From Pages to Practice

By Angela Castellanos, MD

Published January 5, 2022


As obesity rates rise among children and adolescents in the United States, so do rates of type 2 diabetes in this population. When lifestyle modifications fail to control type 2 diabetes in children, pediatric endocrinologists currently turn to metformin. When metformin fails, the next and only choice is the addition of insulin, which can lead to even more weight gain.

In contrast, adults with type 2 diabetes have access to a variety of well-studied oral and injectable agents, including glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors.  The last study to investigate the efficacy and safety of a type 2 diabetes drug in youth was a study of metformin published in 2002, until now.

The NEJM recently published a randomized, placebo-controlled study in which researchers examined the safety and efficacy of liraglutide, an injectable GLP-1 analogue, in children (aged 10–17 years) with type 2 diabetes who were receiving metformin, with or without basal insulin. The results showed that liraglutide was both safe and effective for glycemic control in this population. However, liraglutide was associated with higher rates of gastrointestinal adverse events (e.g., nausea and vomiting). Nevertheless, liraglutide can now be added to the small but growing armamentarium of medications for children and adolescents with type 2 diabetes.

The following NEJM Journal Watch summary further explains the study and findings.


Liraglutide Is Effective for Type 2 Diabetes

Adding daily subcutaneous liraglutide to metformin with or without insulin improved glycemic control in children and adolescents.

Metformin is the approved therapy for type 2 diabetes mellitus, but its efficacy in maintaining glycemic control often dissipates with time.

To determine whether adding the glucagon-like peptide-1 analogue liraglutide to metformin can safely improve glycemic control, investigators conducted an industry-funded, international, multicenter, randomized, controlled, phase III trial involving 135 metformin-treated children with type 2 diabetes (aged 10–16 years). Patients received metformin with or without basal insulin plus either subcutaneous liraglutide (escalated to 1.8 mg per day) or placebo.

Results were as follows:

  • Mean glycated hemoglobin levels at week 26 (the primary endpoint) decreased by 0.64% with liraglutide but increased by 0.42% with placebo (estimated treatment difference, −1.06%; P<0.001); the effect was even greater with liraglutide versus placebo at 52 weeks (−0.50% vs. 0.80%; ETD, −1.30%).

  • Glycated hemoglobin levels below 7% were achieved more often with liraglutide than with placebo (63.7% vs, 36.5%; P<0.001); the difference was observed whether or not patients were receiving insulin.

  • Fasting plasma glucose levels were significantly less at both 26 and 52 weeks with liraglutide.

  • Very-low-density lipoprotein cholesterol levels and triglyceride levels were significantly lower with liraglutide at 26 weeks but not at 52 weeks.

  • Adverse events (mostly gastrointestinal) were more common with liraglutide.

  • Incidence of hypoglycemia was greater with liraglutide; however, only one severe hypoglycemic episode occurred (in the placebo group) during the study.

Comment: Liraglutide is superior to placebo when added to metformin in improving glycemic control in children and adults with type 2 diabetes. Liraglutide should be considered when metformin is not providing satisfactory glycemic control. It is important to inform patients that liraglutide therapy is associated with frequent gastrointestinal adverse effects.

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Angela Castellanos is a general pediatrician and editorial fellow at the NEJM.