· The study shows the effects and side effects of once-weekly dulaglutide treatment for type 2 diabetes mellitus (T2DM) in patients under 18 years of age in Korea.

· We identified 5 patients treated with dulaglutide and found that the treatment led to significant improvements in glycemic control with minimal side effects.

· The patients' hemoglobin A1c concentrations showed notable changes over the study period over 1 year but the body weight change was not significant.

· This suggests that once-weekly dulaglutide could be a promising therapeutic option for juvenile T2DM.

With the global epidemic of adult type 2 diabetes mellitus (T2DM), the number of children and adolescents with T2DM is also increasing dramatically [1,2]. Lifestyle change, measured as an increase in obesity rates due to excessive calorie intake and reduced physical activity, is the most important cause. In patients with juvenile diabetes, family history and genetic background are also important underlying factors. Diabetes is an important public health and social problem in the pediatric population, as, in this group, poor glycemic control is very common, and the occurrence rate of diabetic complications associated with longer lifetime disease exposure is very high [3]. Metformin and insulin are the traditional drugs approved for juvenile T2DM [4]. However, pharmacological therapies lead to suboptimal outcomes in many of these patients. Although insulin treatment is often required, in our daily practice, poor adherence to insulin has been observed commonly and has been associated with side effects, including hypoglycemia, weight gain, and the inconvenience of frequent injections [5]. Psychological problems, such as depression, anxiety, and low self-esteem, have also been observed frequently [6,7]. This group is usually under a high level of stress associated with academic and social achievements. Lifestyle modifications (i.e., diet and exercise therapy) are often not performed well [8]. Intervention studies using very-low-calorie diets are also limited in this age group. As a result, adolescent diabetic patients have often been neglected and exist in a treatment blindspot.

Recently, once-daily liraglutide and once-weekly exenatide injections were approved for adolescent T2DM patients [9,10]. When using the glucagon-like peptide (GLP)-1 agonist, the risk of hypoglycemia is very low, and it also has appetite-control, weight-loss, and glucose-control effects. Furthermore, the once-weekly dulaglutide injection, approved in 2014 and widely used for adult diabetes, showed good blood glucose-control efficacy, reduced cardiovascular events, and limited renal complications in adult T2DM patients [11,12]. The dulaglutide formulation is delivered via a once-weekly disposable pen, which does not require needle manipulation and is simple to use, facilitating better compliance than to insulin injections.

Recently, a clinical study on dulaglutide for juvenile T2DM was published [13]. In the study, at 26 weeks, the 0.75-mg and 1.5-mg administration groups showed average hemoglobin A1c (HbA1c)-lowering effects of 0.6% and 0.9%, respectively, and the rate of achieving an HbA1c concentration of <7% was 51%. The effectiveness was greater than that of the control group who received lifestyle modification alone or with metformin (14%). In addition, there were very few side effects. Notably, the study included a large number of Caucasians and Hispanics but very few Asians.

In this study, we aimed to describe, for the first time, the effects and side effects of dulaglutide in the 12- to 18-year-old juvenile T2DM age group.

In this retrospective analysis, we used data from the Eulji University Hospital database. We identified all T2DM patients <18 years of age treated with dulaglutide from January 1, 2017, to June 31, 2022. Clinical characteristics, such as the age at the diagnosis of T2DM, sex, body mass index (BMI), blood pressure, and family history of diabetes, were obtained by reviewing patient medical records. Laboratory data, including plasma glucose, HbA1c, and fasting C-peptide levels, were also obtained. The presence of islet auto-antibodies (auto-Abs) (antiglutamic acid decarboxylase antibody [anti-GAD Ab], Islet antigen 2 antibodies [IA-2 Abs], and insulin auto-Abs) was determined from the data in the medical records. Levels of GAD Ab were measured by radioimmunoassay (DiaSorin, Stillwater, MN, USA), those of insulin autoAb was measured by a different radioimmunoassay (BioSource, Nivelles, Belgium), and those of IA-2 Abs were measured by enzyme immunoassay assays using radiolabeled recombinant ICA512 as an antigen.

We identified 5 T2DM patients <18 years of age who were treated with 0.75 or 1.5 mg of dulaglutide administered once weekly. The clinical characteristics are shown in Table 1. The mean (SD) age of patients was 16.6 (0.5) years, 4 patients (80%) were female, and the mean (SD) BMI was 29.4 (5.1) kg/m². Additionally, the mean (SD) age at diagnosis was 15.2 (1.6) years. Four patients had been treated previously with metformin alone or in combination with insulin. Four patients were treated with 1.5 mg of dulaglutide and one was treated with 0.75 mg of dulaglutide. In addition, 1.5 mg of dulaglutide was used according to a dose-escalation schedule (i.e., for 2 weeks after treatment with 0.75 mg of dulaglutide). The previous metformin treatment was maintained. The mean (SD) HbA1c concentrations at baseline, 3 months after treatment, and 1 year after treatment, respectively, were 10.0% (2.2%), 6.5% (1.5%), and 6.7% (1.4%) (Fig. 1). These results were statistically different (P=0.019). Meanwhile, the mean (SD) body weight values at baseline, 3 months after treatment, and 1 year after treatment, respectively, were 79.7 (13.3) kg, 80.2 (14.0) kg, and 81.1 (15.3) kg (Fig. 1). These results were not statistically different (P=0.819).

