Effectiveness of Metformin in Preventing Type 2 Diabetes in Children and Adolescents with Overweight or Obesity: A Protocol for a Systematic Review and Meta-Analysis

Abstract

Type 2 diabetes is increasingly prevalent among children and adolescents with overweight or obesity, and although lifestyle interventions remain first-line preventive strategies, long-term adherence and effectiveness are often limited. Metformin has demonstrated efficacy in delaying type 2 diabetes onset in adults at high risk, but its preventive role in pediatric populations remains unclear. This systematic review and meta-analysis aims to evaluate the effectiveness of metformin, alone or in combination with lifestyle interventions, in preventing or delaying type 2 diabetes among children and adolescents with overweight or obesity. The protocol is registered in PROSPERO (CRD42024615622), MEDLINE (PubMed), Embase, Cochrane Library, Scopus, and Web of Science and will be searched from inception to June 2025. Eligible studies include randomized controlled trials, quasi-experimental studies, and prospective cohort studies involving individuals under 18 years of age. The primary outcome is incidence of type 2 diabetes, with secondary outcomes including fasting plasma glucose, HbA1c, insulin resistance, BMI z-score, adherence, and adverse events. Where appropriate, random-effects meta-analyses will be conducted. This review will synthesize current evidence on metformin for pediatric type 2 diabetes prevention and inform future preventive strategies and clinical decision-making.

1. Introduction

Childhood obesity has reached epidemic levels worldwide, contributing to an alarming rise in type 2 diabetes diagnosis among adolescents [1]. The interplay of insulin resistance, increased adiposity, and reduced physical activity contributes to metabolic dysfunction and accelerates the onset of type 2 diabetes [2]. Preventive strategies in children and adolescents have traditionally centered on lifestyle modification (dietary change, physical activity, and weight management), but long-term adherence and durability are challenging in real-world settings. Pharmacologic adjuncts that improve insulin sensitivity like metformin are therefore of interest for high-risk pediatric populations [3].

In adults with impaired glucose tolerance, metformin reduces diabetes incidence by approximately 30% [4]. However, youth are not “small adults”: pathophysiology, glycemic trajectories, and treatment responses differ. Also, pediatric data on β-cell preservation and prevention are sparse [5]. Safety and dosing data from adolescent populations, most robustly in type 1 diabetes (T1D) as adjunct to insulin, suggest that metformin is generally well tolerated and can improve weight and lipid profile [6]. While these studies address a different disease context (T1D), they inform safety and metabolic effects relevant to pediatric use. In addition, safety profile in adolescents is also well-established for polycystic ovary syndrome (PCOS) and insulin resistance, yet evidence for its efficacy in delaying or preventing type 2 diabetes remains inconclusive [7,8,9].

Overall, despite biological plausibility and supportive adult data, large pediatric prevention trials focused on incident type 2 diabetes are lacking. Recent narrative and systematic reviews have highlighted the frequent use of metformin in pediatric obesity and insulin resistance management, despite the limited availability of long-term data on diabetes prevention outcomes [10]. Individual studies in youth populations have reported variable findings; some demonstrating improvements in fasting glucose and insulin sensitivity [6,11], others showing no long-term benefit once medication ceases [9]. Given the growing off-label use of metformin for metabolic risk reduction, a comprehensive synthesis of evidence is needed.

This systematic review will synthesize the available pediatric evidence on metformin, with or without lifestyle interventions, for the prevention or delay of type 2 diabetes in children and adolescents with overweight or obesity. We will also examine changes in glycemic control, insulin resistance, anthropometrics, and adherence using standardized diagnostic criteria and time-anchored outcome windows. By clarifying the current evidence and its limitations, this review aims to inform clinical practice and the design of future pediatric prevention trials.

2. Materials and Methods

2.1. Review Design

This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P 2015) guidelines [12] and it is registered in the PROSPERO International Prospective Register of Systematic Reviews (registration ID: CRD42024615622).

2.2. Search Strategy

We will search the following databases for literature published from inception: PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library. Search terms will include combinations of “metformin,” “type 2 diabetes,” “T2D,” “prediabetes,” “insulin resistance,” “overweight,” “obesity,” “children,” and “adolescents,” using both MeSH terms and free-text keywords, adapted for each database. The complete strategy is available in PROSPERO and will also be provided in Supplementary File S1. Grey literature (conference abstracts, preprints) will be excluded unless they provide sufficient methodological detail and outcome data. Only English-language publications or studies with an English abstract that can be reliably translated will be included. There will be no restrictions on publication date or setting. Additionally, we will manually screen the reference lists of included studies and relevant reviews.

2.3. Eligibility Criteria

Studies will be selected according to predefined inclusion and exclusion criteria based on the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework.

Population: we will include studies enrolling children and adolescents younger than 18 years diagnosed with overweight or obesity according to criteria defined by the study authors or established BMI percentile cut-offs (≥85th or ≥95th percentile).

Intervention: eligible interventions will include metformin monotherapy or metformin combined with lifestyle interventions such as structured dietary, behavioral, or exercise programs with a minimum duration of 12 weeks. Studies that included another pharmacological intervention will also be included and analyzed as a subgroup.

