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In this well-designed and well-executed prospective analysis among 71 519 participants in the Copenhagen General Population Study, Thomsen and Nordestgaard1 categorized individuals at baseline as normal weight, overweight, or obese on the basis of their body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) and according to the absence or presence of metabolic syndrome (MetS), and observed them for occurrence of ischemic heart disease (IHD) to address a question of major clinical and public health importance: Are overweight persons without MetS at increased risk for IHD? With a median of 3.6 years of follow-up and 1781 IHD events overall, the authors showed a clear increase in risk in this group. Among those without MetS, the hazard ratios were 1.26 (95% CI, 1.00-1.61) in overweight and 1.88 (95% CI, 1.34-2.63) in obese participants, compared with normal weight participants without MetS. Using the same comparison group, the hazard ratios among those with MetS were 1.39 (95% CI, 0.96-2.02) in normal weight, 1.70 (95% CI, 1.35-2.15) in overweight, and 2.33 (95% CI, 1.81-3.00) in obese participants. The components that compose MetS are established consequences of excess adiposity, as well as established cardiovascular disease risk factors, so these results seem unexpected. Indeed, much of the impact of obesity is mediated through components of MetS. Hence, one might expect overweight individuals without MetS not to be at increased risk. However, in this and other studies, MetS is defined as a dichotomy, but physiologically it should be thought of as continuous, as are all of its components. Given the continuum, it is plausible that the “metabolically healthy overweight or obese” phenotype may be transient and that those with this phenotype are likely eventually to develop the risk factors that make up MetS. Thus, the overweight or obese individuals with diagnosed MetS seem to include individuals at more advanced stages along the continuum of the pathological process. For example, in this study, the overweight and obese individuals who did not meet the criteria for MetS had worse levels of component parameters and were closer to the higher end within BMI categories, which implies that they were closer to MetS on the continuum than their leaner counterparts. Supporting this concept, a recent prospective cohort study of 4056 adults in Australia showed that a substantial portion of metabolically healthy obese individuals developed MetS (especially those with a relatively high baseline waist circumference) during the 5.5 to 10.3 years of follow-up.2 The authors concluded that one-third of the healthy obese participants were in a transient state and that waist circumference can add to the prediction of future risk of MetS in individuals with this phenotype. In the study by Thomsen and Nordestgaard,1 normal weight individuals with MetS, considered to have the normal weight and metabolically unhealthy phenotype, had an increased risk of IHD, although it was not statistically significant, perhaps because of the relatively small sample size in this category; it seems likely that such individuals do carry an increased risk.
Jackson CL, Stampfer MJ. Maintaining a Healthy Body Weight Is Paramount. JAMA Intern Med. 2014;174(1):23-24. doi:10.1001/jamainternmed.2013.8298