The efficacy of alogliptin in adults has been assessed through a comprehensive clinical development program involving over 50 clinical studies with > 20,000 adult participants. Adults treated with alogliptin 12.5 or 25 mg QD for 26 weeks demonstrated significant reductions in HbA1c and FPG levels compared with those receiving placebo. Notably, the treatment effect was evident as early as the 4th week of treatment, with continued effects at weeks 26 and 52 [19,20,21,22,23].

However, in the present study, no significant difference in HbA1c change from baseline at weeks 12, 18, 26, 39, or 52 was observed among pediatric participants aged 10–17 years. Subgroup analyses based on prior antihyperglycemic treatment, age, sex, race, and BMI produced similar results (Fig. 3b).

Generally, clinical studies involving children/adolescents tend to be more challenging and have a higher rate of failure in establishing both efficacy and safety than studies involving adults [24]. Several common factors contribute to the challenges faced in pediatric trials, including dosing issues, placebo response, study design, and potential differences between the disease processes in pediatric and adult populations [24]. However, the lack of efficacy in this study did not appear to be influenced by dosing, drug exposure, placebo response, or the study design. The dosage of alogliptin used in this study was also used in a PK/PD study in pediatric patients aged 10–17 years that reported similar alogliptin exposure and DPP-4 inhibition levels between pediatric and adult patients with T2DM, and no notable placebo response was observed [17]. Moreover, the study design, which was double-blind and placebo-controlled, was the same as that used in successful adult phase 3 studies showing the positive efficacy of alogliptin [19,20,21,22,23]. After excluding the aforementioned potential factors, it became apparent that the failure of this study in the pediatric population may be attributed to rapid disease progression and the moderate potency of alogliptin as a DPP-4 inhibitor.

Although the pathophysiology of T2DM in pediatric patients was previously reported as comparable to that in adults [25], despite a lack of pediatric vs. adult studies, increasing evidence indicates that the decline in pancreatic beta-cell function may be faster in the pediatric population than in the adult population [9, 26,27,28]. For example, Weiss et al. observed impaired insulin release following glucose stimulation in youth with obesity with T2DM compared with peers with obesity without diabetes as an indicator of early stages of beta-cell function decline [28]. Moreover, several distinct features of T2DM have been observed in pediatric patients compared with adults.

Children with T2DM exhibit higher insulin resistance than adults, even when accounting for the same relative amount of adipose tissue [29,30,31]. The Restoring Insulin Secretion (RISE) studies were designed to directly compare the effects of medication on beta-cell function in pediatric and adult patients with T2DM, using identical hyperglycemic clamp protocols [29]. Youths were reported to have lower insulin sensitivity, hyperresponsive beta cells, reduced insulin clearance [30], and increased beta-cell function deterioration [31] compared with adults. Substantial evidence exists for a more aggressive disease process in youth-onset T2DM compared with adult-onset T2DM [9].

This rapid disease progression also suggests the need for more potent or high–glycemic-efficacy pharmacological therapies. DPP-4 inhibitors, while valuable additions to the treatment armamentarium for T2DM, are generally regarded as less potent than most GLP1-RAs and sodium-glucose cotransporter-2 (SGLT2) inhibitors in terms of their glucose-lowering effects [32]. GLP1-RAs and SGLT2 inhibitors also have a known benefit in significantly lowering body weight [33]. This becomes even more important because most patients in this trial were overweight.

Unlike evidence from trials in adults with T2DM where HbA1c-lowering benefits have been observed [34,35,36,37,38,39], the lack of treatment effect in pediatric patients with T2DM has also been observed in trials with three other DPP4 inhibitors: sitagliptin, linagliptin, and saxagliptin.

There have been three phase 3 studies involving sitagliptin in pediatric patients with T2DM. One study by Shanker et al. investigated the use of sitagliptin (100 mg QD) as an initial therapy for youth with T2DM in a 54-week, double-blind, randomized controlled clinical trial [40]. The study included 190 participants aged 10–17 years with HbA1c levels of 6.5–10% (7.0–10% if on insulin). All participants were overweight or obese at screening and tested negative for pancreatic autoantibody. The study used a placebo control for the first 20 weeks, after which metformin replaced the placebo. The primary efficacy endpoint was the change in HbA1c levels from baseline to week 20. However, the results showed that DPP-4 inhibition with sitagliptin did not significantly improve glycemic control [40].

Similarly, data were pooled from two other 54-week, double-blind, randomized, placebo-controlled studies involving sitagliptin (100 mg QD) or placebo, in addition to the existing treatment for young patients with T2DM aged 10–17 years who had inadequate glycemic control on metformin with or without insulin (ClinicalTrials.gov: NCT01472367 and NCT01760447). The 220 randomized and treated participants had HbA1c levels of 6.5–10.0% (7.0–10% if on insulin) at baseline and were overweight or obese at screening or diagnosis while testing negative for pancreatic autoantibodies. The primary endpoint was the change in HbA1c levels from baseline to week 20 [41]. Consistent with the findings of study by Shanker et al., in participants naïve to treatment, this pooled analysis also demonstrated that the addition of sitagliptin to metformin did not provide a lasting improvement in glycemic control in youth with T2DM [40].

