Metabolically Healthy Obesity and Risk of Mortality: Does the definition of metabolic health matter?

GUY-MARINO HINNOUHO MSC SBASTIEN CZERNICHOW PHD ALINE DUGRAVOT MSC E p i d e m i o l o g y / H e a l t h OBJECTIVEdTo assess the association of a metabolically healthy obese phenotype with mortality using five definitions of metabolic health. RESEARCH DESIGN AND METHODSdAdults (n = 5,269; 71.7% men) aged 39-62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all-cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years. RESULTSdA total of 638 individuals (12.1% of the cohort) were obese, of whom 9-41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HRs] ranged from 1.81 [95% CI 1.16-2.84] for ATP-III to 2.30 [1.13-4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08-2.28] for the Matsuda index to 2.05 [1.44-2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67-1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.153.22). Similar results were obtained for cardiovascular mortality. CONCLUSIONSdFor most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality. - O problem that has reached epidemic besity is a major public health proportions worldwide (1). It is associated with numerous metabolic and cardiovascular disturbances such as insulin resistance, type 2 diabetes, hypertension, and dyslipidemia (25). However, these cardiometabolic abnormalities are not found in all obese people (6,7), as evidenced by the occurrence of a subset of apparently healthy obese subjects referred to as metabolically healthy obese (MHO) (8,9). Several studies have confirmed the existence of MHO individuals (1016), accounting for as much as 40% of the obese population. MHO individuals display a favorable metabolic profile, characterized by high levels of insulin sensitivity, a low prevalence of hypertension, and a favorable lipid and inflammation profile. The long-term health consequences of obesity among those who are metabolically c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c healthy remain unclear. Obesity is known to carry an elevated risk of mortality (17), but few studies have examined associations of the MHO phenotype with mortality, and the evidence from these studies is mixed. In general population samples from Scotland and England, MHO individuals were not at increased risk of allcause and cardiovascular disease (CVD) mortality compared with healthy nonobese individuals (18), a finding replicated in an Italian study of obesity and insulin sensitivity (19). However, overweight and obese individuals without the metabolic syndrome had an increased risk of mortality compared with normal-weight individuals without the metabolic syndrome in a Swedish cohort of middle-aged men (20). Furthermore, in the U.S. National Health and Nutrition Examination Survey III (21), metabolically healthy and abnormal obese individuals had similar elevations in mortality risk compared with metabolically healthy, normal-weight subjects. Several factors may have contributed to these inconsistencies. The comparison group varies when estimating risk of mortality in the MHO phenotype; risk is compared either with metabolically healthy nonobese (18,19) or metabolically healthy, normal-weight people (20,21). Another difference between the studies is that metabolic health is defined in different ways, with little consensus on how best to define it. Therefore, the objective of the current study is to assess whether there is consistency in the association of the MHO phenotype with allcause and CVD mortality using different definitions of metabolic health and reference groups. RESEARCH DESIGN AND METHODS Participants Data were drawn from the Whitehall II cohort, established in 1985 as a longitudinal study among 10,308 (6,895 male and 3,413 female) U.K. government employees (i.e., civil servants) (22). All civil servants aged 3555 years in 20 London-based departments were invited to participate by letter; 73% agreed. The baseline examination (phase 1) took place from 1985 to 1988 and involved a clinical examination and a self-administered questionnaire. Subsequent phases of data collection alternated between postal questionnaire alone (phases 2 [19881990], 4 [19951996], 6 [2001], and 8 [2006]) and postal questionnaire accompanied by a clinical examination (phases 3 [1991 1993], 5 [19971999], 7 [20022004] and 9 [20072009]). Data on metabolic factors for the current study were drawn from phase 3, considered the baseline for the purpose of these analyses. All participants provided written consent and the University College of London ethics committee approved the study. Baseline measurements BMI. With the patients in only underwear, weight was measured to the nearest 0.1 kg on digital Soehnle electronic scales (Leifheit AS, Nassau, Germany). With the participant standing erect in bare feet with the head in the Frankfurt plane, height was measured to the nearest 1 mm using a stadiometer. Reproducibility of measurements over 1 month (correlation coefficient = between-subject variability/[total between + within subject variability]), undertaken for 331 participants, was 0.99 for both weight and height. BMI was calculated by dividing weight (in kilograms) by height (in meters squared) and categorized using the World Health Organization classification (23): underweight, ,18.5 kg/m2; standard weight, 18.5 24.9 kg/m2; overweight, 2529.9 kg/m ; 2 and obese, $30 kg/m2, with the ,18.5 category (n = 80) removed from the analysis. Metabolic health factors. We used standard operating protocols to measure the various components to define metabolic status. Blood pressure was measured twice in the sitting position after 5 min of rest with a Hawksley random-zero sphygmomanometer (Lynjay Services Ltd, Worthing, U.K.). The average of the two readings was considered the measured blood pressure. Venous blood was taken in the fasting state or at least 5 h after a light, fat-free breakfast before undergoing a 2-h, 75-g oral glucose tolerance test (OGTT). Serum for lipid analyses was refrigerated at 248C and assayed within 72 h. HDLcholesterol (HDL-c) was measured by precipitating non-HDL-c with dextran (...truncated)