Challenging the obesity paradox: extreme obesity and COPD mortality in the SUMMIT trial

Discussion

Data from the large, international SUMMIT trial including patients with moderate COPD at heightened cardiovascular risk demonstrates that BMI is associated with risk of all-cause mortality at the extremes; specifically, among underweight (BMI <20 kg·m⁻²) and obese class III (BMI ≥40 kg·m⁻²). Moderate levels of obesity and overweight are associated with lower risk of death. Risk of death due to respiratory causes is highest among underweight individuals, though the leading cause of death in all BMI categories is cardiovascular, with the highest risk among obese class III. A “U-shaped” curve (with a protective association with overweight) was not consistently identified for morbidity outcomes.

The findings support and extend several studies demonstrating that underweight is a substantial risk factor for mortality in patients with COPD [1, 8, 19–21]. It has been argued that there is reverse causation with increasing severity of illness coinciding with weight loss and underweight status [20]. While the ability of nutritional supplementation and weight gain to reduce COPD mortality remains unclear [22, 23], the relationship between underweight and mortality exists even within patients with mild or moderate disease [8], suggesting that disease severity alone may not account for increased mortality among underweight. Furthermore, findings in the SUMMIT population are consistent with prior studies demonstrating a protective association between overweight and obesity and COPD mortality [2, 24–26]. The protective associations with higher BMI are typically strongest with increasing disease severity [8], and are reflected here in a population with moderate disease. In all categories, cardiovascular mortality predominated, consistent with population studies demonstrating cardiovascular disease as a leading cause of death in patients with COPD [11, 12, 27] and reasonable in this population at heightened cardiovascular risk.

Because of the large number of participants in the trial, there were a substantial number with class III obesity. Although class I obesity was associated with a lower mortality risk, individuals with class III obesity demonstrated increased risk for mortality. Indeed, weight gain in obese patients has previously been associated with increased mortality in individuals with severe COPD [28]. While overall increased mortality rates above 40 kg·m⁻² might be expected based on well-known associations with hypertension, hypercholesterolaemia, and diabetes, the prevalence of these conditions were similar between BMI classes II and III at trial initiation, suggesting a potential alternative explanation. Other comorbidities not captured in the SUMMIT data may play a role. For example, class III obesity is also associated with higher rates of sleep apnoea [29], which is linked to increased mortality and is an important comorbidity in COPD [30, 31]. Further, COPD phenotype may play a role in BMI–mortality relationships; patients with an emphysematous phenotype are more likely to be underweight, whereas patients with a chronic bronchitis phenotype are more likely to be overweight [32]. While these diagnoses are not mutually exclusive, it is possible that disease phenotypes are partially responsible for the associations noted.

Few studies in the current literature have examined associations between BMI and COPD morbidity outcomes, although several have combined morbidity and mortality into a single variable [24, 33]. These studies overall demonstrate increased respiratory morbidity in the underweight (i.e. hospitalisations [33], hospital length of stay [24], pneumonia [18]), although at least one previous analysis suggests higher odds of severe COPD exacerbation at the opposite end of the BMI spectrum, class III obesity [34]. Extreme obesity may confer disadvantageous changes in pulmonary function such as increased airway resistance and reduced lung volumes [35], relevant to individuals with COPD with already compromised respiratory mechanics. It is plausible that this may contribute to respiratory morbidity and exacerbations. Interestingly, in the SUMMIT trial population, overweight was associated with a lower risk of pneumonia. This is consistent with previous findings in the TORCH trial [36] demonstrating lower rates of pneumonia in higher BMI groups [18]. Furthermore, overweight was associated with a lower risk of severe COPD exacerbations, but no increased risk was noted in underweight or class III obese populations. In contrast to overweight, lower mortality rates in class I obesity were not matched with reduced morbidity for the measured outcomes, suggesting the potential for an unmeasured morbidity signal. We did not find an association between BMI category and cardiovascular event risk; previous studies of cardiovascular morbidity outcomes in COPD by BMI are sparse, but suggest higher prevalence of heart failure with obesity, though not necessarily stroke or coronary heart disease [34, 37, 38], which comprise the majority of the events captured in the SUMMIT trial. The discordance between morbidity and mortality outcomes in relation to BMI deserves further attention, and the selection of outcomes is important in defining any future nutritional intervention trials.

