Dulaglutide: A new horizon for T2D treatment in kids
A once-weekly subcutaneous dose of the GLP-1* receptor agonist dulaglutide successfully controlled glycaemic levels in youths with type 2 diabetes (T2D) being treated with lifestyle modification with or without metformin or insulin, results of the multinational, phase III AWARD-PEDS** study showed.
“These findings are a potential breakthrough in the paediatric diabetes space and can help address the unmet need for additional treatments available to young people with diabetes, particularly pharmacotherapeutic options,” said Professor Silva Arslanian, director at the Center for Pediatric Research in Obesity and Metabolism, University of Pittsburgh, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, US, who presented the results at ADA 2022.
Participants were 154 individuals aged 10 to <18 years (mean age 14.5 years, 71 percent female) with BMI >85th percentile*** (mean 34.1 kg/m2) and T2D (HbA1C >6.5 to ≤9 or ≤11 percent#; mean 8.1 percent) treated with lifestyle modification with/without metformin or basal insulin. They were randomized, double-blind, 1:1:1 to receive subcutaneous dulaglutide (1.5 mg or 0.75 mg) or placebo once weekly for 26 weeks. Patients in the placebo group then received dulaglutide 0.75 mg/week in a 26-week open-label extension study, while those initially randomized to dulaglutide continued their assigned trial medications (n=139). Self-monitoring of blood glucose levels was done at fasting state and again at another time point and when experiencing hypoglycaemia symptoms.
At 26 weeks, dulaglutide was superior to placebo, with a significant reduction in mean HbA1c levels from baseline in the pooled dulaglutide group compared with an increase in the placebo group (least squares [LS] mean change -0.8 vs 0.6 percentage points; p<0.001). [ADA 2022, abstract 5-LB; N Engl J Med 2022;doi:10.1056/NEJMoa2204601]
The HbA1c benefits with dulaglutide were consistent across multiple subgroups including age, sex, race, ethnicity, diabetes duration or medication use, baseline HbA1c, BMI, and body weight.
While the glycaemic control benefits with dulaglutide were observed through 52 weeks, the authors noted an increase in HbA1c during the open-label phase which they suggested could be attributed to “rapid underlying disease progression” in this age group.
More patients on dulaglutide than placebo achieved HbA1c <7 percent at 26 weeks (51 percent vs 14 percent; p<0.001). Fasting plasma glucose levels increased from baseline in the placebo group (LS mean change 17.1 mg/dL) and decreased in the dulaglutide groups (LS mean change -18.9 mg/dL; p<0.001).
The change in BMI from baseline was comparable between the dulaglutide and placebo groups (LS mean change -0.1 vs 0 kg/m2; p=0.55). There were no significant differences in the change from baseline in body weight or waist circumference within each group.
This contrasts with the weight loss effects of dulaglutide at these same doses in adults with T2D, the reason for which remains uncertain, the authors said.
At week 26, mean total and low-density lipoprotein cholesterol and serum triglyceride concentrations increased in the placebo group and decreased in the dulaglutide groups. However, changes in blood pressure and heart rate from baseline did not differ between the dulaglutide and placebo groups.
No additional safety concerns
Adverse events (AEs) at 26 weeks occurred in 69, 75, and 73 percent of placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg recipients, respectively, and serious AEs in 6, 2, and 2 percent, respectively. One patient each in the placebo and dulaglutide 0.75 mg group and two in the dulaglutide 1.5 mg group experienced an AE leading to treatment discontinuation.
Gastrointestinal (GI) events were among the most common AEs in the first 26 weeks, affecting more dulaglutide than placebo recipients, though 80, 69, and 89 percent of nausea, vomiting, and diarrhoea cases in the dulaglutide groups were mild. Most cases also occurred in the first 2 weeks of dulaglutide treatment. There was one GI event-related discontinuation in the dulaglutide 1.5 mg group. Allergy or hypersensitivity incidence was similar across groups (n=2, 3, and 2 in the placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg groups, respectively), as were injection-site reactions (n=5, 5, and 4, respectively).
Hypoglycaemia incidence was also comparable across groups, with no severe hypoglycaemia events. More placebo than dulaglutide recipients received rescue medication for persistent hyperglycaemia in the first 26 weeks (18, 4, and 2 percent in the placebo, dulaglutide 0.75 mg, and dulaglutide 1.5 mg groups, respectively). There were no pancreatitis or thyroid neoplasms.
“Overall, most AEs were reported during the first 26 weeks, with a similar AE profile through 52 weeks,” the authors noted. The safety profile in this population was consistent with that in adults and there were no deaths during the trial.
A step forward for long-term treatment
While adults with T2D have a wide range of therapeutic options, the choices are limited for youths. Moreover, younger patients with T2D have greater severity of insulin resistance and β-cell dysfunction and high therapeutic failure rates with metformin, the authors pointed out.
“We are encouraged by the strong HbA1c improvements achieved and are hopeful that a [once/weekly] medication could be a step forward for how young people are treated,” stated Arslanian.
If approved for use in youths, in addition to the benefits on glycaemic control, dulaglutide also offers a convenient mode and frequency of administration which is particularly important for long-term treatment of T2D in this population, said the authors.