Video Abstract

Video Abstract

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CONTEXT:

The efficacy and safety of metformin for obesity in children and adolescents remains unclear.

OBJECTIVE:

To assess the efficacy and safety of metformin via systematic review.

DATA SOURCES:

Data sources included PubMed, Embase, the Cochrane Library, Scopus, and ClincalTrials.gov (inception to November 2019).

STUDY SELECTION:

We selected randomized controlled trials (RCTs) in which researchers assessed the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity.

DATA EXTRACTION:

Two researchers independently extracted data and assessed quality. The primary outcomes were mean changes from baseline in BMI, BMI z score, homeostatic model assessment of insulin resistance, and gastrointestinal adverse effects.

RESULTS:

Twenty-four RCTs (1623 patients; range: 16 to 151) were included. Ages ranged from 4 to 19 years, and follow-up ranged from 2 months to 2 years. Metformin resulted in a modest decrease in BMI (range of mean values: −2.70 to 1.30 vs −1.12 to 1.90), BMI z score (range of mean values: −0.37 to −0.03 vs −0.22 to 0.15), and homeostatic model assessment of insulin resistance (range of mean values: −3.74 to 1.00 vs −1.40 to 2.66). Metformin resulted in a higher frequency of gastrointestinal adverse effects (range: 2% to 74% vs 0% to 42%).

LIMITATIONS:

The available evidence is of varying quality, with high heterogeneity between trials, suggesting some uncertainty in the benefits of metformin in this population.

CONCLUSIONS:

With this systematic review of RCTs, we suggest that metformin has modest but favorable effects on weight and insulin resistance and a tolerable safety profile among children and adolescents with obesity.

Approximately 43 million children worldwide have overweight, and 92 million are considered to be at risk for having overweight.1  The US Centers for Disease Control and Prevention defines a BMI in the >95th percentile as class I obesity.2  The prevalence of obesity has increased dramatically over the last decades.3  In 2016, the prevalence of class I obesity among children in the United States was 19%.4  Obesity is the most common cause of insulin resistance in children,5  and it is associated with dyslipidemia, type 2 diabetes, and long-term vascular complications, among others.6,7 

Although lifestyle interventions remain the standard of care for childhood obesity, many children will eventually require drug therapy.8,9  Metformin is not approved for use in those aged <18 years in Canada. In the United States, metformin is the only approved oral medication for use in children aged >10 years with type 2 diabetes.10,11  Several randomized controlled trials (RCTs) conducted in children revealed promising short-term (≤6 months) results regarding weight loss and homeostatic model assessment of insulin resistance (HOMA-IR) levels with metformin compared with a placebo and lifestyle interventions.1214  However, other studies revealed no benefit.15,16  These individual studies included small numbers of participants, had variable follow-up durations, and produced heterogeneous results. In addition, adverse effects were usually secondary end points.1519  Therefore, we conducted a systematic review to assess the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle intervention, in children and adolescents with obesity, focusing on BMI, insulin resistance, and gastrointestinal (GI) adverse effects.

In our systematic review, we followed a prespecified protocol, which was registered on PROSPERO (identifier CRD42019126099). Results are reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (Supplemental Information).20,21 

We systematically searched PubMed, Embase, the Cochrane Library, Scopus, and ClinicalTrials.gov from inception to January 2019 for RCTs and observational studies in which metformin with or without lifestyle interventions was compared with a placebo with or without lifestyle interventions in children and adolescents (0–19 years) with obesity (with and without insulin resistance), prediabetes, or nonalcoholic fatty liver disease (NAFLD), defined by a liver biopsy specimen with >5% steatosis within a 6-month period. We updated the search in November 2019. Medical Subject Headings terms were used in PubMed and the Cochrane Library, and Emtree terms were used in Embase. There were no language restrictions. The detailed search strategy is available in the Supplemental Information. We manually searched bibliographies of studies to retrieve additional studies that may not have been identified in our electronic search. Investigators were contacted for unpublished data.