Strengths include a study design that allowed for longitudinal assessment of a large number of participants including a critical population with obesity class III, limited in previous COPD studies. Patients with severe and very severe COPD were excluded, providing the opportunity to investigate the paradox in a dedicated cohort with less-severe COPD, which may mitigate confounding of lower weight by higher disease severity. Cardiovascular risk was defined, allowing for adjustment but also mitigating competing respiratory risk in cause-specific mortality analyses. Deaths within the study were carefully adjudicated, with high ascertainment of vital status and confidence in primary and secondary outcomes. Ability to define cause-specific morbidity and mortality outcomes in a single population is unique. International representation increases generalisability of results, while precise characterisation of lung function and rigorous assessment of cardiovascular health enhances validity of application among populations with moderate COPD at heightened cardiovascular risk.

Weaknesses are acknowledged. While cardiovascular comorbidities were well defined, additional comorbidities were not captured, limiting assessment of potential contributing factors. Furthermore, the relatively small number of cardiovascular events (compared with all-cause mortality) may have limited power to distinguish between BMI groupings. In this study, a BMI of 20 kg·m⁻² was chosen as the lower limit of the normal weight category for primary analyses. This cut-off point may reduce comparability with other disease states, and falls between the BMI of 21 kg·m⁻² in the BODE index [39] and 18.5 kg·m⁻² in WHO guidelines [17] to define at-risk/underweight populations. However, 20 kg·m⁻² has been used in previous studies demonstrating the obesity paradox in populations with COPD [24, 25], and is of proposed benefit in facilitating international comparisons [40]. This approach combined with sensitivity analyses using the cut-off point of BMI 18.5 kg·m⁻², provides increased granularity and generalisability. History of smoking was an inclusion criterion in the trial, and so differential associations among smokers/nonsmokers and resultant selection bias by smoking was not explored [41]. Residual confounding by region may exist. Underweight individuals were more likely to be enrolled in Asia, whereas obese class II/III individuals were more likely enrolled in Europe and the USA, and outcomes may be influenced by local patterns of medical care and exposures. Adjustment for additional covariates not available within the SUMMIT data may provide more precision in estimates, and reveal factors that adjust or modify the obesity–mortality association in the direction of protection or harm. Multi-collinearity was not assessed. While multi-collinearity has the potential to decrease precision and skew estimates, presented crude death rates mirror the adjusted pattern, and variable inclusion was determined on the basis of clinical relevance and aim to isolate direct BMI associations, avoiding mediation and confounding where possible. Further, collider stratification bias should be considered as a partial or complete methodologic explanation for findings of a protective association with obesity, and bears mention and consideration as an alternative to causality [42, 43]. COPD sub-phenotyping, including imaging or symptom data, was not available for further stratification or adjustment. Finally, all patients were selected for inclusion in a randomised controlled trial and may therefore differ from patients in the general population; caution is warranted in application to populations outside of the trial inclusion criteria.

In conclusion, we have demonstrated a U-shaped curve in the association between BMI category and mortality in an international population with moderate COPD at heightened cardiovascular risk. This relationship extends previous studies demonstrating increased risk of mortality in underweight, and a protective association between overweight and moderate obesity. However, we provide evidence supporting recurrence of increased mortality risk with extreme obesity, at BMI ≥40 kg·m⁻². Understanding the impact of overweight and obesity on COPD is paramount in the context of rising numbers of individuals with COPD [44] and shifts in prevalence of overweight and obesity worldwide [45]. The relationship described emphasises the need to better understand the impact of BMI-driven nutritional supplementation and weight loss interventions when applied to populations with COPD.