Author + information
- Rishi Puri, MB, BS∗ ( )()
- Cleveland Clinic Coordinating Center for Clinical Research (C5R) and the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- ↵∗Reprint requests and correspondence:
Dr. Rishi Puri, Atherosclerosis Imaging Core Laboratory, C5Research, Mail Code JJ65, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195.
- cardiovascular disease
- coronary artery calcium score
- coronary artery disease
- metabolically-healthy obesity
We are in the midst of a well-publicized, worldwide obesity epidemic (1). Yet, despite its known deleterious multiorgan effects at an individual level and the economic constraints of obesity-related illnesses on global health systems, there remains an ongoing debate regarding the impact of obesity on mortality rates. Fueling this debate has been the recent publication of 2 large-scale but somewhat conflicting meta-analyses. Although 1 analysis concluded that nearly one-fifth of total mortality within the United States is attributable to obesity (2), by contrast, the other uncovered possible protective effects of being overweight, with greater survival observed among people with body mass indexes (BMIs) between 25 and 30 kg/m2 than among a normal-weight cohort (BMIs between 18.5 and 25 kg/m2) (3). Even more controversial has been the concept of “metabolically-healthy obesity,” defined as an obese (BMI >25 kg/m2) state without demonstrable obesity-related metabolic abnormalities such as dyslipidemia or impaired glucose tolerance. Consequently, some have postulated that metabolically-healthy obese people need not receive preventative therapies, because they would appear unlikely to experience long-term morbidity on the basis of their seemingly normal metabolic status (4). However, the incidence of obesity-related metabolic abnormalities varies considerably among overweight and obese people. Prior analyses that evaluated the prognosis of metabolically-healthy obese people have been flawed by their inability to quantify changes in metabolic parameters over time. Additionally, the inclusion of patients with known cardiovascular risk factors in the metabolically-healthy obese group and overweight people in the normal comparator group confounded some of these prior comparisons (5). Nevertheless, this has left many to ponder whether obesity per se or component metabolic abnormalities mediate cardiovascular risk.
With this in mind, in this issue of the Journal, Chang et al. (6) report a comparison of coronary artery calcium (CAC) scores between metabolically-healthy obese versus metabolically-healthy normal-weight Koreans (6). Their rationale was based on the notion that CAC scoring is a surrogate means of assessing subclinical coronary atherosclerosis, with known significant associations with incident major adverse cardiovascular events, and that this imaging method might illuminate the true relationship between obesity, metabolic health, and subclinical atherosclerotic cardiovascular disease. The overall population sample consisted of 14,828 metabolically-healthy people (mean age of 39 years, >74% male) who took part in a comprehensive regional health screening program. Metabolic health was defined as the absence of all of the following: fasting blood glucose ≥100 mg/dl (or use of glucose-lowering agents), blood pressure ≥130/85 mm Hg (or use of blood pressure–lowering agents), triglycerides ≥150 mg/dl (or use of lipid-lowering therapies), high-density lipoprotein cholesterol <40 mg/dl in men (or <50 mg/dl in women), and a homeostasis model of insulin resistance ≥2.5. A comprehensive questionnaire pertaining to past medical history and measures of physical activity, alcohol consumption, and smoking habits was also collected. All patients had BMI measured; however, less than one-third of the population had waist circumference measured. This metabolically-healthy population was then stratified according to BMI into 1 of 4 categories: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to 22.9 kg/m2), overweight (BMI 23.0 to 24.9 kg/m2), and obese (BMI ≥25 kg/m2). CAC scores were analyzed across these BMI strata.
