ESPE Yearbook of Paediatric Endocrinology

Brief summary: This randomized, double-blind, phase 3 trial of youths with inadequately controlled T2D, dulaglutide treatment was superior to placebo in reducing the glycated hemoglobin level at 26 weeks.

Comment: T2D in children and adolescents is an aggressive disease with early onset of complications, leading to significant morbidity and mortality. After three decades with no efficient treatment, there is finally light at the end of the tunnel.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted in the fasting state, by intestinal enteroendocrine cells at low basal levels, and that rises briskly within minutes of food consumption.¹ GLP-1 controls meal-related glycemic excursions through augmentation of insulin secretion and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, leading to weight loss. GLP-1 has a short half-life of approximately 2 minutes, as it is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). To increase GLP-1 activity, DPP-4 inhibitors and GLP-1 receptor agonists have been developed.

Dulaglutide (Trulicity), is a GLP-1 receptor agonist that is administered subcutaneously once weekly. Dulaglutide has been approved since 2014 for the treatment of adults with T2DM. This study tested its efficacy and safety in adolescents. A clear benefit is its once-weekly administration. Indeed, this study reported 99% adherence to treatment.

55% of participants identified as Hispanic/Latino and 15% as Black/African American. Their mean age was 14.5 years, mean (BMI 34.1 kg/m², mean duration of T2D 2.0 years and mean HbA1C 8.1%). Treatment resulted in significant reductions in HbA1c levels relative to placebo treatment, at week 26, according to the intention-to-treat estimate. HbA1c decreased from baseline by 0.8% but increased by 0.6% in the placebo group. Gastrointestinal symptoms were among the most common adverse events, but they were primarily mild and were most likely to occur soon after the initiation of therapy. There were no clinically meaningful differences in the incidence or annual rate of hypoglycemia between the dulaglutide groups and the placebo group. However, body weight did not decrease significantly following the treatment.

The EU approved dulaglutide as an adjunct to diet and exercise, to improve glycemic control in youth with T2D aged 10 years and older. In November 2022, the FDA approved its use as well.

Reference: 1. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018 Apr 3;27(4):740–756. doi: 10.1016/j.cmet.2018.03.001.