Reevaluating First-line Therapies in Youth-Onset Type 2 Diabetes

Abstract

The prevalence of youth-onset type 2 diabetes is growing worldwide and current first-line treatment with metformin and intensive behavior and lifestyle changes are suboptimal in over 50% of youth within 2 years of diagnosis. This perspective article is a call to action for reevaluation of existing strategies and critical appraisal of metformin as first-line therapy in youth-onset type 2 diabetes. Increased attention should be given to novel therapeutics approved in youth, including glucagon-like 1 receptor agonists, sodium glucose cotransporter-2, and sociocultural interventions that will promote diabetes self-management.

Worldwide, rates of youth-onset type 2 diabetes (Y-T2DM) have increased in tandem with the childhood obesity epidemic and are expected to continue unabated for at least the next 30 years. Two recently published articles highlight the high prevalence of diabetic retinopathy in Y-T2DM; 1 in 2 Y-T2DM have documented retinal changes within a decade after diagnosis (1, 2). These studies add to the growing body of literature highlighting the burden of cardiometabolic complications that disproportionally affects Y-T2DM from socioeconomically disadvantaged and minoritized groups (3). Over 50% of Y-T2DM have hypertension, nephropathy, and/or neuropathy within 10 years of diagnosis. As the chronic disease burden of type 2 diabetes extends beyond childhood, those with Y-T2DM are saddled with rising health care costs in their peak productivity years and increased risk of death by their fourth decade of life (4). These contemporary trends in diabetes-related complications coupled with the recent introduction of novel therapies for managing T2DM in youth are a call to action to reevaluate current treatment regimens. This perspective offers a critical examination of contemporary therapeutic targets in Y-T2DM and 2 novel agents, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose transporter 2 (SGLT-2) inhibitors, that were recently approved in youth.

Over the last 3 decades, the lack of effective and targeted therapeutics was a major barrier to mitigating the Y-T2DM public health burden. International guidelines, established since the early 2000s, recommend the combination of intensive health behavioral and lifestyle (IHBL) changes and metformin as first-line of treatment of Y-T2DM (5). Yet, both randomized controlled clinical trials and real-world experiential data confirm that the outcomes of this first-line approach are suboptimal (4). While IHBL interventions are the cornerstone of Y-T2DM management, IHBL alone or in combination with metformin are suboptimal in over 50% of youth within 2 years of diagnosis. Furthermore, long-term efficacy of behavioral interventions varies by race/ethnicity and by income group. In the United States, non-Hispanic Black youth have the highest rates of Y-T2DM and >60% dropout rates in IHBL interventions compared with ∼25% in White adolescents (6).

The poor long-term durability of metformin in Y-T2DM was surprising. Metformin is the oldest, safest, and most commonly prescribed antidiabetic agent worldwide. With over a half a century of experience on its safety and efficacy in youth and adults, metformin is arguably one of the most influential glucose-lowering agents in diabetes history. Yet, there is still no consensus on its molecular targets and its main mechanism of action remains debatable. In adults, metformin increases insulin sensitivity and delays β-cell decline. Differences in metformin response between youth- and adult-onset T2DM may be because Y-T2DM have more severe disease and increased rates of hepatic insulin resistance early in their disease course (7). Importantly, metformin treatment failure in Y-T2DM was not related to access, stressors scores, depression, or poor medication adherence.

Still, the reduced efficacy in Y-T2DM was unexpected since conventional dogma dictates that metformin's primary mechanism of action is to reduce rates of gluconeogenesis and increase hepatic insulin sensitivity. In contrast, contemporary studies suggest that metformin has pleiotropic effects with only weak action on in vivo gluconeogenic pathways at pharmacological doses in humans. In metabolic clinical trials, we and others have shown that metformin alone or in combination with insulin was insufficient to mitigate the high rates of gluconeogenesis or accelerated β-cell dysfunction in youth with prediabetes or early Y-T2DM (8). We posit that variability in metformin response in Y-T2DM is related to metformin's modest ability to lower gluconeogenesis (a prominent and early feature of Y-T2DM) and its pleiotropic effects. While cellular models of metformin action suggest metformin may inhibit gluconeogenesis as an indirect consequence of reducing hepatic fat and energy stores, human clinical trials failed to show an effect of metformin on reducing visceral hepatic fat or rates of whole-body lipolysis in Y-T2DM. In addition, the effect size for metformin's extrahepatic modulation on the enteric–insular axis via the gut microbiome was modest and insufficient to slow the progressive nature of Y-T2DM. Therefore, metformin and IHBL therapy alone is inadequate to halt the rapid disease progression in Y-T2DM, but the combination of metformin with newer antidiabetic agents may be advantageous.

