Anti-obesity pharmacotherapy to decrease BMI and improve insulin sensitivity in adolescents with obesity and type 2 diabetes

Project Abstract/Summary
Development of type 2 diabetes (T2D) prior to the age of 20 years has been associated with rapid disease
progression and early exogenous insulin dependence.1 Furthermore, adolescents with T2D are more likely to
develop diabetes-related comorbidities, such as hypertension, atherosclerosis, and kidney disease earlier
compared to adults, highlighting the need for a fundamentally different (and perhaps more aggressive) treatment
approach in adolescents.1 Obesity (body mass index [BMI] >95th percentile for age and sex) is a primary risk
factor for the development and progression of T2D.2,3 However, current treatment guidelines for T2D in
adolescents recommend lifestyle management and metformin (+ insulin) as first-line therapy, which rarely result
in BMI reduction or slowing of T2D disease progression.1,4-7 Therefore, novel treatments that meaningfully reduce
BMI, delay exogenous insulin dependence, and potentially slow the progression of T2D need to be investigated
in adolescents with T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may represent an ideal first-
line therapy for adolescent T2D. GLP-1 RAs increase postprandial insulin secretion and reduce glucagon
production, and at higher doses, can result in clinically meaningful BMI reduction by suppressing appetite and
enhancing satiety.8 Liraglutide (a daily injectable GLP-1 RA) at its 1.8 mg/day dose was approved for adolescents
with T2D in 2019, but liraglutide has not been studied with a primary focus on BMI reduction and insulin sensitivity
or ß-cell function in adolescents with T2D.9,10 Therefore, the overall objectives of this study will be to 1) evaluate
the effects of liraglutide at its obesity medicine dose (3.0 mg/day) versus standard-of-care on BMI reduction, and
2) evaluate its effect on insulin sensitivity and β-cell function in adolescents with T2D and obesity. The overall
hypothesis is that liraglutide 3.0 mg/day will result in a greater mean BMI percent change as well as
improvements in insulin sensitivity and β-cell function as compared to placebo plus standard-of-care. The focus
on using liraglutide at its obesity medicine dose in adolescents with T2D is novel and important; prior studies
evaluating liraglutide have not been generalizable to adolescents with this aggressive disease nor have prior
studies had the majority of patients on the maximum liraglutide dose, making dose-dependent weight-loss
evaluations difficult. The proposed study will generate preliminary data to inform the design of a larger and
sufficiently-powered R01 trial. Importantly, this mentored project will provide essential training in clinical trial
design and implementation in a unique and challenging patient population, as well as measures of insulin
sensitivity/β-cell function. These skills will facilitate my scholarly independence and serve as the foundation of
my future career focusing on the application of obesity medicine principles in the treatment of adolescents with
T2D.

Grant Number: 5K23DK129721-05
NIH Institute/Center: NIH
Principal Investigator: Megan Bensignor