Comparators: comparators will consist of placebo, lifestyle modification alone, or no intervention.

Outcomes: the primary outcome will be the incidence of type 2 diabetes, either as reported by study authors or defined using the International Society of Pediatric and Adolescents Diabetes (ISPAD) [13] or American Diabetes Association (ADA) [14] diagnostic criteria. Secondary outcomes will include changes from baseline in glycemic parameters (HbA1c, fasting plasma glucose, 2 h oral glucose tolerance test), insulin resistance indices (homeostasis model assessment of insulin resistance (HOMA-IR) or equivalent), body mass index (BMI) or BMI z-score, treatment adherence (pill counts, self-report, Morisky scale [15] and adverse events.

2.4. Study Design

Eligible study design will comprise RCT (parallel or cluster), quasi-experimental studies, and prospective cohort studies evaluating metformin for prevention of type 2 diabetes. We will exclude retrospective or cross-sectional studies, case reports or case series, narrative or systematic reviews, and animal or mechanistic studies. Retrospective and cross-sectional designs are excluded because they do not allow assessment of temporal relationships between exposure and outcome, which is essential for evaluating preventive effects.

2.5. Study Selection

All search results will be imported into Rayyan.ai [16] for deduplication and screening. Two reviewers will independently assess titles and abstracts, followed by full-text screening using predefined criteria. Prior to full screening and data extraction, reviewers will undergo a pilot calibration exercise on a subset of studies to ensure consistent application of eligibility criteria and data extraction procedures. Any persistent disagreements will be resolved through discussion and, when necessary, adjudication by a third senior reviewer.

A PRISMA 2020 flow diagram will document the screening process and reasons for exclusion.

2.6. Data Extraction

To ensure a systematic and transparent synthesis, we will extract standardized information for each included study based on a structured evidence framework (

Table 1. Summary of extracted evidence on metformin for the prevention of type 2 diabetes in children and adolescents with overweight or obesity.

Population							Intervention		Comparator
Author and year	Country	Study Design	Age range	Sample size	Baseline BMI (SDS)	Baseline glycemic status	Intervention description	Co-interventions	Comparator Group
Outcomes
Adherence Assessment Method	T2D incidence	Change in HbA1C	Change in FPG	Change in 2h-OGTT	Change in HOMA-IR	Change in BMI	Timepoint reported	Follow-up duration	RoB tool and rating (Low; some concerns; High)

Abbreviations: BMI: body mass index; SDS: standard deviation score; T2D: type 2 diabetes; HbA1c: glycated hemoglobin; FPG: fasting plasma glucose; 2h-OGTT: 2 h oral glucose tolerance test; HOMA-IR: homeostasis model assessment of insulin resistance; RoB: risk of bias.

). Data will be extracted using a standardized form including: study identifiers (authors, year, country), study design, duration, funding source, participant characteristics (age, sex, BMI z-score, ethnicity), intervention details (metformin dose, duration, lifestyle co-interventions), comparator type, outcomes measured, definitions used, follow-up duration, attrition, adherence, and adverse events. Two reviewers will extract data independently; discrepancies will be reconciled by consensus.

2.7. Risk of Bias Assessment

The risk of bias of included studies will be assessed independently by two reviewers using tools appropriate to study design. Randomized controlled trials (RCT) will be evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool [17], which assesses bias across domains including randomization and deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. Quasi-experimental and prospective cohort studies will be assessed using the Newcastle–Ottawa Scale (NOS) [18], considering selection of participants, comparability of study groups, and outcome assessment. Disagreements between reviewers will be resolved through discussion or adjudication by a third reviewer.

Risk-of-bias assessments will be incorporated into the interpretation of findings and will inform subgroup and sensitivity analyses, as well as decisions regarding inclusion in quantitative synthesis.

Overall evidence quality will be graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework [19].

2.8. Data Synthesis and Statistical Analysis

If data are sufficiently homogeneous, quantitative synthesis (meta-analysis) will be conducted using the Review Manager 5.4 software.

For dichotomous outcomes, effect estimates will be expressed as risk ratios (RRs) with 95% confidence intervals (CIs), while continuous outcomes will be summarized using mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. Statistical heterogeneity will be assessed using the I² statistic and Cochran’s Q test, with I² values greater than 50% indicating substantial heterogeneity. Where sufficient homogeneity exists, a random-effects meta-analysis will be conducted.

Given the anticipated methodological and clinical heterogeneity—particularly related to the study design—intervention characteristics, outcome definitions, and non-randomized studies will be excluded from quantitative synthesis when appropriate and will instead contribute to a narrative synthesis.

Planned subgroup analyses will explore the influence of study design (randomized vs. non-randomized), intervention type (metformin alone vs. metformin combined with lifestyle intervention), age group (<13 years vs. ≥13 years), baseline BMI category (overweight vs. obese classification), geographic region, and duration of follow-up.

