Treatment of Type 2 Diabetes in Youth

Glucagonlike peptide1 receptor agonists (GLP1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatric type 2 diabetes and the mechanism of action of GLP1RAs as it pertains to physiological pathways relevant for type 2 diabetes, obesity and their related comorbidities. The outcomes of paediatric trials evaluating liraglutide, exenatide, semaglutide and dulaglutide in paediatric type 2 diabetes and obesity will be closely examined, including differences compared with adult studies. Finally, potential barriers and strategies to expanding GLP1RA access in adolescents will be discussed. Future studies are needed to determine if the cardioand renalprotective benefits of GLP1RAs apply to youthonset type 2 diabetes.

G lucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP-1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatric type 2 diabetes and the mechanism of action of GLP-1RAs as it pertains to physiological pathways relevant for type 2 diabetes, obesity and their related comorbidities. The outcomes of paediatric trials evaluating liraglutide, exenatide, semaglutide and dulaglutide in paediatric type 2 diabetes and obesity will be closely examined, including differences compared with adult studies. Finally, potential barriers and strategies to expanding GLP-1RA access in adolescents will be discussed. Future studies are needed to determine if the cardio-and renal-protective benefits of GLP-1RAs apply to youth-onset type 2 diabetes.
The incidence of youth-onset type 2 diabetes (T2D) is increasing. 1,2 Growing evidence has demonstrated that youth-onset T2D is rapidly progressive, with earlier onset of life-limiting complications compared with adult-onset T2D. 3,4 Initiation of effective treatment that can restore beta cell function is critical. Until 2019, metformin and insulin were the only medications approved by the United States Food and Drug Administration (FDA) for the treatment of youth with T2D. In 2019, liraglutide became the first glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for youth with T2D, followed by exenatide in 2021 and dulaglutide in 2022. [5][6][7] According to the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes' current clinical practice guidelines for the management of youth-onset T2D, metformin monotherapy is the standard initial treatment for youth with T2D, once metabolic control is restored with insulin in those who present with ketosis and/or marked hyperglycaemia. 8 However, data collected from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated early glycaemic failure on metformin monotherapy, with a median treatment failure time of 11.5 months. 9 Escalation of treatment, including the initiation of insulin, is recommended. 10 The recommendation to start insulin therapy following metformin failure in youth contrasts with the guidelines for adults with T2D. 11 In the management guidelines for adults with T2D, insulin or sulphonylureas are only added to the regimen if other medications fail to achieve the goal haemoglobin A1c (HbA1c) to avoid additional weight gain, which could worsen insulin resistance and overall glycaemic control and cardiometabolic health. 11,12 Despite multiple new pharmacotherapies to treat adult-onset T2D, as of 2023 there remains only five medications that are approved by the FDA for the treatment of youth-onset T2D. Accordingly, medications approved for adult T2D have been used off-label in this cohort to improve weight and glycaemic outcomes. 13,14 Across the lifespan, there is growing interest in utilizing GLP-1RAs in the treatment of T2D, given the potential to control hyperglycaemia and promote weight reduction, thus addressing the underlying pathophysiology of T2D. [15][16][17] GLP-1RAs stimulate postprandial insulin secretion, reduce glucagon secretion, delay gastric emptying and decrease appetite, leading to improvements in glycaemic control and weight reduction. 17 Given the rapid progression of beta cell failure and development of complications, there is considerable interest in treating youth with new oral and injectable agents that have been approved for use in adults with T2D. 18,19 The objectives of this review are to: (1) review the mechanism of action of GLP-1RAs in T2D; (2) summarize the use of GLP-1RAs in youth-onset T2D, highlighting recent data on the use of dulaglutide in this age group; (3) discuss accessibility of GLP-1RAs in the paediatric population; and (4) conclude by reviewing the challenges of conducting phase III randomized clinical trials of these medications in the paediatric population, and discussing a potential pathway to facilitate approval of these drugs for adolescents with T2D. 20 GLP-1 is secreted by the distal ileum and colon and a population of neurones in the NTS, in response to nutrient and neural inputs. 22 GLP-1 level is lowest during fasting and rapidly increases after feeding. 23 Luminal exposure of the L cells to nutrients (carbohydrates, amino acids and lipids) induces GLP-1 secretion into the intestinal microvasculature to exert its humoral effects and stimulate enteric neurones. GLP-1 secretion is also stimulated by neurotransmitters from vagal and enteric neurones. 24 In the brain, the NTS neurones are the primary source of endogenous GLP-1, whose secretion is stimulated by leptin and gastric Early rodent studies demonstrating GLP-1RA treatment expansion of the beta cell mass generated excitement about its potential to reverse T2D in humans. 22 Subsequent work showed that GLP-1R-mediated stimulation of beta cell proliferation only occurred in young but not older rodents. 33 In human subjects, while GLP-1RAs may improve beta cell function during treatment, there is no clinical evidence of sustained improvement after treatment discontinuation in either adults or adolescents. [34][35][36][37] As GLP-1RAs stimulate insulin secretion, the question of its potential to promote beta cell exhaustion has also been raised. Prior studies have shown that patients treated with sulfonylureas are at increased risk for beta cell functional decline. 38 In a humanized mouse model using transplanted islets, daily injection of high-dose liraglutide for more than 200 days resulted in beta cell dysfunction. 39     (the gene encoding GLP-1R) expression increased food intake and body weight. 22 In addition to its effect on homeostatic feeding, GLP-1RAs also activate brain areas in the mesolimbic system to suppress reward behaviour and palatability. 22 The combination of GLP-1 action on homeostatic and hedonic feeding likely contributes to its appetite suppressant and weight loss effect.

