A Biologically Based Approach to Prevent Obesity in Older Adolescents and Young Adults

About This Grant

Abstract Once obesity develops and becomes entrenched, achieving sustained weight loss is extremely difficult. Thus, preventing the accumulation of excess adiposity in high-risk individuals is the ideal course of action. Adolescents/young adults (AYAs) are high-risk individuals, as this is a life stage characterized by susceptibility for accelerated weight gain. However, most obesity prevention interventions targeting AYAs have reported null findings or modest effects. It is possible that failure to address the underlying physiology of the energy regulatory system is at least partly responsible for the underwhelming results. Previous obesity prevention interventions in AYAs have almost entirely focused on modifying individual behaviors and/or external environmental conditions and have not addressed the biological pathways driving energy regulation. Effectively targeting the underlying physiological processes promoting body fat storage, such as with pharmacotherapy, may be an essential component of successful obesity prevention for some individuals. When used in combination with lifestyle-based weight gain prevention counseling, low-dose preventative pharmacotherapy has the potential to halt or slow unhealthy weight gain by targeting key mechanisms in the energy regulatory system. Phentermine/topiramate is among the most cost-effective obesity medications approved for adolescents and adults. Its mechanisms of action may be ideal for impeding weight gain and ultimately preventing the onset of obesity because they are multifactorial and involve reducing appetite, enhancing satiety, and potentially increasing energy expenditure. Flexible dosing with phentermine/topiramate provides the option to introduce preventative pharmacotherapy at low levels of exposure yet allows for dose escalation if weight gain were to ensue. In the proposed clinical trial, we plan to diverge significantly from historical obesity prevention approaches by pairing lifestyle-based weight gain prevention coaching with low-dose preventative pharmacotherapy to target the underlying biological processes implicated in weight gain. We will target AYAs (18 to <25 years old) at risk of developing obesity: defined as those with a BMI between 25-29.9 kg/m2 (overweight classification) and a family history of obesity (one biological parent with severe obesity and/or two biological parents with obesity). We will randomize 140 of these individuals (1:1) to phentermine/topiramate or placebo with both groups additionally receiving lifestyle- based weight gain prevention coaching. Over a period of two years, we will: 1) compare changes between groups in BMI trajectories as well as incidence of obesity and regression to normal weight; 2) identify mechanisms of action related to appetite, satiety, cravings and energy expenditure as well as determine if there are differences between groups in diet quality and disordered eating behaviors; and 3) investigate changes in visceral adipose tissue and its relation to cardiometabolic risk. In this study we will take a fundamentally different approach to the science of obesity prevention by targeting the underlying biological processes driving unhealthy weight gain in AYAs, a group that has been underrepresented in medication trials.