Effectiveness of metformin for weight control in pediatric patients on SGA

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PROJECT SUMMARY: Antipsychotic-induced Weight Gain (AIWG) affects up to 80% of children taking atypical/second generation antipsychotic (SGA) drugs. Changes in the physical appearance can lead to poor medication adherence. Childhood onset obesity carries a greater risk for type 2 diabetes and cardiovascular diseases than its onset in adults. Metformin is the most extensively studied adjuvant intervention for the management of AIWG in adults. In children and adolescents, the data are consistent but much more limited. The beneficial effect of adjuvant metformin established in trials has yet to be examined in real world SGA recipients. Our prior work found that most of the AIWG in children and adolescents happened during the first three months of SGA treatment, and SGA discontinuation only reversed a quarter of the weight patient gained during the treatment within one year of SGA cessation. The timeline for AIWG and its limited reversibility highlights the importance of AIWG prevention and early intervention, however, the optimal timing for adjuvant metformin initiation has not been investigated in the pediatric population. It is known that children and adolescents follow distinctively different weight development trajectories. Our preliminary findings suggest similar variations may also exist in pediatric AIWG. It remains unknown whether individuals following the different trajectories also respond differently to adjuvant metformin. The GOAL of the proposed study is to comprehensively examine the effectiveness of adjuvant metformin in a real world sample. To achieve the goal, we will identify children and adolescents aged 6 to 19 years who were treatment naive and received adjuvant metformin during the first 24 months of SGA treatment using a large national electronic medical record (EMR) database. The adjuvant metformin recipients are further categorized as early, intermediate and late initiators based on the period between SGA commencement and metformin initiation. The proposed study has two specific aims: Aim I: To compare the effectiveness of 1) adjuvant metformin on AIWG between propensity score weights matched 1) users and non- users, and among matched 2) early, intermediate, and late initiators using weighted linear mixed model with repeated measures. Aim II: To identify patient subgroups following certain weight development trajectories who are most likely to benefit from 1) the use adjuvant metformin, and from 2) the early initiation of metformin using group-based trajectory modeling integrated with propensity score. We hypothesize that H1: There is less increase in age-sex-specific weight z score when comparing 1) adjuvant metformin users vs. non-users, and when comparing 2) early and intermediate initiators vs. late initiators during a 12-month period since metformin initiation. H2: The magnitude of adjuvant metformin effect on AIWG, and the dependency of its effect upon the stage of SGA treatment at metformin initiation differ in patients following various weight trajectories. The proposed project will test new hypotheses using novel analytical approaches. The findings will provide new evidence to support the management of pediatric AIWG, and improve patient safety.