We propose a paradigm shift to combination first-line pharmacotherapy for Y-T2DM. GLP-1 RAs are attractive candidates because of their potency, track record of safety, and pathophysiologic targets. Early targeted treatment with combination metformin and GLP-1 RAs could be beneficial in youth who are early in their disease course (<5 years) when there would be maximal potential for improving beta cell dysfunction. Combination therapy would target rapidly declining β-cell function, weight gain, and insulin resistance in Y-T2DM. In 2019, liraglutide became the first GLP-1 RA to be approved by the FDA to treat Y-T2DM. Approvals for exenatide XR and dulaglutide swiftly followed and practitioners can now choose among 3 long-acting agents in the GLP-1 RA class for escalating diabetes care in Y-T2DM. The introduction of weekly long-acting GLP-1 RAs was monumental because it allowed consideration of a class of agents that addresses glycemic control (up to 1% reductions in hemoglobin A1c) and weight gain with the potential to augment medication adherence and quality of life in youth.

Still, whether the combination of metformin and a GLP-1 RA will attenuate high rates of gluconeogenesis in Y-T2DM is less well-defined. Among healthy adult volunteers, liraglutide increased insulin:glucagon ratio and suppressed gluconeogenesis. But we and others have shown that short-term liraglutide did not suppress rates of gluconeogenesis in youth or adults with type 2 diabetes. It is interesting to speculate that longer acting GLP-RAs and/or chronic therapy may reduce hepatic glucose production via modulation of complex neurohormonal mechanisms, but the long-term effects of GLP- RA in Y-T2DM remain an area of active investigation.

SGLT-2 inhibitors are also promising candidates for combination therapy with metformin in Y-T2D. In June 2023, empagliflozin became the first in class and only the second oral agent to be FDA approved as an adjunct to IHBL for treatment of Y-T2DM. Empagliflozin is now indicated alone or in combination with metformin for the treatment of Y-T2DM who are 10 years of age and older. This class of medications offers much needed oral options for treatment in Y-T2DM, though there are modest reductions in hemoglobin A1c (∼0.5-0.8%) and minimal weight loss. SGLT-2 inhibitors are a convenient and effective addition to the diabetes Y-T2DM tool box, but its mechanism of action does not target the major pathophysiological defects in Y-T2DM. SGLT-2 inhibitors promote urinary glucose excretion with compensatory increases in rates of gluconeogenesis and ketosis. Over the short-term, there is efficient regulation of gluconeogenesis to maintain euglycemia. However, the long-term impact of chronic increases in gluconeogenesis, especially among Y-T2DM who have pathological defects in regulating gluconeogenesis, is unknown and needs further investigation.

Importantly, the long-term durability and safety profile of both GLP-1 RAs and SGLT-2 inhibitors in Y-T2DM is unknown. GLP-1 RAs have a robust safety record in adults, but approximately 1 in 4 youth experience mild adverse effects, predominantly gastrointestinal symptoms. The existing black box warning for thyroid C-cell tumor risk also deserves critical assessment as there is conflicting evidence on whether a GLP-1 RA modestly increases the risk for this rare cancer. SGLT-2 inhibitors also have a strong safety profile in adults, but these agents increase risk for euglycemic ketoacidosis and genitourinary infections. It is also unclear whether this class of agents will confer similar renal and cardiac benefits as observed in adults. Adverse event-reporting for these 2 medication classes in youth is minimal with less than 5 years of reporting in the real-world setting. To support use of these novel agents in Y-T2DM, implementation of national registries to document treatment outcomes and medication adverse events is essential.

Nevertheless, the availability of these 2 classes of antidiabetic drugs encourages a tailored approach, such that health care providers may implement early and aggressive normalization of weight and glycemia, using a variety of antidiabetic agents, in Y-T2DM. FDA drug approval is only the first step to mitigating the disease burden in this vulnerable group of youth. A major treatment gap remains. For instance, insurance approvals of GLP-1 RAs in the United States are often conditional upon failing metformin therapy or meeting a relatively arbitrary hemoglobin A1c threshold. Yet, there is increasing recognition that diabetes care for Y-T2DM should target weight loss and metabolic risk reduction rather than a singular focus on glycemic control. Mechanistic trials, like the RISE study, highlighted the failure of glycemic-only strategies in slowing Y-T2DM progression.

Access to high-quality care and IHBL interventions and resources are critical for supporting these proposed first-line management strategies in Y-T2DM. Policy changes that acknowledge and address structural factors and the obesogenic environment will be imperative for preventing and treating Y-T2DM. This call to action encourages diabetes leaders to advocate within their communities for improved medication access and insurance coverage. Maximum community impact will also depend on prioritizing early therapeutic approaches with sociocultural interventions to reduce common challenges afflicting Y-T2DM, such as reduced medication adherence, adverse medication side-effect profiles, chronic disease management, and access.

Abbreviations

FDA

Food and Drug Administration

GLP-1 RA

glucagon-like peptide-1 receptor agonist

IHBL

intensive health behavioral and lifestyle

SGLT-2

sodium glucose transporter 2

Y-T2DM

youth-onset type 2 diabetes

Funding

S.T.C. and L.M. are supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Disclosures

The authors have no conflicts of interest to disclose.

Data Availability

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