Management of diabetic nephropathy
The TODAY study demonstrated that diabetic nephropathy (DN) occurs early in youth-onset T2D, with a baseline prevalence of 8% at study entry (mean diabetes duration of 7.8 months) and a cumulative incidence of 54.8% after a mean diabetes duration of 13.3 years. 48

Other metabolic effects
Elevated alanine aminotransferase -a marker recommended for screening of nonalcoholic fatty liver disease -has been found in 48% of patients with paediatric T2D. 56

Safety and efficacy of glucagon-like peptide-1 receptor agonists in paediatric type 2 diabetes
Currently, there are three GLP-1RAs approved for the treatment of T2D in youth aged 10 years and older, including liraglutide, extended-release exenatide and dulaglutide ( Table 1)   Adolescents with T2D display more insulin resistance and glycaemic failure compared with adults. 1,19 GLP-1RA treatment of adults with T2D resulted in less weight loss compared with participants without T2D. 67 The AWARD-PEDS investigators thus speculated that the catabolic effect of hyperglycaemia in the placebo group may obscure detection of weight loss in the dulaglutide-treated groups. Although the mechanism is unknown, it is possible that the insulin resistance observed during adolescence may also contribute to the relative resistance to GLP-1RAmediated weight loss.

Safety and efficacy of glucagon-like peptide-1 receptor agonists in paediatric obesity
Following the observed benefit of higher GLP-1RA doses on weight loss in adults, multiple studies have been conducted evaluating GLP-1RAs specifically for obesity in the adolescent population ( Table 2). [68][69][70][71][72] A study was completed in 2012 evaluating daily exenatide for weight loss in youth 9-16 years of age, with dose increased from 5 μg twice daily to 10 μg twice daily over a 3-month period. 70   Beyond prescription pattern, GLP-1RA access may also be limited due to cost. As a class, the high cost of these medications contributes to limited insurance coverage of these medications, especially for the indication of obesity. 75 The above clinician experience assessment by Gourgari 76,77 Even when covered by insurance, the outof-pocket expense may be cost prohibitive.

Glucagon-like peptide/glucose-dependent insulinotropic polypeptide dual agonist therapy
Glucose-dependent insulinotropic polypeptide (GIP) is another gutsecreted hormone with a dominant insulinotropic effect. Physiologically, it is secreted from the K cells in the duodenum and jejunum. 78 In the adult population, tirzepatide, which is a GLP-1/GIP dual agonist, was demonstrated to be even more effective than GLP-1RA monotherapy.
Studies in adults have shown that tirzepatide is superior to placebo, GLP-1RAs and basal insulin in terms of glycaemic control and body weight reduction. Data are currently lacking in the paediatric population, and further studies are needed to support its potential use.

Future directions
Despite clinical guidelines recommending a 5-10% weight reduction for youth-onset T2D, there remains a gap regarding recommendations for utilization of novel agents that target the multifaceted pathophysiology of T2D in this age group. The recent FDA approval of several GLP-1RAs for paediatric T2D and obesity heralds a much-welcomed increase in the armamentarium for the management of these conditions. Much work is needed, however, to expand the use of GLP-1RAs in children.
Many barriers exist in gaining paediatric approval for medications already approved for adult use. The FDA mandates phase III clinical trials for all new medications for each clinical indication to protect patient safety. Completion of such trials in adolescents with T2D is difficult due to a relatively small patient population (compared with adults), stringent exclusion criteria, and the difficulty of participants/caregivers repeatedly taking time off from school and work. 79 Families of historically marginalized races and ethnicities may also be reluctant to participate in clinical trials. Pragmatic designs are needed to allow trials to augment enrollment and overcome historical barriers. These strategies may include involvement of pertinent stakeholders in trial design, recruitment and execution. 80 In addition, long-term follow-up studies will be needed to determine if GLP-1RAs render the same cardio-and renal-protective benefits in youth-onset T2D.
There may also need to be a shift in the paradigm in balancing conducting rigorous safety and efficacy trials of novel agents in paediatric cohorts, against prescribing these agents off-label when available evidence supports a substantial potential health benefit. For many clinicians, the lack of safety and efficacy data impacts prescribing practices and agent selection. Although sparse, the randomized controlled trials that do exist in youth support the efficacy and safety of GLP-RAs in this population. One might argue that once there is FDA approval of one agent in a class of medications, in the context of safety and efficacy data of other agents in the class among adults, the initial data are sufficient to begin the utilization of that agent if the benefit outweighs the risk.
Consideration needs to be given to the health outcome of adolescents who cannot benefit from novel medications, due to the length of time required to conduct clinical trials in a relatively small patient population.
Specifically, for GLP-1RAs, their mechanism of action may provide an opportunity to not only target weight reduction and glycaemic control, but also reduce cardiovascular, renal and hepatic risk factors, all of which could significantly improve the health trajectory of youth with T2D and associated microvascular and macrovascular complications. Taken together, the pharmacotherapy profile for GLP-1RAs is very favourable for youth-onset T2D. However, high cost and inadequate insurance coverage may continue to limit access to these agents in paediatric cohorts. Further investigation both at the policy and clinical guideline levels must be conducted to support an equitable and accessible roll-out of these agents into paediatric clinical care. q