Natural History of Obesity Subphenotypes: Dynamic Changes Over Two Decades and Prognosis in the Framingham Heart Study.

The natural histories of obesity subphenotypes are incompletely delineated. To investigate dynamic changes in obesity subphenotypes and associations with outcomes. Framingham Offspring Cohort participants (n = 4291) who attended the examination cycles 2 (1979 to 1983) to 7 (1998 to 2001), which included 26,508 participant observations. Obesity subphenotypes [metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO)] were ascertained based on metabolic health (<2 Adult Treatment Panel III criteria). The outcomes were subclinical cardiovascular disease (CVD), incident diseases [diabetes, hypertension, chronic kidney disease (CKD), CVD], and all-cause mortality. At baseline, 4% and 31% of participants exhibited the MHO and MUNO subphenotypes, respectively. Four-year probability of MHO participants becoming MUO was 43% in women and 46% in men. Compared with MHNO, MHO participants had 1.28-fold (95% CI, 0.85 to 1.93) and 1.92-fold (95% CI, 1.38 to 2.68) higher odds of subclinical CVD and coronary artery calcification, respectively; corresponding values for MUNO were 1.95 (1.54 to 2.47) and 1.92 (1.38 to 2.68). During follow-up (median of 14 years), 231 participants developed diabetes, 784 hypertension, 423 CKD, 639 CVD, and 1296 died. Compared with MHNO, MHO conferred higher risks of diabetes [hazard ratio (HR), 4.69; 95% CI, 2.21 to 9.96] and hypertension (HR, 2.21; 95% CI, 1.66 to 2.94). Compared with MUO, MHO conferred lower risks of diabetes (0.21; 0.12 to 0.39), CVD (0.64; 0.43 to 0.95), and CKD (0.44; 0.27 to 0.73), but similar hypertension, cardiovascular mortality, and overall mortality risks. Over time, most MHO participants developed metabolic abnormalities and clinical disease. The MHO subphenotype is a harbinger of future risk.