A study comparing linagliptin, another DPP4 inhibitor, to empagliflozin, an SGLT-2 inhibitor, in youth aged 10–17 years with T2DM was recently published [42]. The DINAMO study compared the efficacy and safety of linagliptin (5 mg) with those of empagliflozin (10 mg) and placebo. This trial involved 158 pediatric patients with T2DM previously treated with metformin or insulin. The primary outcome was the change in HbA1c levels from baseline at 26 weeks. The study showed that the empagliflozin group had a significant reduction of 0.84% in HbA1c at week 26 compared with the placebo group (95% CI − 1.5, − 0.2; p = 0.01); however, linagliptin did not show the same HbA1c benefit [42]. Empagliflozin has subsequently been approved as an adjunct treatment to diet and exercise to improve glycemic control in adults and pediatric patients aged ≥ 10 years with T2DM, whereas linagliptin was another DPP-4 inhibitor that failed to demonstrate efficacy in pediatric trials [43].

Saxagliptin, another DPP-4 inhibitor, also failed to demonstrate efficacy in children and adolescents [44]. In this 26-week, randomized, phase 3 trial in patients aged 10–17 years, with uncontrolled T2DM (HbA1c levels 6.5–10.5%) treated with metformin, insulin, or both, patients received saxagliptin, dapagliflozin, or placebo. At week 26, the difference in the adjusted mean change in HbA1c levels versus placebo was significant for dapagliflozin (− 1.03 percentage points [95% CI − 1.57, − 0.49, p < 0.001]) and non-significant for saxagliptin (− 0.44 percentage points [95% CI − 0.93, 0.05, p = 0.078]) [44].

In contrast to the DPP4 inhibitors, injectable incretin-based treatments with the GLP1-RAs liraglutide, exenatide, and dulaglutide have been reported to improve glycemic control after 24, 26, and 52 weeks of treatment in youth with T2DM [45,46,47], with all three currently approved for use in this population [13,14,15]. It has been well established that GLP1-RAs are more efficacious than DPP-4 inhibitors in adults with T2DM [48]; therefore, it could be postulated that the stronger potency of GLP1-RAs was sufficient to overcome the severe insulin resistance in pediatric T2DM, whereas the potency of DPP-4 inhibitors was not.

Another issue worth mentioning is related to managing the influence of background therapy with metformin and/or insulin from confounding the outcomes of placebo-controlled studies. We introduced a prerandomization stabilization period for this trial to overcome this. This step was important to ensure patient eligibility and stabilize the background therapy before randomization. Despite the infrequent use of these run-in periods, we recommend their inclusion in additional clinical trials in the future to minimize the risk of confounding.

This study has several limitations that also need consideration. Although the study was statistically powered, the subgroups based on previous antihyperglycemic therapy were underpowered, making it challenging to draw meaningful comparisons between the different groups. Another important factor to consider is that the participants were recruited from six different countries, representing a global population. This variability in geographic location may have introduced unaccounted differences in access to healthcare and other resources relevant to diabetes management, which could have influenced the study results; conversely, it also provides a good representation from a global perspective. Furthermore, the frequency, consistency, and content of the diabetes education and home glucose-monitoring training sessions may have varied according to local guidelines, resources, and training available at each study site. Additionally, the exact duration or continuity of training sessions for each participant was not tracked, which may have impacted the depth of education and support they received over the course of the study. Lastly, it was not feasible to determine whether other medication use, specifically insulin use, increased or decreased during the trial or if there were any differences in insulin dosage between the alogliptin and placebo groups. Given the complexities of insulin dosing in this cohort, some of whom were treatment-naïve and some on basal plus/minus multiple daily dosing, and variable duration of insulin use and timing of hyperglycemic rescue, it was challenging to conduct a meaningful analysis on the change in insulin dosing throughout the trial. However, the study design included two features that we believe balanced background therapies between the two treatment groups. First, randomization was performed in a blinded manner; second, the study protocol required participants to maintain their background antihyperglycemic therapy (if applicable) at the same dose (e.g., baseline insulin dose) as at the time of randomization throughout the first 26 weeks of the double-blind treatment period. Thus, no dosage difference before and after the start of the trial would be expected for individual participants.

Overall, this study contributes to the body of scientific literature on the efficacy and safety of DPP-4 inhibitors in pediatric patients with T2DM, and the findings are consistent with those of other studies exploring the use of DPP-4 inhibitors (i.e., sitagliptin, linagliptin, and saxagliptin) in the pediatric population [40,41,42, 44].