The screening process and management of search results was conducted in Rayyan (Qatar Computing Research Institute, Doha, Qatar).22  The titles and abstracts were screened independently by 2 reviewers (R.M. and S.A.), with any publication deemed potentially relevant by either reviewer carried forward for full-text evaluation. Disagreements during full-text review were resolved by consensus or, when necessary, by a third independent reviewer (V.C.B.). We restricted inclusion to RCTs in which metformin with lifestyle interventions was compared with a placebo with lifestyle interventions; lifestyle intervention represents the current standard of care for obesity in this population.2,8  We included RCTs if any of the following was reported: BMI, BMI z score, body weight (in kilograms), fasting plasma glucose (FPG) level (in milligrams per deciliter), HOMA-IR, waist circumference (in centimeters), total cholesterol level (in milligrams per deciliter), triglyceride level (in milligrams per deciliter), GI adverse effects (ie, nausea, vomiting, diarrhea, abdominal pain, loose stool), and hepatic toxicity, defined as abnormal results on liver function tests. The mean change from baseline in BMI, BMI z score, and HOMA-IR and the incidence of GI adverse effects were the primary end points. Although our prespecified protocol included observational studies, given the important limitations of this literature (mainly confounding by indication), they were excluded from the final systematic review. Furthermore, we excluded studies conducted in children with type 2 diabetes given the established use of metformin for type 2 diabetes and the corresponding lack of clinical equipoise.

Two independent reviewers (R.M. and either S.A. or V.C.B.) extracted data using a standardized form. For each trial, the following data were extracted: publication year, location, number of randomly assigned patients, dose, follow-up duration, age, indication, outcomes, baseline anthropometric and metabolic measures, mean change from baseline, and adverse effects (focusing on GI adverse effects). When multiple follow-up periods and end points were reported for a given study, we extracted data from the publication with the most comprehensive reporting of outcomes and/or the longest follow-up.

The quality of RCTs was assessed by using the Cochrane Collaboration’s tool for assessing risk of bias (RoB 2; Cochrane Collaboration, London, United Kingdom).23  The tool is structured into 5 domains through which bias may be introduced. The 5 domains are bias arising from the randomization process, bias due to deviations from the intended interventions, bias due to missing data, bias in measurement of the outcome, and bias in selection of the reported results. We focused our quality assessment on the primary outcomes of BMI and BMI z score. Each domain was assigned a high, low, or unclear risk of bias. Two reviewers (R.M. and V.C.B.) assessed quality independently, with disagreements adjudicated by a third reviewer (K.B.F.).

The mean difference from baseline and SD for each treatment arm were extracted for continuous outcomes. The mean difference from baseline and SD for studies in which continuous outcomes were reported as mean and SE or 95% confidence interval (CI), median and interquartile range, or median, minimal, and maximal value were estimated by using the method described by Hozo et al24 . Version 3.5.3 of the R Environment (R Foundation for Statistical Computing, Vienna, Austria) was used to construct forest plots to graphically present study-specific treatment effects.

Our systematic search is described in Fig 1. Our systematic search yielded 2799 citations, of which 70 citations were considered for full-text review. Twenty-four RCTs were included in the systematic review, with absolute values for continuous outcomes reported in 8 RCTs and mean changes from baseline for continuous outcomes or rates of adverse effects reported in 16 RCTs.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram describing study selection process for a systematic review of trials in which the efficacy and safety of metformin is assessed among children and adolescents with obesity.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram describing study selection process for a systematic review of trials in which the efficacy and safety of metformin is assessed among children and adolescents with obesity.

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Study characteristics of RCTs are summarized in Table 1 and Supplemental Table 4. In the 24 included RCTs, 1623 (range: 16 to 151) children and adolescents were randomly assigned to metformin (861 participants) or a placebo (762 participants). The indication for metformin was uncomplicated obesity in 10 RCTs, obesity with insulin resistance in 9 RCTs, prediabetes in 3 RCTs, and NAFLD in 2 RCTs. All RCTs except one25,26  included a lifestyle cointervention in both treatment arms. The age of participants ranged from 4 to 19 years. A total of 9 RCTs included prepubertal, pubertal, and postpubertal children and adolescents,13,14,2733  10 RCTs included pubertal and postpubertal children,12,15,19,25,26,3438  and 5 RCTs included prepubertal and pubertal children and adolescents.17,3942  The duration of RCTs ranged from 2 months to 2 years. GI adverse effects included diarrhea, abdominal pain, epigastric pain, anorexia, vomiting, nausea, and loose stool and were reported in 16 RCTs overall. The total daily dose of metformin ranged from 500 to 2000 mg/day, and 60% to 90% of children in the metformin treatment group adhered to the treatment regimen.