In this study, we showed that the use of a once-weekly dulaglutide treatment in juvenile T2DM in Koreans <18 years of age provided very good glycemic control and efficacy in the majority of patients. In addition, it led to few side effects and good compliance, which suggests its potential as a promising therapeutic agent in this age group. In 4 of the 5 enrolled patients, near-remission of glycemic dysregulation was maintained for 1 year. The maximum dose of 1.5 mg was used as the initial hyperglycemia was severe in the 4 patients, who did not experience any unacceptable side effects. With the use of a dose-escalation schedule, 1.5 mg of dulaglutide led to few gastrointestinal side effects. In 2 of the patients, the possibility of replacing the previous insulin treatment arose, while in the other 2 patients, insulin treatment could be delayed. In 1 patient, however, the glucose-lowering efficacy of 0.5% was less than expected. This patient was obese and had a family history of T2DM. Despite her normal fasting C-peptide level, beta-cell failure may have been the cause of her high glucose levels and suboptimal treatment response.

Our patients were in early stages of diabetes and did not have microvascular complications. However, in 4 of the 5 patients, obesity-related complications, such as fatty liver disease and hypertension, were observed despite their young age. Four of the 5 patients in this study were obese T2DM patients, and a genetic predisposition to diabetes was identified in 3 of these patients. All 3 patients with available homeostatic model assessment for insulin resistance data showed increased insulin resistance.

An appetite-control effect and a decrease in food intake were reported by all patients, but there was a significant difference in weight change.

Weight gain was observed in 3 of the 5 treated patients who had very high blood glucose levels at baseline, and their weight gain may have occurred due to improvement in the catabolic status from initial hyperglycemia. In the other 2 patients, the weight reduction was substantial, ranging from 4–5 kg of loss during a period of 1 year. Overall, the weight effect was neutral before and after dulaglutide treatment. In previously published clinical studies of juvenile T2DM using GLP-1 agonists, the GLP-1 agonist group did not exhibit a significant BMI-reduction effect compared to the placebo group. In the placebo group, the weight may have decreased due to rapidly worsening hyperglycemia, and, in the GLP-1 agonist group, the blood glucose reductions and release from the catabolic state may have caused weight gain. In adult T2DM studies, the counteracting effects of initial severe hyperglycemia on weight-loss from dulaglutide treatment have been reported [14,15].

It is known that there are significant differences in the pathophysiology and natural course of T2DM between adolescents and adults. The rate of onset of the disease and the interaction between insulin resistance and impaired insulin secretory function may be different in early-onset T2DM [16,17]. Usually in adults, it takes several years for hyperglycemia to appear and progress; however, in children, the course progresses very rapidly. The TODAY (treatment options for type 2 diabetes in adolescents and youth) study showed that beta-cell function decreased by 20%–35% annually in pediatric T2DM, which was faster than the annual decline of 3%–5% recorded in adults [16,18]. Therefore, additional research is needed to determine whether the effectivity of dulaglutide seen in Korean juvenile diabetes occurs through an improvement in insulin resistance, an improvement in insulin secretory function, or both. GLP-1 agonist therapy acts on GLP-1 receptors in the pancreas, resulting in blood glucose–dependent insulin secretion and glucagon suppression. In addition, it acts on receptors in the central nervous system to suppress appetite and also acts in the intestine to slow gastric emptying and decrease postprandial blood glucose [19,20].

Previously, T2DM had only been reported in 1%–2% of children, with type 1 diabetes mellitus accounting for the vast majority (>97%) of cases in children. However, recent reports from some areas in the United States have suggested as many as 8%–45% of newly diagnosed diabetes cases in children are T2DM cases [21]. Recently, it has become increasingly difficult to distinguish between the 2 subtypes of diabetes—namely, type 1 diabetes mellitus and T2DM—and double or hybrid diabetes, in which the 2 subtypes of diabetes coexist in a single patient, has been proposed as a new disease category [22,23].

There are several limitations in this study. First, this study was a small retrospective study with short-term follow-up, and it is necessary to confirm the effect of dulaglutide on diabetic complications and additional side effects through long-term follow-up. Second, the test for the maturity-onset diabetes of youth (MODY) gene was not conducted in our patients; thus, MODY patients may have been included in this study. Third, it is difficult to analyze the exact mechanism of the glycemic effect of dulaglutide in these patients because the insulin secretion and resistance index were not regularly assessed during the treatment period.

In this study, there were a few patients in whom the switch from insulin to dulaglutide was successful. Since it is an important issue in children who use insulin, additional prospective clinical studies are required to confirm the results of this study. Moreover, it is also necessary to investigate whether the combination of insulin and dulaglutide therapy can be effective in hybrid types of pediatric diabetes, such as pediatric double diabetes.

In conclusion, once-weekly dulaglutide treatment was effective with few side effects in Korean juvenile T2DM. Nationwide studies are urgently needed to confirm the findings of this study.