Sensitivity analyses will be performed by excluding studies at high risk of bias to assess the robustness of pooled estimates. In addition, given potential variability in how type 2 diabetes incidence and glycemic outcomes are defined and reported across studies, outcome definitions will be harmonized where possible using standardized thresholds. When studies apply different diagnostic criteria (e.g., ISPAD, ADA, or author-defined definitions), sensitivity analyses will be conducted according to the diagnostic criteria used. Where harmonization is not feasible, findings will be synthesized narratively.

When meta-analysis is not feasible, findings will be summarized narratively, structured by study design and outcome domain.

2.9. Ethics and Dissemination

Ethical approval is not required, as the review uses published and publicly available data. Findings will be disseminated via publication in a peer-reviewed journal.

2.10. Artificial Intelligence (AI) Disclosure

During the conduct of this systematic review, the authors used Rayyan (Rayyan Systems Inc., Cambridge, MA, USA; web-based application, accessed in 2025) to support blinded and collaborative screening of titles, abstracts, and full-text articles. In addition, ChatGPT v 5.1 (OpenAI, San Francisco, CA, USA) was used to assist with language editing and formatting suggestions. No artificial intelligence tools were used to generate, analyze, or modify re-search data or results. The authors remain fully responsible for the content of the manuscript and its accuracy.

3. Expected Results

The following expected results are presented to outline the potential scope and direction of the planned analyses and should be interpreted as exploratory and hypothesis-generating, rather than as definitive conclusions. We anticipate identifying a limited number of randomized and quasi-experimental studies evaluating metformin for the prevention or delay of type 2 diabetes in children and adolescents with overweight or obesity. Based on previous meta-analyses, we expect that metformin, compared with placebo or lifestyle-only interventions, will be associated with modest but statistically significant improvements in BMI or BMI z-score, insulin sensitivity indices (HOMA-IR), and fasting glucose, particularly during short-term follow-up (3–6 months). However, we expect that few studies will have directly assessed incident type 2 diabetes as a primary endpoint, and the duration of follow-up will likely be insufficient to evaluate sustained preventive effects. Variability in intervention duration, adherence, and co-interventions (dietary or behavioral support) may contribute to heterogeneity. We also expect that metformin will be generally safe and well tolerated, with gastrointestinal effects being the most frequent adverse events, consistent with prior pediatric studies. By synthesizing current evidence, this review aims to quantify metformin’s potential to modify early metabolic trajectories in high-risk youth and to identify critical gaps for future longitudinal and preventive trials.

4. Discussion

The expected findings of this review will provide an updated synthesis of metformin’s role in the primary prevention of type 2 diabetes among children and adolescents. Existing studies suggest that metformin may improve surrogate markers of insulin resistance and adiposity but rarely extend to the formal prevention of diabetes onset [1,4,6,20,21].

The pathophysiological context of youth differs markedly from adults: puberty is characterized by transient physiological insulin resistance, rapid β-cell workload, and strong environmental influences on behavior and adherence. These factors may partly explain why the benefits seen in the adult Diabetes Prevention Program (DPP) are less evident in younger populations [4]. The RISE Pediatric Medication Study further demonstrated that metformin did not preserve β-cell function or prevent glycemic deterioration in youth with prediabetes or recent-onset type 2 diabetes, suggesting that prevention may need to target an even earlier stage of dysmetabolism [22].

Nevertheless, the short-term metabolic improvements consistently observed in pediatric studies, particularly reductions in BMI, HOMA-IR, and fasting glucose, may hold potential clinical relevance. However, evidence regarding whether these short-term effects translate into sustained prevention of type 2 diabetes remains insufficient. Current pediatric guidelines highlight the need for comprehensive, multidisciplinary obesity management, and acknowledge that pharmacotherapy, including metformin, may be considered only in selected cases where behavioral interventions alone are inadequate, pending stronger long-term data [20].

Our review also aims to highlight methodological limitations that currently preclude definitive conclusions: small sample sizes, short treatment durations, inconsistent outcome reporting, and variability in diagnostic definitions. These gaps underscore the need for standardized trial designs that include diabetes as an outcome, appropriate control groups, and extended follow-up beyond six months.

Lastly, the synthesis of available data will help delineate whether metformin should be considered a preventive adjunct for selected high-risk youth or remain limited to treatment of established type 2 diabetes. The findings will also inform future trial design, particularly regarding participant stratification (pubertal stage, baseline insulin resistance), dose optimization, and long-term safety evaluation.

Given the protocol-based nature of this work and the anticipated heterogeneity of the available literature, we intended to provoke an exploratory discussion, highlighting potential patterns, methodological gaps, and areas for future research rather than drawing firm clinical conclusions.

5. Conclusions

Metformin is one of the most frequently studied pharmacologic agents for addressing metabolic risk in youth with overweight or obesity, though its role in the prevention of type 2 diabetes remains uncertain. While evidence supports modest short-term improvements in metabolic parameters, robust data on diabetes incidence prevention are lacking. This systematic review and meta-analysis will consolidate current pediatric evidence, identify knowledge gaps, and inform the design of future prevention trials that integrate pharmacologic and behavioral strategies.

Given the escalating burden of obesity-related insulin resistance in youth, defining the preventive role of metformin represents a timely and clinically relevant step toward mitigating the early onset of type 2 diabetes.