Youth Along the T2D Risk Continuum Remain Concerningly Refractory to Therapeutic Interventions

Pediatric obesity remains a pervasive public health concern. In the United States, 20% of children and adolescents are now obese, with the greatest increased prevalence in those with severe obesity. Most recently, COVID-19 mitigation efforts have created an obesogenic environment for youth, defined by school closures, reduced structured physical activities, and impaired access to nutritious foods; already, these behaviors have accelerated pediatric obesity—a trend not likely to be easily reversed. Unfortunately, pediatric obesity and the resultant metabolic complications of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) disproportionately impact disadvantaged racial/ethnic minority populations living in complex cultural and psychosocial environments, factors which preclude adherence to the long-recognized “gold standard” intervention of lifestyle therapy. These same factors impede robust study of pediatric obesity/dysglycemia, as the targeted patient population is often difficult to recruit and retain in research studies, a factor that greatly slows the study of pediatric-specific pathophysiology and optimization of therapeutic approaches. As a pertinent example, liraglutide received FDA approval to treat youth-onset T2D in 2019, the first non-insulin drug to receive such an indication in over 10 years and a full 9 years after receiving approval in adult-onset T2D. This delay may perhaps best be explained by the difficulties identifying and enrolling eligible pediatric subjects into the prerequisite clinical trials: the trial heralding pediatric FDA approval of liraglutide required 5 + years and 84 multinational sites to enroll just 135 subjects (1) whereas a similar trial enrolled 8 times as many adult T2D subjects in just 2 years (2).

There is a temptation to discount smaller (but hard-fought) pediatric trials and instead extrapolate findings from larger, more robust studies in adults. These extrapolations may be used to justify off-label prescribing or assumptions of anticipated clinical outcomes in obese youth along the T2D risk continuum. Caution must be exercised, however, as studies have revealed that adults and youth with insulin resistance/β-cell dysfunction possess overlapping but unique metabolic profiles and natural histories. For example, obese youth with IGT/T2D have been found to have hyperresponsive β-cells and lower insulin sensitivity as compared to adults (3), tendencies that are further exacerbated by puberty. Youth with T2D also have more rapid glycemic deterioration after diagnosis, perhaps explained by 3- to 4-fold faster rates of β-cell decline than adults (4).

Distinctions between pediatric and adult pathophysiology and therapeutic responsiveness are further revealed by comparing outcomes of clinical trials conducted in both age groups. Until 2019, metformin was the only non-insulin medication with FDA approval in pediatric and adult T2D and has therefore been most extensively studied across all ages. The TODAY Study of subjects with youth-onset T2D uncovered much higher rates of metformin treatment failure in youth than in adults, particularly in those with greater β-cell dysfunction at baseline (4). The RISE Consortium conducted head-to-head clinical trials in adults and youth cohorts, with treatment initiated earlier in the disease process, defined as IGT and recent-onset T2D (3, 5). In these studies, metformin failed to preserve or improve β-cell in youth (3) but did preserve β-cell function in actively treated adults (5). Perhaps the most widely cited study of metformin’s impact on insulin resistance and β-cell function is the Diabetes Prevention Program (DPP), in which metformin was found to slow progression to T2D in obese adults with IGT (6). Children were not included in the DPP. Despite this, there is a persistent tendency for some practitioners to apply the DPP findings to children (ie, prescribing metformin as pediatric T2D prevention). This tendency must be reconsidered, given the more recent TODAY and RISE studies, both highlighting the much more aggressive nature of youth-onset IGT/T2D and its general refractoriness to metformin therapy (3, 4). Youth-onset T2D is simply not the same disease as adult-onset T2D.

In this issue of the Journal of Clinical Endocrinology & Metabolism, Kelsey and colleagues hypothesized that, given the aggressive nature of youth-onset T2D, metformin may confer better β-cell protection if administered earlier during the metabolically challenging pubertal phase. A placebo-controlled randomized trial was conducted in 44 early-pubertal normoglycemic obese youth to determine the impact of a 2-year course of metformin on β-cell function and insulin sensitivity (7). The study was beset by recruiting difficulties, 50% subject attrition, and poor treatment adherence over the 2-year trial period, despite subject incentivization. While these factors limit robust conclusions and were undoubtedly frustrating for the investigators, they do not discount or minimize the findings, because this is the reality of pediatric obesity/T2D research and clinical care. These challenges are wholly reflective of this patient population in that obese/at-risk youth tend toward suboptimal adherence and there are very high rates of clinical attrition.

As in the RISE and TODAY studies, Kelsey and colleagues found that metformin did not improve β-cell function or insulin sensitivity in obese peripubertal youth, again revealing metformin to be an ineffective T2D prevention strategy in at-risk youth. While not the primary outcome measures, 2 years of metformin treatment improved body mass index (BMI) standard deviation score and body fat percent, which may confer cardiometabolic benefit over time. While the study was likely too small to fully assess these secondary measures, the disconnect found here between weight and BMI improvements and metabolic function was also seen in a trial of liraglutide in obese adolescents in which 56 weeks of liraglutide improved BMI standard deviation score, but failed to improve metabolic markers or β-cell function measures (8). These findings require further study but overall, they suggest insulin resistance/β-cell dysfunction in obese youth is difficult to reverse, even with weight loss.

The overarching trend for a more aggressive disease process and reduced responsiveness to available pharmaceutical approaches in pediatric relative to adult obesity/T2D is clinically worrisome and demands cautious and tempered extrapolation and application of adult findings to pediatric populations. Current knowledge indicates that metformin, while perhaps modestly beneficial in weight management, is not helpful in pediatric T2D prevention. Therapeutic advancements mandate better understanding of pediatric-specific obesity/T2D pathogenesis and the development of unique therapeutic approaches. True youth-onset T2D prevention, however, likely requires primary pediatric obesity prevention, a daunting but necessary public health task.

Glossary

Abbreviations

BMI

body mass index

DPP

Diabetes Prevention Program

IGT

impaired glucose tolerance

T2D

type 2 diabetes

Additional Information

Disclosures: P.W. and S.C. have nothing to declare.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.