a significant independent predictor of increased mortality (HR 0.65; 95% CI: 0.18–2.32) and did not have a major impact on body fat (HR 0.91; 95% CI: 0.85–0.97) as an independent predictor of mortality, although it did modestly weaken LMI (HR 0.96; 95% CI: 0.85–1.08), whereas LMI was a much stronger predictor of mortality when COPD status was not included in the model (HR: 0.81; 95% CI: 0.65–1.00). Therefore, our data suggests that body composition influenced the relationship between COPD and mortality in patients with stable CHD.

Role of cardiorespiratory fitness (CRF) and physical activity (PA) on the obesity paradox

Despite the effects of the obesity paradox, it has been shown that CRF is an important contributor to the outcome (30). These findings were observed in the Aerobic Center Longitudinal Study, where higher CRF was seen to alter the association between adiposity and subsequent outcomes (31). Fogelholm (32) found that the risk of all-cause mortality, and due to CVD, was lower in individuals with higher BMI and good aerobic capacity; but these results were not applicable to individuals with BMI ≥35 kg/m². McAuley et al. (33) found six studies on the obesity paradox and CRF, which were supporting the hypothesis that patients with higher CRF had lower mortality rates, whereas those with low CRF had considerably higher mortality and a stronger obesity paradox, with highest mortality noted in the leaner subjects with low CRF. Sabino et al. (34) studied 32 patients with COPD categorized into underweight, overweight and obese. Overweight/obese individuals had higher FFM as well as higher exercise capacity and better functional outcomes. Therefore, it can be hypothesized that optimal CRF can alter the obesity paradox. Yet, the impact of weight loss in reducing mortality risk in obese COPD patients is not very clear.

Additionally, PA has clearly proven positive results in reducing deconditioning. Intentional weight loss due to PA and exercise training is supported in CVD, type 2 DM, and mortality, as recently reviewed by Swift et al. (35). Clearly, efforts to increase PA throughout the healthcare system are needed (36). However, the role of PA promotion among those with COPD and its impact on the obesity paradox and its related outcomes have not been well studied, suggesting potential future research on the obesity paradox and PA in COPD.

Future recommendations

Some points that need to be addressed in future research include:

1. Studying the long term outcome of obesity on outcomes among COPD patients through prospective cohorts or from existing databases;

2. Identifying the role of promoting CRF and PA and its impact on obesity and outcomes;

3. Determining the underlying mechanism of obesity paradox in COPD –is it going to be the same or different as that observed in other conditions;

4. Assessing how this paradox will alter outcomes during acute exacerbations of COPD.

Conclusion

Obesity seems to be associated with better outcomes in COPD, although CRF may be the main contributor in this “obesity paradox.” The impact of PA on improved outcomes is still unclear, although PA is likely the main contributor of increased CRF. There is clearly a strong need to increase levels of CRF among those with COPD and thereby work towards improving outcomes among those with COPD across all BMI categories.

Declaration of Interest Statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.