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Expert commentary

by Raghu G. Mirmira, MD, PhD

Obesity in adolescents is rising and is becoming a public health concern. An estimated 40% of adolescents aged 12-19 in the US are overweight (BMI 85th to 95th percentile) or obese (BMI≥95th percentile).1 Obesity during childhood increases the risk of morbidities, including type 2 diabetes, fatty liver disease, sleep apnea, depression, and eating disorders. Obesity during childhood also portends obesity during adulthood, and is thereby associated further with comorbidities seen in adults. In recent years, there has been an emphasis on studies designed to address obesity and overweight in adolescents. Lifestyle changes are first line approaches and involve behavioral modification that should include family involvement. However, lifestyle changes can be self-limiting, as adaptations to weight loss, such as increased appetite and decreased satiety, can intervene to reverse the initial effects. Unlike in adults, pharmacologic approaches to management of adolescent obesity are more limited, since more modern therapies are not yet approved in this age group. Use of GLP-1 receptor agonist therapy with liraglutide in adolescents was recently shown to be superior to placebo with regards to the change from baseline in the BMI standard-deviation score.2 That study also found that a greater reduction was observed with liraglutide than with placebo for BMI and for body weight, amounting to an absolute body weight difference of -4.5 kg. These data offer some hope that a combination of lifestyle changes and pharmacologic intervention might be feasible as an approach to maintain weight loss.

In this study, Fox and colleagues conducted a randomized, placebo-controlled trial of the effect of once-weekly exenatide (a GLP-1 receptor agonist) on the favorable changes in weight and cardiometabolic risk factors induced by short-term meal replacement therapy (MRT) among adolescents with severe obesity. The authors hypothesized that participants randomized to receive exenatide would have superior maintenance of BMI reduction induced by MRT at 52 weeks (primary outcome) and superior maintenance of improvements in cardiometabolic risk indices (body fat, TG/HDL ratio, fasting glucose and insulin, HbA1c, and quality of life) at 52 weeks. In this study, 66 participants (age 12-18) with BMI ≥120% of the 95th percentile who achieved BMI reductions ≥5% on MRT were randomized 1:1 to either exenatide XR (2 mg/week subcutaneously) + lifestyle therapy or placebo + lifestyle therapy for 52 weeks. Primary analysis of the results demonstrated a placebo-subtracted exenatide treatment effect of -4.1% (p=0.078). After excluding participants with major protocol deviations, the results demonstrated a placebo-subtracted exenatide treatment effect of -5.7% (p=0.030). Secondary endpoints did not show a statistically significant change with exenatide treatment.

A major strength of this study was the randomized, placebo-controlled design with a relatively high retention rate. Limitations included inadequate power to detect differences in secondary outcomes and underrepresentation of non-white participants, which limited the broader applicability of the findings. The results of this study suggest a modest effect of exenatide on the ability to maintain weight reduction following lifestyle changes. Future directions include the assessment of other GLP-1 receptor agonists, and even dual GLP-1/GIP receptor agonists, which show greater weight reduction effects in adults.3 Factors predictive of GLP-1 receptor agonist responsiveness may allow for selection of patients who are likely to respond better to this class of agent.

 

References

  1. Skinner AC, Ravanbakht SN, Skelton JA, Perrin EM, Armstrong SC. Prevalence of Obesity and Severe Obesity in US Children, 1999-2016. Pediatrics. 2018;141(3).
  2. Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD, Prabhu N, Arslanian S, NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020 28;382(22):2117–28.
  3. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018 Nov 17;392(10160):2180–93.
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