In the current study of overweight or obese adults with T2DM, several important findings were observed. First, consistent with the findings from previous study , the ILI was not associated with lower risk of incident CVD or all-cause mortality on follow-up compared with DSE. Second, the rising weight variability was significantly associated with a higher risk of all-cause mortality independent of weight and traditional risk factors. In contrast, the weight variability was not associated with risk of incident CVD after adjustment for potential confounders. Third, these associations between weight variability and all-cause mortality were just observed in participants received DSE, but not in participants received ILI. Our findings suggested that higher weight variability was an important risk factor for death in overweight or obese adults with T2DM, but the risk of death associated with weight variability might be removed by ILI. Therefore, weight loss and subsequent maintenance may be contributed to the lower risk of death in overweight or obese adults with T2DM, but the guideline-recommended ILI  to reduce weight may be still benefit even if the weight may be regained later.
Although the evidence about the effect of weight variability in overweight or obese adults with T2DM is limited, some data focused on the general population [14, 15] or the patients with T2DM [6, 7, 16] or coronary artery disease (CAD)  suggest that the higher weight variability was associated with higher mortality and a higher rate of cardiovascular events. A prospective cohort from Framingham Heart Study was the earlier study to explore the association between variability of body weight and health outcomes in community population about 30 years ago . In analysis of 3,130 general participants, the relative risks of mortality and coronary heart disease (CHD) ranged from 1.27 to 1.93 in participants whose weight varied substantially compared with those with lower weight variability , with similar findings in the analysis of 6,748,773 subjects from Korea . In a post hoc analysis of the Treating to New Targets (TNT) trial, the fluctuation in body weight was associated with an 85% higher risk of cardiovascular event and a 124% higher risk of death compared with the lowest variation in body weight among the 9,509 patients with CAD . Recently, a prospective cohort study from U.S. of 6,408 subjects with T2DM demonstrated that weight variability was positively associated with an increase in the risk of death (HR 1.16; 95% CI 1.10–1.22) and any cardiovascular event (HR 1.08; 95% CI 1.03–1.14) . A Korean cohort of 624,237 subjects with T2DM also reported a significant higher risk of all-cause mortality (HR 1.58; 95% CI 1.53–1.62), myocardial infarction (HR 1.15; 95% CI 1.10–1.20), and stroke (HR 1.22; 95% CI 1.18–1.26) among the individuals with the highest weight variability compared with those with the lowest weight variability . In the present study, our data confirmed the association weight variability and all-cause mortality in overweight or obese adults with T2DM, which could be of additional value to further illustrate the effect of higher weight variability on all-cause mortality.
Besides focusing on the overweight or obese adults with T2DM, our study had a few strengths over previous studies. The finding from the Chicago Western Electric Company study  indicated that the length of the follow-up period may influence the observable effect of weight variability. In previous studies focused on the patients with T2DM, the mean follow-up period was 3.9–4.9 years in the U.S. study  and 7.6–7.8 years in Korean cohort study . However, our study comprised a longer follow-up period with 9.6 years for the analysis of survival. In addition, a prospective cohort study of 6,537 middle-aged Japanese American men from the Honolulu Heart Program  shown that the association between weight fluctuation and mortality were partially explained by the presence of pre-existing disease. Thus, this association might be better demonstrated in the population with fewer comorbidities. Compared with previous observational studies [6, 7], our study population enrolled in clinical trial (Look AHEAD trial) tend to be less comorbidities and heterogeneity than those in the community.
As mentioned above, the weight loss often accompanied by weight fluctuations, which was defined as “yo-yo effect” by Kelly D. Brownell at Yale University . Some data shown that approximately 79% of adults who intentionally achieve successful weight loss will regain the weight within 1 year . According to the findings from previous studies [6, 7, 14–17] and our study, the weight cycling (higher weight variability) was associated with the higher risks of death. Dr. William Kannel joked that once you are fat, you better stay fat, when he made a presentation for Framingham study regarding weight cycling. Of course, such recommendation hardly can be created due to the risks of CVD and death secondary to obesity. Therefore, a strategy that not only can lose the body weight but also is able to avoid the risks of death associated with weight fluctuations is particularly important for the overweight or obese adults. Of note, the findings presented herein supported that achieving weight loss by ILI might be able to avoid the risks of death associated with the high weight variability, and further provided the information for making decisions about the benefits of ILI. Although this finding was considered exploratory, such information contributed to strengthening the recommendation from 2020 ADA guideline that supported the ILI was used to achieve the weight loss in overweight or obese adults with T2DM .
The strengths of this investigation are worth note. We had a large sample size of the cohort focused on the overweight or obese adults with T2DM and defined the 4-year weight variability based on five equally spaced medical measurements. Our study is not without limitations. First, as in all observational studies, there may be a potential for reverse causation. Therefore, we conducted a sensitivity analysis in participants (n = 3643) without any outcomes occurred within 4 years and found the consistent results with our main findings. Second, the residual measured or unmeasured confounders were difficult to exclude, although the effect of various confounding factors had been adjusted in the Cox regression model and the study population had a lower heterogeneity due to enrolling in clinical trial (Look AHEAD trial). Moreover, the consistency of results in several sensitivity analyses and subgroup analyses for key variables (age, gender, race, weight, SBP, HbA1c, total cholesterol and serum creatinine) supported the robust findings. Third, due to the non-interventional observational study, the findings are unable to make a causality but are merely hypotheses-generating. Therefore, the interpretation of the findings should be cautious. Finally, although the study population had the multiethnic diversity, the findings might not be generalizable to the overweight or obese adults with T2DM who would not have qualified for taking part in the Look AHEAD trial.