Abstract
Cardiometabolic diseases, including cardiovascular disease (CVD) and type 2 diabetes (T2D), are the leading cause of death globally. Because T2D and obesity are strongly associated, weight loss is the cornerstone of treatment. However, weight loss is rarely sustained, which may lead to weight cycling, which is associated with increased mortality risk in patients with T2D. Meta-analyses show that weight loss is not generally associated with reduced mortality risk in T2D, whereas weight cycling is associated with increased all-cause and CVD mortality. This may be attributable in part to increased variability in CVD risk factors that often accompany weight cycling, which studies show is consistently associated with adverse CVD outcomes in patients with T2D. The inconsistent associations between weight loss and mortality risk in T2D, and consistent findings of elevated mortality risk associated with weight cycling, present a conundrum for a weight-loss focused T2D prevention and treatment strategy. This is further complicated by the findings that among patients with T2D, mortality risk is lowest in the body mass index (BMI) range of ~25-35 kg/ m2 . Because this "obesity paradox" has been consistently demonstrated in 7 meta-analyses, the lower mortality risk for individuals with T2D in this BMI range may not be all that paradoxical. Physical activity (PA), cardiorespiratory fitness (CRF), and muscular fitness (MF) are all associated with reduced risk of T2D, and lower risk of CVD and all-cause mortality in individuals with T2D. Reducing sedentary behavior, independent of PA status, also is strongly associated with reduced risk of T2D. Improvements in cardiometabolic risk factors with exercise training are comparable to those observed in weight loss interventions, and are largely independent of weight loss. To minimize risks associated with weight cycling, it may be prudent to adopt a weight-neutral approach for prevention and treatment of individuals with obesity and T2D by focusing on increasing PA and improving CRF and MF without a specific weight loss goal.