Obesity is typically associated with increased risk of cardiovascular events. However, a subset of obese individuals does not present phenotypic traits that characterize increased cardiovascular risk, such as insulin resistance. This condition has been called ‘metabolically healthy’ obesity. Indeed, 10–25% of obese individuals may not be impacted by metabolic abnormalities , which is a substantial number considering that obesity affects 300 million people worldwide. In a sub-analysis of the National Health and Nutrition Examination Surveys 1999–2004 (NHANES 1999–2004), 51.3% of overweight adults and 31.7% of obese adults were metabolically healthy as they showed either no or one metabolic syndrome trait . The concept of healthy obesity challenges the notion that all overweight and obese individuals should be treated. Selecting such individuals for watchful surveillance could spare significant amounts of societal and economic resources.
In this issue of the Journal, however, Lee et al. present the results of a prospective observational study, which contests the concept of healthy obesity. The authors followed 2352 middle-aged and elderly normotensive participants enrolled in two cohorts, one urban, the other rural, of the Korean Genome Epidemiology Study, and checked for the incidence of hypertension over the course of 8 years through biennial clinical assessments. Six groups were studied based on BMI and metabolic syndrome components: healthy normal weight, unhealthy normal weight, healthy overweight, unhealthy overweight, healthy obesity, and unhealthy obesity, unhealthy meaning the presence of at least one component of metabolic syndrome. On the final year of follow-up, about 65% of participants were retained for the analyses. After multiple adjustments including family history of hypertension and cardiovascular diseases, progressively increasing risk for incident hypertension in the combined urban and rural cohorts was observed in unhealthy overweight, and both healthy and unhealthy obese groups as compared with the healthy normal weight individuals. In each separate cohort, healthy obesity was still associated with a higher incidence of hypertension. Notably, the increased risk for incident hypertension was observed in healthy obese individuals starting on the fourth year of follow-up. Indeed, the risk of incident hypertension was higher in healthy obese than in unhealthy overweight participants. The authors concluded that the risk of incident hypertension is increased in obesity regardless of the presence of other metabolic syndrome components. Similar results have been recently reported by Hwang et al., who showed that not only hypertension but also type 2 diabetes mellitus and metabolic syndrome develop more frequently in healthy obese individuals than in normal weight controls after a 5.4-year follow-up.
Major strengths of the current study are its prospective design, biennial assessments, and a lengthy follow-up. Many studies characterizing healthy obesity in different populations are cross-sectional. The distinction of a healthy and an unhealthy obese phenotype can be generally established in these studies. However, the fact that many healthy obese individuals could indeed become metabolically unhealthy over time is untenable in cross-sectional studies. One limitation of the present study though is its rather large percentage of lost to follow-up.
Wildman et al. observed that younger age, moderate alcohol drinking, non-Hispanic blacks, and greater physical fitness are associated with healthy obesity, whereas older age, smoking, and larger waist circumference are predictors for a higher prevalence of the metabolic abnormalities. Therefore, time ‘per se’ appears to be an important factor in the development of unhealthy obesity. Likewise, in the present study, 20% of the participants initially categorized as healthy obese developed the unhealthy phenotype after 2 years of follow-up, whereas 60% of initially healthy obese participants had become phenotypically unhealthy after 8 years. These results are in line with a sub-analysis of the community-based Atherosclerosis Risk in Communities Study (ARIC Study) . At the outset, up to 40% of obese individuals were metabolically healthy. However, the risk of developing metabolic syndrome was four times higher than that in normal weight adults over 9 years of follow-up. In the ARIC Study, body size was the strongest factor in predicting incident metabolic syndrome, along with weight gain, age, and female sex, whereas physical fitness was protective.
Importantly, had the present study included prehypertensive patients in the obese healthy group from the outset, the cross-over from healthy to unhealthy obesity might have been even more dramatic. In regard to this aspect of the study, the authors appropriately opted for a conservative approach, which raises another issue in regard to the classification of healthy obesity: the very lack of a unified and universally accepted definition. This lack of a definition implies great uncertainty in regard to the true estimation of the incidence and prevalence of healthy and unhealthy obesity .
