Not only the status of body weight and metabolic health matters for cardiovascular events, but also the temporal changes

Increased mortality risk has been reported in obese compared with non-obese individuals, which has been attributed to increased risk of cardiovascular disease and cancer.1 Among obese individuals, those with features of metabolic syndrome (MS), the so-called metabolically unhealthy obese (MUO), have been demonstrated to be at greater cardiovascular risk compared with metabolically healthy obese (MHO) individuals.2 However, “metabolically healthy obesity” appears not to be an entirely benign condition, as indicated by the higher incidence of cardiovascular events in MHO patients compared with metabolically healthy non-obese (MHN) individuals.3 The presence of chronic low-grade inflammation in obesity, including macrophage infiltration in adipose tissue with production of pro-inflammatory cytokines, appears to contribute to the development of metabolic decompensation.4 Importantly, a more favorable inflammatory profile has been reported in MHO compared with MUO individuals, but worse than MHN individuals.5,6 In this context, the original research article by Guo et al., entitled “The effects of transitions in metabolic health and obesity status on incident cardiovascular disease: Insights from a general Chinese population”, not only confirmed the aforementioned notions about the prognostic significance of “metabolically healthy obesity”, but refined the assessment of cardiovascular risk in MHO individuals, taking into account the transition of the status of body weight and metabolic health, implying that the shift from MHO to MUO may be more sinister than the maintenance of MHO throughout (Figure 1).7 Although consistent results have been previously reported, this study explored these issues for the first time in an Asian population, in whom the anthropometry is different from other races and a lower threshold for definition of obesity exists (body mass index ≥25 kg/m2).8 In this respect, “metabolically healthy obesity” should be regarded as an initial step in the process of metabolic deterioration of obesity and, thus, MHO individuals should be managed as potential precursors of MUO individuals. Therefore, the preventive measures, including weight loss and exercise training, in MHO patients should be intensified early enough to prevent the harmful transition from MHO to MUO.9 Comparison of cardiovascular risk according to the status of body weight and metabolic health, as well as the transition of the status during follow-up. The transition from MHO to MUO may be more sinister than the maintenance of MHO throughout. The increased cardiovascular risk of MHO individuals appears to be mainly attributed to coronary events. MHN: metabolically healthy non-obese; MHO: metabolically healthy obese; MUO: metabolically unhealthy obese. Arrow (→): transition from one status of body weight and metabolic health to another status during follow-up; brain image: strokes; heart image: coronary events. Comparison of cardiovascular risk according to the status of body weight and metabolic health, as well as the transition of the status during follow-up. The transition from MHO to MUO may be more sinister than the maintenance of MHO throughout. The increased cardiovascular risk of MHO individuals appears to be mainly attributed to coronary events. MHN: metabolically healthy non-obese; MHO: metabolically healthy obese; MUO: metabolically unhealthy obese. Arrow (→): transition from one status of body weight and metabolic health to another status during follow-up; brain image: strokes; heart image: coronary events. Notably, Guo et al. found an increased incidence of cardiovascular events in MHO, but not in metabolically unhealthy non-obese (MUN) compared with MHN individuals, though a head-to-head comparison between MUN and MHN was not performed. This issue needs further investigation. A novel finding by Guo et al. that deserves attention is the differential effects of MUN and MHO status on the type of future cardiovascular events, since MUN individuals were found to suffer more from stroke, whereas the cardiovascular events of MHO patients were shown to be mainly coronary. Indeed, MHO individuals were previously reported not to have increased risk of stroke.10 In addition, a recent meta-analysis showed that obesity was not associated with stroke incidence, but only with coronary events.11 Furthermore, Guo et al. demonstrated that in the studied population most stroke risk was attributed to high blood pressure, while abdominal obesity explained most coronary events. Considering that high blood pressure was the most common MS component of MUN individuals in this study, the presence of metabolically unhealthy phenotype was tightly associated with increased blood pressure and, thus, higher risk of stroke. On the other hand, the common denominator of MHO individuals was an increase in waist circumference during follow-up. Consistently, MHO individuals were essentially different from MHN at the end of follow-up regarding waist circumference, indicating an inappropriate management of abdominal obesity in MHO individuals. In other words, the higher burden of coronary events in MHO patients may be explained, at least in part, by abdominal obesity. These considerations should take into account the lower cut offs of waist circumference for Asian populations, which may render the findings of this study not necessarily comparable with the results of studies in non-Asian populations. Further well-designed studies are needed to confirm these findings and investigate the possible underlying mechanisms. It should be acknowledged that Guo et al. used MHN individuals as a reference group for their analysis, including not only lean individuals, who represent the ideal reference group, but also overweight individuals. Although an analysis using the lean rather than the combined group of lean and overweight is expected to result in more marked differences from obese individuals, the analysis of Guo et al. may be more clinically relevant in evaluating the continuum of transition from non-obese to obese status without the intermediate gap of overweight status. An important methodological issue that is commonly raised in studies investigating MHO individuals is the definition of metabolic health. Most studies have used as a definition of “metabolically healthy obesity” the absence of MS (i.e. no more than two components of MS).12 Although this definition accepts some degree of metabolic dysfunction in MHO individuals, it appears to be more realistic in clinical practice compared with a more strict definition requiring the absence of any component of MS, since the overwhelming majority of obese patients have increased waist circumference, rendering the prevalence of “metabolically healthy obesity” with the latter definition extremely low and, thus, not relevant to clinical decision-making at the general population level.5 Consistently, Guo et al. defined “metabolically healthy obesity” as the absence of MS in the primary analysis, while the prevalence of obese individuals with no components of MS was <1%, resulting in an analysis that was not powered enough to reveal any significant changes in the studied outcomes. Although the evaluation of the incidence of fatal or non-fatal strokes and coronary events by Guo et al. represents the most conventional analysis of cardiovascular outcomes, the studied outcomes did not include heart failure with preserved ejection fraction, which has been reported to be associated with obesity.13 This issue needs to be investigated in future studies with MHO individuals. In conclusion, MUO individuals appear to have the highest cardiovascular risk, whereas MHN individuals may have the lowest. MHO and MUN possibly have intermediate cardiovascular risk, with more coronary events for the former and more strokes for the latter. Furthermore, the temporal changes of body weight and metabolic health possibly confer incremental prognostic value over and above the status of body weight and metabolic health at a specific time point. These considerations have profound implications in the management of obese individuals enabling a more precise risk stratification and appropriate aggressiveness of treatment, according to metabolic profile and the history of changes in body weight and metabolic profile. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.