TABLE 1

Characteristics of RCTs in Which Metformin Is Examined in Children and Youth

Study, yStudy DesignLocationTreatment Arms (No. Patients Randomly Assigned)Control Arm (No. Patients Randomly Assigned)Indication for Metformin, AgeFollow-up, moEnd Points and Side Effects
Warnakulasuriya et al,41  2018 Triple-blind RCT Sri Lanka Metformin 500–1000 mg BID + structured diet + physical activity (68) Placebo + structured diet + physical activity (82) Uncomplicated obesity, 8–16 y (prepubertal + pubertal) 12 BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects, AST, ALT 
Garibay-Nieto et al,29  2017 Double-blind RCT Mexico Metformin 1 g/d + lifestyle intervention (14) Placebo + lifestyle intervention (17) Uncomplicated obesity, 8–18 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR, triglycerides 
Pastor-Villaescusa et al,40  2017 Double-blind RCT Spain Metformin 500 mg BID + diet (68) Placebo + diet (72) Uncomplicated obesity, 7–14 y (prepubertal + pubertal BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
van der Aa et al,33  2016 Double-blind RCT Netherlands Metformin 2000 mg/d + dietary diary (23) Placebo + dietary diary (19) Obesity with insulin resistance, 10–16 y (prepubertal + pubertal + postpubertal) 18 BMI, wt, HOMA-IR, HbA1c, GI side effects, liver toxicity 
Clarson et al,27  2014 RCT Canada Metformin XR 500–2000 mg QD + lifestyle changes (50) Placebo QD + lifestyle changes (59) Uncomplicated obesity, 10–16 y (prepubertal + pubertal + postpubertal) 12 BMI, GI side effects, liver toxicity 
Evia-Viscarra et al,12  2012 Double-blind RCT Mexico Metformin 500 mg BID (14) Placebo (12) Uncomplicated obesity, 9–18 y (pubertal + postpubertal) BMI, wt, WC, FPG, GI side effects, liver toxicity 
Gómez-Díaz et al,13  2012 Double-blind RCT Mexico Metformin 850 mg BID + diet + exercise (28) Placebo + diet + exercise (24) Prediabetes, 4–17 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR, HbA1c, GI side effects, AST, ALT 
Kendall et al,14  2013 Double-blind RCT United Kingdom Metformin 1000 and 500 mg QD + diet and exercise counseling (74) Placebo + diet and exercise counseling (77) Prediabetes, 8–18 y (prepubertal + pubertal + postpubertal) BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Mauras et al,30  2012 RCT ITT United States Metformin 500–1000 mg BID + lifestyle intervention (35) Placebo + lifestyle intervention (31) Uncomplicated obesity, 7–18 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR 
Lavine et al,39  2011 Double-blind, double-dummy RCT United States Metformin 500 mg BID + diet and exercise counseling (57) Placebo + diet and exercise counseling (58) NAFLD, 8–17 y (prepubertal + pubertal) 24 BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, liver toxicity, ALT, AST 
Rynders et al,19  2012 RCT United States Metformin 500–1000 mg BID + diet + exercise (7) No placebo; diet + exercise (9) Uncomplicated obesity, 10–17 y (pubertal + postpubertal) BMI, wt 
Yanovski et al,42  2011 Double-blind RCT United States Metformin 1000 mg BID + diet (53) Placebo + diet (47) Obesity with insulin resistance, 6–12 y (prepubertal + pubertal) BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects, AST, ALT, vitamin B12 
Rezvanian et al,31  2010 Triple-masked RCT Iran Metformin 1500 mg/d + diet + exercise (41) Placebo + diet + exercise (42) Uncomplicated obesity, 10–18 y (prepubertal + pubertal + postpubertal) BMI, WC, GI side effects 
