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

Context: The natural histories of obesity subphenotypes are incompletely delineated. Objectives: To investigate dynamic changes in obesity subphenotypes and associations with outcomes. Design, Setting, Participants, and Measurements: 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. Results: 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. Conclusion: Over time, most MHO participants developed metabolic abnormalities and clinical disease. The MHO subphenotype is a harbinger of future risk.