Physical Activity and Weight Loss Among Adults With Type 2 Diabetes and Overweight or Obesity: A Post Hoc Analysis of the Look AHEAD Trial

[Introduction] Nearly 10% of cardiovascular events are attributed to type 2 diabetes (T2D). [..] Prior large RCTs [randomized controlled trials], including Look AHEAD (Action for Health in Diabetes), DIRECT, and the Diabetes Prevention Program, attempted to investigate the cardiovascular benefits of weight loss and increased PA [physical activity] volume among individuals with prediabetes or T2D, but no relationship between lifestyle-induced weight loss and cardiovascular benefits has been reported. [..] this study evaluates the interactions of weight loss and PA volumes in association with the risk of cardiovascular events by conducting a post hoc secondary analysis of the Look AHEAD trial among individuals with T2D and overweight or obesity, defined as a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or greater (or ≥27 if currently taking insulin). [..]

[Methods] [..] the Look AHEAD trial was a multicenter RCT that investigated the cardiovascular benefits of an intensive lifestyle intervention (ILI), aiming for at least 7% weight loss from the baseline body weight, compared with diabetes support and education (DSE).

[For measuring weight loss] a 4-year weight loss percentage was calculated by subtracting the body weight at year 4 from the baseline weight, then dividing this difference by the baseline weight.

[For measuring PA] a valid wear-day was defined as the accelerometer being worn for at least 10.5 hours within 1 day. Nonwear time was defined as consecutive 0 count of the accelerometer for more than 60 minutes. Participants were instructed to wear the accelerometer for 7 days, including a weekend day, placing the device vertically at waist at the horizontal level of the anterior iliac spine. PA that lasted for at least 10 consecutive minutes with an intensity greater than 3 metabolic equivalent of tasks (METs) was considered valid moderate-to-vigorous PA. The total PA volume (MET-min/wk) was calculated by summing up the minutes of moderate-to-vigorous PA and multiplying the corresponding intensity (METs). [..]

The primary outcome was the first postrandomization occurrence of a composite cardiovascular outcome including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Three secondary composite cardiovascular outcomes included (1) death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; (2) death from any cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina; and (3) death from any cause, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina combined with coronary artery bypass grafting, percutaneous coronary intervention, hospitalization for heart failure, carotid endarterectomy, or peripheral vascular disease. The outcomes were adjudicated by a masked outcome committee. [..]

[Results] During a median follow-up of 9.5 years, 54 participants with weight loss of 7% or greater (16.2%), 144 participants with weight loss of less than 7% (16.1%), 151 participants with low PA volume (16.9%), and 47 participants with high PA volume (13.9%) developed the primary outcome. No significant association was observed between weight loss or high PA volume with the primary outcome. [..]

The joint association between weight loss and PA volume with the risk of cardiovascular events was further assessed. Compared with the participants with low PA and no weight loss (reference group), individuals with high PA and weight loss had a significantly lower risk of the primary outcome (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81). The cardiovascular benefits from high PA volume were more significant among participants with weight loss of 7% or greater (P for interaction = .01). The association between 4-year accumulative PA volume and primary and secondary outcomes differed between those with and without weight loss of 7% or greater. Higher PA volume was linearly associated with a decreased risk of cardiovascular events among participants with weight loss (1000 MET-min/wk: HR, 0.83; 95% CI, 0.68-1.01; 2000 MET-min/wk: HR, 0.33; 95% CI, 0.10-1.11). However, for those who failed to lose weight, the cardiovascular benefits appeared to reach a plateau at the guideline-recommended PA volume, at approximately 1000 MET-min/week (1000 MET-min/week: HR, 0.97; 95% CI, 0.91-1.04; 2000 MET-min/week: HR, 0.96; 95% CI, 0.70-1.31).

[..] among those without weight loss, the benefits from increasing PA remained constant over time (2 years: HR, 0.60; 95% CI, 0.84-1.16; 4 years: HR, 0.61; 95% CI, 0.80-1.03; 6 years: HR, 0.58; 95% CI, 0.76-0.96), while among those who did not lose weight, the results were not statistically significant at 2, 4, or 6 years (2 years: HR, 0.73; 95% CI, 0.90-1.12; 4 years: HR, 0.77; 95% CI, 0.92-1.08; 6 years: HR, 0.73; 95% CI, 0.86-1.02). [..]

[Discussion] In the current study, increasing PA only or losing weight only were not associated with cardiovascular benefits in adults with T2D and overweight or obesity. Consistent with prior post hoc analyses, losing 7% or greater of body weight may be insufficient for the individuals in Look AHEAD, who had a very high baseline body mass index (BMI; mean [SD], 36.4 [6.0]), and the cardiovascular benefits from increasing PA may be modest in such population. Combined with the previous and conflicting findings of incorporating weight loss and exercise, it suggests that the benefits from PA may vary among individuals with different baseline characteristics. This may also partially explain the lower risk of cardiovascular events we observed in those incorporating weight loss and high PA volume and the enhanced benefits from increasing PA during and after losing weight. Nevertheless, our findings should be interpreted cautiously because there was limited evidence on the complicated associations between increasing PA, lifestyle-induced weight loss, cardiovascular benefits, and their joint associations. Based on the recent studies, our findings imply the cardiovascular benefits of moderate-to-vigorous PA may vary among individuals with differing characteristics.

The cardiovascular benefits attained from increasing PA and weight loss are multifaceted. Prior systematic reviews summarized the mechanisms, including improved metabolism and vascular health as well as stimulating the release of cardiovascular-protective exerkines. However, the mechanisms that weight loss enhanced the cardiovascular benefits of PA in individuals with T2D and overweight or obesity were understudied. [..]

This study highlights the association between combined weight loss and increased PA with a reduced risk of cardiovascular events in individuals with T2D and overweight or obesity. First, maintaining a high PA volume and losing weight are important, but the combination may be more beneficial in this population. It may be more helpful when clinicians give prescriptions and lifestyle suggestions considering the association between cardiovascular benefits, PA, and weight loss with the individual’s characteristics. Second, future RCTs targeting individuals with T2D and overweight or obesity should consider lifestyle interventions based on basic characteristics or combining weight loss and increased PA to elucidate the causal relationships between exercise, weight loss, and cardiovascular events. Third, this study provides new evidence to support the current guideline recommendations on maintaining weight loss and increasing PA volume to lower risk of cardiovascular events.”

Full article, Z Huang, X Zhuang, R Huang et al., JAMA Network Open, 2024.2.22