An opposing point of view on the obesity paradox

Excess adiposity that impairs health defines obesity. Obesity has increased over the last decades to the extent that currently 39.6% of people in the United States are classified as having obesity (body mass index [BMI]≥30 kg/m²) and 7.7% severe obesity (BMI≥40 kg/m²) [1].

Obesity is a strong independent predictor for cardiovascular diseases (CVD) and CVD risk factors. Such an association has been confirmed in several epidemiologic studies over the years [2], proposing weight loss as an efficacious therapeutic to prevent CVD. Nevertheless, clinical trials investigating the long-term effects of weight loss in primary prevention have failed to improve clinical outcomes [3], unless the degree of weight loss is large and sustained over time [4]. On the other hand, weight loss can improve several risk factors, particularly metabolic risk factors, such as insulin resistance, leading to the prevention of type 2 diabetes mellitus (T2DM) in those with obesity and prediabetes [5]. Taken together, the current evidence suggests that in patients without established CVD, weight loss is a reasonable approach to improve CVD risk factors, and in fact, recommended for the prevention of T2DM in the setting of a comprehensive lifestyle modification, including increased physical activity (PA) and exercise training, and reduced sedentary behaviors [5,6].

When patients develop CVD, however, the relationship between obesity and worse prognosis is not straightforward. In fact, in secondary prevention for some CVD, particularly heart failure (HF) and coronary heart disease (CHD), not only does obesity not associate with worse outcomes but in some circumstance even predicts improved prognosis [7,8]. This paradoxical relationship between obesity and CVD has been termed the ‘obesity paradox’.

In a recent issue of the Journal, Chrysant et al. [9] discuss the ability of BMI to stratify the CVD risk in patients with obesity. Specifically, despite presenting several large epidemiologic studies clearly supporting the obesity paradox using the BMI, they suggest that BMI alone may be misleading, requiring additional assessments to perform a more accurate risk status stratification in individuals with obesity. The authors also discuss several studies showing that obesity increases the risk to develop CVD, proposing the prevention of obesity as a key strategy to prevent CVD in the first place, at least in primary prevention. Similarly, we strongly advocate for the prevention of obesity; in fact, we believe that individuals and clinicians should make strongest efforts possible to prevent the development of obesity and the related increased risk for metabolic diseases and CVD [10].

As for Chrysant et al. [9], we also advocate for an improved nutritional status assessment in patients with obesity, which should include an assessment of body composition (i.e. fat mass, fat-free mass, lean mass) and body fat distribution (i.e. waist circumference [WC], waist–hip ratio), when possible [11]. However, we also would like to highlight that the BMI, although highly criticized, remains a strong prognosticator [12]. An assessment of body composition would be desirable in every individual, but we also acknowledge that it is not always a feasible approach in clinical practice, with a variety of tools available to measure body composition compartments yet presenting different degrees of accuracy and precision, not to mention being time-consuming and sometimes costly. In both HF and CHD, an obesity paradox has been described not only when using BMI [13] but also when using fat mass and waist circumference [14], at least at a population level. Interestingly, also a higher BMI measured several years prior to HF diagnosis has been associated with a more favorable prognosis once HF was established [15].

We strongly agree with Chrysant et al. [9] that the assessment of cardiorespiratory fitness (CRF) perhaps allows for the most accurate risk status stratification. Patients with HF, but with relatively greater CRF measured either with a maximal cardiopulmonary exercise testing with gas-exchange analysis to measure peak oxygen consumption [16] or estimated metabolic equivalents for task [17], do not present an obesity paradox, and actually present an excellent long-term prognosis [16,17]. In fact, the obesity paradox seems to only be present in those with lower CRF [16,17], suggesting that therapies targeting CRF, such as exercise training and increased PA, rather than body mass alone (i.e. weight loss), should be implemented. The explanation for the protective role of obesity in the setting of reduced CRF remains to be elucidated, however, the typical obesity phenotype presents with a preserved or even increased amount of lean mass, a major surrogate for skeletal muscle mass, which is, in turn, an independent predictor of CRF and muscle strength. For such reason those patients with obesity, yet with reduced lean mass (i.e. sarcopenic obesity), typically present a worse prognosis, likely as a result of a reduced CRF and muscle strength [11,18]. Importantly, a recent analysis presented compelling evidence that the reduced CRF may also mediate the increased risk for HF in patients with obesity [19]; this finding is extremely relevant, as it would suggest that in individuals with obesity, the risk to develop HF could be mitigated by improving CRF. Similar to what is seen in HF, also in CHD, CRF outperforms several nutritional status assessments, including BMI, fat mass and WC, proposing that even in this setting, therapies that increase CRF should receive priority [20].

In addition to body composition and CRF, an additional component may also help explaining the obesity paradox. Systemic low-grade inflammation characteristic of obesity seems to mediate many of the detrimental effects of obesity. In patients with CHD and concomitant obesity, individuals presenting with the greatest fat mass, but the lowest levels of systemic inflammation assessed by measuring C-reactive protein, presented the best prognosis [21]. Preclinical data also suggest the animals with obesity, but with low systemic inflammation, have better cardiac function [22], a finding which is extremely relevant particularly to HF, in which cardiac dysfunction remains the hallmark of the clinical syndrome.

In conclusion, obesity remains a strong independent predictor for several cardiometabolic diseases, suggesting that therapeutics targeting obesity may reduce the subsequent risk for CVD. However, independent of changes in body mass, recent evidence suggests that improving CRF may mediate such risk in primary prevention, particularly as it relates to the risk to develop HF. In patients with established CVD, however, obesity has been associated with improved prognosis, describing an obesity paradox. Several factors need to be accounted in this setting for a more accurate picture of each individual: BMI, body composition, body fat distribution, CRF, PA, and systemic low-grade inflammation. Nevertheless, in the absence of many of those variables when assessing a patient with CVD, the use of BMI allows for a valid first nutritional status stratification. As opposed to decades ago in which obesity was always considered to be detrimental on people’s lives, we would advocate for spending more time with our underweight and normal weight patients in the setting of established CVD, as their overall risk may be greater than those with overweight and obesity. Finally, clinicians and researchers should put a major effort in promoting therapeutics with proven beneficial effects on CRF, such as exercise training and increased PA, as increased CRF resulting from these strategies has been associated with improved prognosis in different chronic noncommunicable diseases, irrespective of BMI, body composition and body fat distribution.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

S Carbone is supported by a Career Development Award [19CDA34660318] from the American Heart Association.