Wiegand et al,38  2010 RCT Germany and Switzerland Metformin 500 mg BID + diet (36) Placebo + diet (34) Prediabetes, 14–16 y (pubertal + postpubertal) Wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Wilson et al,34  2010 Double-blind RCT United States Metformin XR 2000 mg QD + lifestyle intervention (39) Placebo + lifestyle intervention (38) Uncomplicated obesity, 13–18 y (pubertal + postpubertal) 12 BMI, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Clarson et al,28  2009 RCT Canada Metformin 1500 mg QD + lifestyle intervention (14) Lifestyle intervention alone (11) Obesity with insulin resistance, 10–16 y (prepubertal + pubertal + postpubertal) BMI, FPG, triglycerides 
Nadeau et al,37  2009 Double-blind RCT United States Metformin 850 mg BID + wellness education (37) Placebo + wellness education (13) NAFLD, 12–18 y (pubertal + postpubertal) BMI, wt, FPG, total cholesterol, triglycerides, GI side effects, AST, ALT 
Atabek and Pirgon,17  2008 Double-blind RCT Turkey Metformin 500 mg BID + diet + exercise (90) Placebo 500 mg BID + diet + exercise (30) Obesity with insulin resistance, 8–16 y (prepubertal + pubertal) BMI, wt, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Burgert et al,15  2008 Double-blind RCT United States Metformin 1500 mg/d + lifestyle counseling (15) Placebo + lifestyle counseling (17) Obesity with insulin resistance, 13–18 y (pubertal + postpubertal) BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides 
Love-Osborne et al,36  2008 Double-blind RCT United States Metformin 850 mg BID + diet + exercise (48) Placebo + diet + exercise (16) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) BMI, GI side effects 
Freemark,25  2007 Double-blind RCT United States Metformin 500 mg BID (14) Placebo (15) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) GI side effects, AST, ALT 
Srinivasan et al,32  2006 RCT Australia Metformin 1000 mg BID (10) Placebo (12) Obesity with insulin resistance 9–18 y, (prepubertal + pubertal + postpubertal) GI side effects 
Kay et al,35  2001 Double-blind RCT United States Metformin 850 mg BID + low-calorie diet (12) Placebo + low-calorie diet (12) Obesity uncomplicated, 14–16 y (pubertal + postpubertal) Wt, FPG, total cholesterol, triglycerides, GI side effects 
Freemark and Bursey,26  2001 Double-blind RCT United States Metformin 500 mg BID (14) Placebo (15) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) BMI, FPG, HOMA-IR, HbA1c, total cholesterol, triglycerides, GI side effects 
Study, yStudy DesignLocationTreatment Arms (No. Patients Randomly Assigned)Control Arm (No. Patients Randomly Assigned)Indication for Metformin, AgeFollow-up, moEnd Points and Side Effects
Warnakulasuriya et al,41  2018 Triple-blind RCT Sri Lanka Metformin 500–1000 mg BID + structured diet + physical activity (68) Placebo + structured diet + physical activity (82) Uncomplicated obesity, 8–16 y (prepubertal + pubertal) 12 BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects, AST, ALT 
Garibay-Nieto et al,29  2017 Double-blind RCT Mexico Metformin 1 g/d + lifestyle intervention (14) Placebo + lifestyle intervention (17) Uncomplicated obesity, 8–18 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR, triglycerides 
Pastor-Villaescusa et al,40  2017 Double-blind RCT Spain Metformin 500 mg BID + diet (68) Placebo + diet (72) Uncomplicated obesity, 7–14 y (prepubertal + pubertal BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
van der Aa et al,33  2016 Double-blind RCT Netherlands Metformin 2000 mg/d + dietary diary (23) Placebo + dietary diary (19) Obesity with insulin resistance, 10–16 y (prepubertal + pubertal + postpubertal) 18 BMI, wt, HOMA-IR, HbA1c, GI side effects, liver toxicity 
Clarson et al,27  2014 RCT Canada Metformin XR 500–2000 mg QD + lifestyle changes (50) Placebo QD + lifestyle changes (59) Uncomplicated obesity, 10–16 y (prepubertal + pubertal + postpubertal) 12 BMI, GI side effects, liver toxicity 
