New Agents for Youth-Onset Type 2 Diabetes 'Finally in Sight'

Dr Kenneth C. Copeland

There are limited treatment options for children and youth with type 2 diabetes, but a few novel therapies beyond metformin are on the horizon, experts told the virtual American Diabetes Association (ADA) 81st Scientific Sessions.

"Type 2 diabetes in youth only emerged as a well-recognized pediatric medical problem in the 1990s and the first decade of the 21st century," session chair Kenneth C. Copeland, MD, told Medscape Medical News.

"Fortunately, a number of clinical trials of antidiabetic pharmacologic agents in diabetic youth have now been completed, demonstrating both safety and efficacy, and at long last, a...variety of agents are finally in sight," he noted.

Type 2 diabetes in youth is profoundly different from type 2 diabetes in adults, added Copeland, pediatrics professor emeritus, University of Oklahoma, Oklahoma City. In youth, its course is typically aggressive and refractive to treatment.

Concerted efforts at lifestyle intervention are important but insufficient, and a response to metformin, even when initiated at diagnosis, is often short-lived, he added.

Because of the rapid glycemic deterioration that is typical of type 2 diabetes in youth and leads to the full array of diabetic complications, early aggressive pharmacologic treatment is indicated.

"We all look forward to this next decade ushering in new treatment options, spanning the spectrum from obesity prevention to complex pharmacologic intervention," Copeland summarized.

Increasing Prevalence of T2D in Youth, Limited Therapies

Rates of type 2 diabetes in youth continue to increase, especially among non-White groups, and most of these individuals have less than optimal diabetes control, Elvira Isganaitis, MD, MPH, a pediatric endocrinologist at the Joslin Diabetes Center and assistant professor of pediatrics at Harvard Medical School, Boston, Massachusetts, told the meeting.

Although the US Food and Drug Administration (FDA) has approved more than 25 drugs to treat type 2 diabetes in adults, "unfortunately," metformin is the only oral medication approved to treat the disease in a pediatric population, "and a majority of youth either do not respond to it or do not tolerate it," she told Medscape Medical News.

Copeland observed that "the TODAY study demonstrated conclusively that, despite an often dramatic initial improvement in glycemic control upon initiation of pharmacologic and lifestyle intervention, this initial response was followed by a rapid deterioration of beta-cell function and glycemic failure, indicating that additional pharmacologic agents were sorely needed for this population."

The RISE study also showed that, compared with adults, youth had more rapid beta-cell deterioration despite treatment.

Until the June 2019 FDA approval of the injectable glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk) for children 10 years or older, "except for insulin, metformin was the only antidiabetic medication available for use in youth, severely limiting treatment options," he added.

Liraglutide "a Huge Breakthrough," Other Options on the Horizon

Dr Elvira Isganaitis

The FDA approval of liraglutide was "a huge breakthrough" as the first noninsulin drug for pediatric type 2 diabetes since metformin was approved for pediatric use in 2000, Isganaitis said.

The ELLIPSE study, on which the approval was based, showed liraglutide was effective at lowering A1c and was generally well tolerated, although it was associated with a higher incidence of gastrointestinal symptoms (N Engl J Med. 2019;381:637-646).

In December 2020, the FDA also approved liraglutide (Saxenda) for the treatment of obesity in youth age 12 and older (at a dose of 3 mg as opposed to the 1.8-mg dose of liraglutide [Victoza]), "which is wonderful news considering that the majority of pediatric patients with type 2 diabetes also have obesity," Isganaitis added.

"The results of studies of liraglutide on glycemia in diabetic youth are impressive, with both an additional benefit of weight loss and without unacceptable identified risks or side effects," Copeland concurred.

Waiting in the Wings

Isganaitis reported that a few phase 3 clinical trials of other therapies for pediatric patients with type 2 diabetes are in the wings.

The 24-week phase 3 T2GO clinical trial of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (AstraZeneca) versus placebo in 72 patients with type 2 diabetes aged 10 to 24 was completed in April 2020, and the data are being analyzed.

An AstraZeneca-sponsored a phase 3 trial of the safety and efficacy of a weekly injection of the GLP-1 receptor agonist exenatide in 10- to 17-year-olds with type 2 diabetes (N = 82) has also been completed and data are being analyzed.

A Takeda-sponsored phase 3 pediatric study of the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in 10- to 17-year-olds with type 2 diabetes (N = 150) is estimated to be completed by February 2022.

And the phase 3 DINAMO trial, sponsored by Boehringer Ingelheim, which is evaluating the efficacy and safety of the SGLT2 inhibitor empagliflozin (10 mg/25 mg) versus the DPP-4 inhibitor linagliptin (5 mg) versus placebo over 26 weeks in 10- to 17-year-olds with type 2 diabetes (estimated 186 participants), is expected to be completed in May 2023.

"I hope that these medications will demonstrate efficacy and allow pediatric patients with type 2 diabetes to have more treatment options," Isganaitis concluded.

Type 2 Diabetes More Aggressive Than Type 1 Diabetes in Kids

According to Isganaitis, "there is a widely held misconception among the general public and even among some physicians that type 2 diabetes is somehow less worrisome or 'milder' than a diagnosis of type 1 diabetes."

However, the risk of complications and severe morbidity is higher with a diagnosis of type 2 diabetes versus type 1 diabetes in a child, so "this condition needs to be managed intensively with a multidisciplinary team including pediatric endocrinology, nutrition [support], diabetes educators, and mental health support," she emphasized.

Many people also believe that "type 2 diabetes in kids is a 'lifestyle disease,'" she continued, "but in fact, there is a strong role for genetics."

The ADA Presidents' Select Abstract "paints a picture of youth-onset type 2 diabetes as a disease intermediate in extremity between monogenic diabetes [caused by mutations in a single gene] and type 2 diabetes [caused by multiple genes and lifestyle factors such as obesity], in which genetic variants in both insulin secretion and insulin response pathways are implicated."

Along the same lines, Isganaitis presented an oral abstract at the meeting that showed that among youth with newly diagnosed type 2 diabetes, those whose mothers had diabetes had faster disease progression and earlier onset of diabetes complications.

Isganaitis has reported no relevant financial relationships. Copeland has reported serving on data monitoring committees for Boehringer Ingelheim and Novo Nordisk, and on an advisory committee for a research study for Daiichi Sankyo.

ADA 2021 Scientific Sessions. Presented on June 27, 2021.

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