Across a series of analyses that adjusted for potential confounding variables, and across a range of CAC score categories (Agatston scores 1 to 80 and >80), the metabolically-healthy obese group had a significantly greater prevalence of coronary atherosclerosis than their metabolically-healthy but normal-weight counterparts. However, after additional adjustment for metabolic risk factors and low-density lipoprotein cholesterol levels, the greater prevalence of subclinical coronary atherosclerosis in the metabolically-healthy obese group no longer remained statistically significant. The authors drew 2 major conclusions from their analyses: 1) an obese yet metabolically healthy state was associated with a greater prevalence of subclinical coronary atherosclerosis, and therefore, obesity cannot be considered a benign condition; and 2) despite the fact that the metabolic risk parameters of the participants fell well within the normally accepted range, it appeared that the association between a metabolically-healthy obese state and subclinical coronary artery disease was still ultimately determined by component metabolic parameters that fell below specific laboratory/clinical threshold levels.
The analysis by Chang et al. (6) was limited by its cross-sectional design, the lack of anthropometric tools used to better assess levels of visceral fat, and its confinement to a young Korean population. Furthermore, the use of CAC scoring in such a young, low-risk population for population health screening is currently controversial and must be highlighted. That being said, the results are concordant with the findings of a recent large-scale meta-analysis by Kramer et al. (7), who analyzed all-cause and cardiovascular mortality across 8 studies comprising >60,000 people followed up for at least 10 years. Compared with metabolically-healthy normal-weight people, metabolically-healthy obese people were at significantly greater risk for death and cardiovascular events, which affirms the notion that obesity portends an adverse long-term prognosis irrespective of the presence or absence of concomitant metabolic abnormalities.
The studies by Chang et al. (6) and Kramer et al. (7) cast serious doubt on the concept of obese people maintaining a benign prognosis and highlight the fact that obesity per se is a genuine disease. They also seriously call into question the fundamental concept of the quest to define a subset of obese people as metabolically healthy. Is it simply to stimulate academic debate, or is there a compelling clinical and practical reason for doing so? If we were to find a means of labeling a subset of obese people as metabolically healthy, of what benefit would this be to society? Given our current lack of a “cure” or efficient means of successfully treating obesity over the longer term, might the resources spent on trying to define and justify the existence of a metabolically-healthy obese population be more wisely allocated to elucidating ways to prevent or treat obesity? Obesity adversely affects almost all physiological homeostatic mechanisms, and its presence is associated with both cardiac and many noncardiometabolic disorders, including malignancy, infection, infertility, joint disease, depression, and cognitive decline. Our society faces a monumental challenge to successfully tackle obesity and its complications. By labeling a subset of obese people as metabolically healthy, would we not undermine the ultimate task that physicians and health organizations face to curb the current obesity epidemic and prevent the next generation of people from becoming obese? Failure to promote weight loss strategies to all obese people and a strategy of only offering treatment to obese patients with overt metabolic derangements would appear futile and short-sighted. Any perceived short- to medium-term cost savings would be quashed by the inevitable longer-term socioeconomic burden of treating numerous noncardiometabolic ailments faced by obese people. It is also prudent to note that obesity is not a disease acquired overnight. People evolve from normal weight to being overweight before further evolution to an obese state. Although the analysis by Chang et al. (6) failed to uncover a significantly greater burden of subclinical atherosclerotic disease in the overweight compared with normal-weight people, the meta-analysis by Kramer et al. (7) clearly demonstrated a significant association between being overweight and cardiovascular events. Given that overweight people are at heightened risk for evolving into an obese state, interventions that target the overweight population are equally critical.
There is still much for us to learn about obesity and the underlying molecular mechanisms of obesity-related organ disease. A recent elegantly designed genome-wide analysis uncovered the association between an obese phenotype and deoxyribonucleic acid methylation, with subsequent alteration of the functional status of HIF3A, a gene involved in the regulation of physiological responses to hypoxia (8). This epigenetic phenomenon is just 1 example of the deleterious effects of obesity. The “omics” revolution, coupled with vascular imaging, is likely to yield tremendous insight into factors that promote cardiovascular disease across a variety of population subsets, with the obese population being a primary target for such investigations. This will foster the development of more specific and targeted therapies for tackling obesity. But first, we must simply accept obesity as a disease and consider no level of obesity to be healthy. The analysis by Chang et al. (6) strengthens the argument that “healthy obesity” is simply a myth.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Puri has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation