Another glucagon-like peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth ages 10 to 18 with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.
The US Food and Drug Administration (FDA) has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.
AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower A1c at 26 weeks than patients who received placebo.
Eli Lilly is now submitting these trial results to the FDA for this indication.
Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.
The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index (BMI).
The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the American Diabetes Association (ADA) 82nd Scientific Sessions in New Orleans.
Might Dulaglutide Target Pathophysiologic Impairments in Youth?
Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told Medscape Medical News.
Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh, Pennsylvania.
“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.
Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults — which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”
Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
“With supply chain shortages and health insurance coverage issues that are common in the US, it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston, Massachusetts.
Phase 3 trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Arslanian noted, “but as always, recruitment is slow with adolescents.”
“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.
Potentially Promising Therapy
In their article published in the New England Journal of Medicine, Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”
The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.
“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”
Phase 3 Superiority Trial
The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension.
Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m2.
In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.
At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by –0.6% in the 0.75-mg dulaglutide group and by –0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).
Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c < 7.0% (51% vs 14%; P < .001).
Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (−18.9 mg/dL; P < .001).
There were no group differences in BMI or adiposity-related parameters even at 52 weeks.
“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Arslanian speculated.
“Only future studies will be able to address this issue,” she concluded.
The study was funded by Eli Lilly. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.
ADA 2022 Scientific Sessions. Abstract 5-LB. Presented June 4, 2022.
N Engl J Med. Published June 4, 2022. Full Text