Pharmacological management of type 2 diabetes mellitus in children and adolescents: A systematic review and network meta-analysis

Abstract

Background: The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents is increasing, yet there is limited information on the available pharmacological interventions to combat T2DM and prevent associated comorbidities.

Aim: To assess the effectiveness of current pharmacological treatments in managing T2DM in children and adolescents. The protocol of the study was registered in PROSPERO (CRD42022382165).

Methods: Searches were performed in PubMed, EMBASE, Scopus, and ClinicalTrials.gov for publications between 1990 to September 2024 without language restrictions. Randomized control trials (RCTs) of pharmacotherapy in children and adolescents with T2DM (aged < 19 years) were included. The primary outcome was a change in glycated hemoglobin (HbA1c) from baseline to follow-up. Secondary outcomes were changes in body weight, body mass index (BMI), total cholesterol, triglycerides, high density lipoprotein, and low-density lipoprotein from baseline, and incidence of adverse events during study periods. Screening, full-text review, data extraction, and assessments of risk of bias were done by two reviewers. Conflicts on each step were resolved by a third reviewer. Data analysis was performed using Review Manager Version 6.5 (RevMan 6.5) and 'R' software via RStudio, 'meta' and 'netmeta'.

Results: A total of 12 studies having low to moderate risk of bias with 1658 participants, and follow-up duration 12-52 weeks were included. In our network meta-analysis, compared to control(s), the reduction of HbA1c was significantly larger for dulaglutide [mean difference (MD), 95% confidence interval: -1.20, -2.12 to -0.28], followed by dapagliflozin (-0.94, -1.44 to -0.44), liraglutide (-0.91, -1.37 to -0.45), empagliflozin (-0.87, -1.40 to -0.34), exenatide (-0.59, -1.07 to -0.11) and linagliptin (-0.45, -0.87 to -0.02) while other drugs had little or no effect. While liraglutide was associated with a change in body weight [MD -2.41 (-4.68, -0.14) kg], no other drug treatment was associated with significant changes in body weight, BMI, and lipids. Apart from level 1 hypoglycemia with liraglutide [risk difference (RD): 0.20, 0.04-0.37] and minor adverse events with dulaglutide (RD: 0.24, 0.08-0.40), no other treatment was associated with excess risk of hypoglycemia or minor or major adverse events.

Conclusion: Pharmacotherapy of T2DM with dulaglutide, dapagliflozin, liraglutide, empagliflozin, exenatide, and linagliptin in children is associated with modest reduction of HbA1c. Larger RCTs with longer follow-up durations are needed to guide better therapeutic decision making.

Keywords: Adolescents; Children; Diabesity; Glycemic control; Obesity; Pharmacotherapy; Type 2 diabetes mellitus.

Figure 1

The study flow diagram and the selection process.

Figure 2

Network plots. A: Connections between each study agent included in the randomized controlled trials that assessed glycated hemoglobin; B: Network map for connections between each study agent included in the randomized controlled trials that assessed body weight changes; C: Network graph for level 1 hypoglycemia; D: Network map for minor adverse events; E: Network graph for serious adverse events. ¹One study only; ²two studies.

Figure 3

Network forest plots. A: The network meta-analysis assessing changes in glycated hemoglobin for the drugs vs placebo; B: Body weight changes; C: Risk of level 1 hypoglycemia; drug vs comparator. Apart from liraglutide, other pharmacological agents used for treatment are not associated with statistically significant effects on level 1 hypoglycemia; D: Minor adverse events; E: Serious adverse events. MD: Mean difference; RD: Risk difference.