SLEAP: a Sleep ancillary to the Long-term Effectiveness of the Anti-obesity medication Phentermine trial

PROJECT SUMMARY Sleep is a crucial, modifiable determinant of energy balance and body weight regulation but is rarely considered in treatment strategies for obesity. The current standard of care for obesity treatment is lifestyle- behavior therapy (LBT) to promote improvements in diet and physical activity; however, changes in these behaviors are difficult to sustain. Anti-obesity medications (AOM) have emerged as a promising modality to augment LBT. Phentermine is a low-cost sympathomimetic agent accounting for 75% of all AOM prescription fills. While phentermine can inhibit food intake by increasing norepinephrine levels in hypothalamic nuclei, this activation of the sympathetic nervous system also promotes arousal and disrupts sleep. Insomnia is a reported side effect of phentermine monotherapy; however, empirical data are limited. Systematic investigation of the impact of phentermine on sleep is needed given the key role of sleep in determining energy balance and body weight: suboptimal sleep leads to obesogenic eating behaviors and predicts poorer weight loss outcomes in response to treatment. Given the stimulant properties of phentermine and robust relationship between sleep and energy balance behaviors, we postulate that sleep will influence the treatment response to phentermine monotherapy and that the magnitude of phentermine’s effect on sleep will vary with the timing of administration. To address these knowledge gaps and test our working model, we plan to leverage the “Long- term Effectiveness of the Anti-obesity medication Phentermine” (LEAP) trial, a placebo-controlled randomized trial funded by the NHLBI to test the impact on body weight of phentermine monotherapy as an adjunct to an LBT program over 24 mo in 1,000 adults with overweight and obesity. The proposed ancillary study plans to assess free-living sleep at baseline, 6, 12, and 24 mo visits via objective measures (actigraphy and home sleep testing) in up to 580 participants (290/arm). Our aims are 3-fold: (1) to test the impact of phentermine vs. placebo on objective measures of sleep during the treatment period; (2) to assess the influence of timing of treatment administration during the day on nocturnal sleep; (3) to evaluate whether differences in sleep during the intervention period influence treatment effects on change in body weight, diet, and physical activity at 24 mo. We anticipate that phentermine will adversely affect sleep relative to placebo, but that adverse effects will be attenuated among those completing their dosing earlier, relative to later, in the day. Further, given the role of sleep in weight management, we hypothesize that differences in sleep in response to treatment will moderate the efficacy of phentermine in producing long-term improvements in body weight and energy balance behaviors. Results of this ancillary will provide novel insight into the role of sleep in the effect of phentermine on weight loss and help to identify individuals who might benefit most from this low-cost AOM. Consequently, findings will guide obesity treatment recommendations to optimize sleep for maximal efficacy.