Prediabetes is an abnormal state of glucose homeostasis in which blood glucose levels are elevated above the range of normal but are not high enough to be classified as diabetes. A staggering 28% of U.S. youth ages 12 to 19 years are living with prediabetes. This number more than doubled from 1999 to 2018. Prediabetes and obesity are strongly correlated in a high-risk genetic backdrop, making them almost two sides of the same coin. The ongoing COVID-19 pandemic has caused a rapid increase in both these problems in children.
There is to support that even before its progression to type 2 diabetes, prediabetes independently is a toxic metabolic state causing an increased risk of cardiovascular disease and mortality. It is important to note that pediatric type 2 diabetes is a from adult type 2 diabetes in that it has a very aggressive course that leads to rapid beta cell failure and insulin dependence.
What can we, as pediatricians and pediatric endocrinologists, do about this disease that has now affected more than one in four adolescents in our country?
Unfortunately, there are currently no FDA-approved pharmacological treatment options that can be offered to children with prediabetes. Their visit to the "prediabetes expert" is often a frustrating one because all we can offer are lifestyle changes such as increased activity and decreased caloric intake. This can sound a lot like "eat healthy and exercise," and seems unhelpful and generic to most patients. While intense lifestyle changes, when practiced stringently and persistently, can improve outcomes in some patients, they require continued effort, resources for healthy foods, and structured activity that are not universally available. This is especially true for structurally disadvantaged groups -- often the groups with a higher prevalence of prediabetes.
The lack of safe, FDA approved medications leaves clinicians helpless in offering a broader range of solutions to young patients with prediabetes. Consequently, there is a glaring unmet need to allocate funding for research in this population.
Trials should be developed to study medications that can preserve beta cell function and ultimately prevent diabetes. Specifically, incretins (glucose-dependent insulinotropic peptide [GIP] and glucagon-like peptide-1 [GLP-1]) are gut hormones that serve multiple physiological functions including regulating insulin release postprandially. The two incretins, and their receptor analogues (RA), in adults and children with obesity and type 2 diabetes. Two GLP-1 RAs, liraglutide (Saxenda) (daily) and exenatide (Bydureon) (weekly), both subcutaneous, have for pediatric obesity and type 2 diabetes respectively, and have shown promising results thus far. Weekly subcutaneous administration of another GLP-1 RA (semaglutide) is currently in children for the same diseases.
Poly-agonists (molecules that activate multiple metabolic receptors) such as dual GIP/GLP-1 RAs and tri-agonists (GIP/GLP-1/glucagon RAs) are still in development; the dual GIP/GLP-1 RA tirzepatide (Mounjaro) has shown with weight loss in adults with obesity along with improvement in beta-cell function and insulin sensitivity in type 2 diabetes. Therefore, incretin-based therapies seem to have promising potential to be explored in children with prediabetes.
Other novel and emerging anti-obesity pharmacological candidates that are in development and in pediatric prediabetes include amylin analogues (pramlintide [SymlinPen 60]), amylin/calcitonin dual analogues, leptin sensitizers, melanocortin-4-receptor (MC4) analogues, neuropeptide Y antagonists, peptide tyrosine tyrosine (PYY) agonists, fibroblast growth factor-21 (FGF-21) agonists, growth differentiation factor 15 (GDF-15) analogues, mitochondrial uncouplers, and drugs targeting the ghrelin pathway.
Nevertheless, there are currently no evidence-based treatment guidelines for pediatric patients with prediabetes. The quest for innovative pharmacological candidates that reverse prediabetes is the need of the hour and warrants rigorous investigation.
is an assistant professor in pediatrics in the division of pediatric endocrinology and diabetes at the Yale School of Medicine. She is currently serving a primarily clinical role in both diabetes and endocrinology with an interest in medical education. is a professor in pediatrics in the division of pediatric endocrinology and diabetes at the Yale School of Medicine, and has served as chief of the division for over 37 years. The authors reported no relevant disclosures.
, is an assistant professor in pediatrics in the division of pediatric endocrinology and diabetes at the Yale School of Medicine. She is currently serving a primarily clinical role in both diabetes and endocrinology with an interest in medical education. , is a professor in pediatrics in the division of pediatric endocrinology and diabetes at the Yale School of Medicine, and has served as chief of the division for over 37 years. The authors reported no relevant disclosures.