There is a widening appreciation that excess adiposity may be a more important risk factor for multiple cardiometabolic outcomes than previously imagined. Gains in knowledge from well-conducted epidemiological studies, genetics, and follow-ups of bariatric surgery studies have stimulated more interest in the role of intentional weight loss in preventing or treating cardiometabolic disease. However, it is less well appreciated that the timing of such benefits may vary dependent on the disease process considered (Figure 1). Such issues are important as the results of several outcome trials (e.g. SELECT,1 SURPASS-CVOT2) testing the benefits and safety of agents that cause considerable weight loss, often 10 kg or more, will report over the next several years.3,4 As the relevant drugs also likely deliver direct tissue benefits, the pattern and timing of any outcome benefits in these trials will be eagerly scrutinized to try to decipher the relative contributions of direct drug effects vs. impacts of their large-scale weight loss.