Given the time lag for the development of hypertension in healthy obese individuals as compared with unhealthy ones, it can be predicted that the overall cardiovascular risk in the healthy obese individuals is likely intermediate between healthy lean and unhealthy obese individuals. Of note, Manu et al. have shown that healthy obese men exhibit higher insulin resistance, insulinemia, non-high-density lipoprotein (HDL) cholesterol, and C-reactive protein levels, and lower HDL-cholesterol levels. Healthy obese women not only present the characteristics mentioned above but also exhibit higher SBP and increased low-density lipoprotein-cholesterol levels. Additionally, the carotid intima–media thickness, a marker of atherosclerosis closely associated with visceral obesity was intermediate between healthy non-obese and unhealthy obese women . Another cross-sectional study expanded these findings showing that, in addition to increased carotid intima–media thickness, healthy obese women exhibit increased coronary and aortic calcification and augmented pulse wave velocity as compared with normal weight controls . Furthermore, in a recent publication of the Journal, subtle changes in left ventricular structure and function have been described in healthy obesity .
Another important question arises from the study by Lee et al.. Assuming that the healthy obesity phenotype transforms with time into a metabolically less favorable phenotype, what would be the impact of healthy obesity on mortality? Other longitudinal studies have addressed this issue. The Cremona study  did not demonstrate increased all-cause mortality associated with healthy obesity over 15 years of follow-up. Nevertheless, the prevalence of healthy obesity in the Cremona study was half that widely accepted, that is, 11% rather than 20%, which makes this condition far less common than initially envisioned. Again, this difference in the estimated prevalence of healthy obesity is most likely associated with its chosen definition, in that case based exclusively on BMI and indices of insulin sensitivity rather than the classical components of the metabolic syndrome. Two acknowledged limitations of the Cremona study were the lack of intermediate analysis and the small number of participants with insulin-sensitive obesity (i.e., healthy obesity). Thus, the frequency of cross-overs in this study is unknown. In contrast to the findings in the Cremona study, another study which classified healthy obesity based on insulin sensitivity and/or aggregates of metabolic syndrome components from a NHANES III database  demonstrated comparable increases in all-cause mortality in healthy and unhealthy obese individuals over an 8-year follow-up. Their estimate of the prevalence of healthy obesity was 6% of the obese population, thus also less than the accepted figures. One might speculate that the lack of mortality differences between healthy and unhealthy obese could have been partly due to the transformation of healthy into unhealthy obese as observed in the present study. Indeed, the authors highlighted such possibility given that the unhealthy obese were older and heavier than the healthy ones. Nevertheless, increased all-cause mortality in healthy and unhealthy obese individuals might be unrelated with metabolic abnormalities because obese individuals are more likely to die from trauma, are diagnosed with cancer at more advanced stages, and are less likely to receive prompt healthcare attention .
In regard to cardiovascular mortality, it has been reported that the frequency of cardiovascular events is similar in normal weight and healthy obese individuals after 3–11 years of follow-up. However, the risk of events in healthy obese individuals increases after 16 years , which strongly suggests that the transformation of healthy into unhealthy phenotype might be mediated through the aggregation of cardiovascular risk factors, including hypertension as presently shown. One particular exception might be the protective effect of fitness on healthy obesity given that, in a study with more than 43 000 participants, healthy obese individuals had 30–50% less risk of nonfatal and fatal cardiovascular disease, cancer, and all-cause mortality than the unhealthy obese individuals . Despite presenting a fair estimate of incident hypertension in healthy obese individuals, no morbidity or mortality results have been presented in the Journal.
Interestingly, in the present study, hypertension developed in healthy obese individuals irrespective of the presence of metabolic syndrome components. Additionally, adjustments for physical activity, current smoking, alcohol consumption, and family history of hypertension, or cardiovascular disease did not significantly affect the risk of incident hypertension in healthy and unhealthy obese groups. Furthermore, the magnitude of insulin resistance was similar in healthy and unhealthy obese at the beginning of the study. Thus, the factors mechanistically associated with the development of incident hypertension in healthy obese individuals remain to be determined. Nonetheless, the fact that insulin resistance was comparable in healthy and unhealthy obese groups at baseline could have contributed to the development of incident hypertension. Of note, unlike the present study, other studies reported that normal insulin sensitivity is associated with healthy obesity .
In conclusion, longitudinal studies suggest that healthy obesity might not be a stable condition and that obese individuals considered to be metabolically healthy at baseline may exhibit subclinical signs of cardiovascular disease and later develop overt cardiovascular risk factors such as hypertension, as demonstrated by Lee et al. published in the current issue of the journal. These findings are important from a public health perspective as they suggest that obesity should always be treated irrespective of the accompanying metabolic status and, thus, should never be considered a benign condition.
Conflicts of interest
There are no conflicts of interest.
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