Evia-Viscarra et al,12  2012 Double-blind RCT Mexico Metformin 500 mg BID (14) Placebo (12) Uncomplicated obesity, 9–18 y (pubertal + postpubertal) BMI, wt, WC, FPG, GI side effects, liver toxicity 
Gómez-Díaz et al,13  2012 Double-blind RCT Mexico Metformin 850 mg BID + diet + exercise (28) Placebo + diet + exercise (24) Prediabetes, 4–17 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR, HbA1c, GI side effects, AST, ALT 
Kendall et al,14  2013 Double-blind RCT United Kingdom Metformin 1000 and 500 mg QD + diet and exercise counseling (74) Placebo + diet and exercise counseling (77) Prediabetes, 8–18 y (prepubertal + pubertal + postpubertal) BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Mauras et al,30  2012 RCT ITT United States Metformin 500–1000 mg BID + lifestyle intervention (35) Placebo + lifestyle intervention (31) Uncomplicated obesity, 7–18 y (prepubertal + pubertal + postpubertal) BMI, wt, WC, HOMA-IR 
Lavine et al,39  2011 Double-blind, double-dummy RCT United States Metformin 500 mg BID + diet and exercise counseling (57) Placebo + diet and exercise counseling (58) NAFLD, 8–17 y (prepubertal + pubertal) 24 BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, liver toxicity, ALT, AST 
Rynders et al,19  2012 RCT United States Metformin 500–1000 mg BID + diet + exercise (7) No placebo; diet + exercise (9) Uncomplicated obesity, 10–17 y (pubertal + postpubertal) BMI, wt 
Yanovski et al,42  2011 Double-blind RCT United States Metformin 1000 mg BID + diet (53) Placebo + diet (47) Obesity with insulin resistance, 6–12 y (prepubertal + pubertal) BMI, wt, WC, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects, AST, ALT, vitamin B12 
Rezvanian et al,31  2010 Triple-masked RCT Iran Metformin 1500 mg/d + diet + exercise (41) Placebo + diet + exercise (42) Uncomplicated obesity, 10–18 y (prepubertal + pubertal + postpubertal) BMI, WC, GI side effects 
Wiegand et al,38  2010 RCT Germany and Switzerland Metformin 500 mg BID + diet (36) Placebo + diet (34) Prediabetes, 14–16 y (pubertal + postpubertal) Wt, FPG, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Wilson et al,34  2010 Double-blind RCT United States Metformin XR 2000 mg QD + lifestyle intervention (39) Placebo + lifestyle intervention (38) Uncomplicated obesity, 13–18 y (pubertal + postpubertal) 12 BMI, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Clarson et al,28  2009 RCT Canada Metformin 1500 mg QD + lifestyle intervention (14) Lifestyle intervention alone (11) Obesity with insulin resistance, 10–16 y (prepubertal + pubertal + postpubertal) BMI, FPG, triglycerides 
Nadeau et al,37  2009 Double-blind RCT United States Metformin 850 mg BID + wellness education (37) Placebo + wellness education (13) NAFLD, 12–18 y (pubertal + postpubertal) BMI, wt, FPG, total cholesterol, triglycerides, GI side effects, AST, ALT 
Atabek and Pirgon,17  2008 Double-blind RCT Turkey Metformin 500 mg BID + diet + exercise (90) Placebo 500 mg BID + diet + exercise (30) Obesity with insulin resistance, 8–16 y (prepubertal + pubertal) BMI, wt, HOMA-IR, total cholesterol, triglycerides, GI side effects 
Burgert et al,15  2008 Double-blind RCT United States Metformin 1500 mg/d + lifestyle counseling (15) Placebo + lifestyle counseling (17) Obesity with insulin resistance, 13–18 y (pubertal + postpubertal) BMI, wt, FPG, HOMA-IR, total cholesterol, triglycerides 
Love-Osborne et al,36  2008 Double-blind RCT United States Metformin 850 mg BID + diet + exercise (48) Placebo + diet + exercise (16) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) BMI, GI side effects 
Freemark,25  2007 Double-blind RCT United States Metformin 500 mg BID (14) Placebo (15) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) GI side effects, AST, ALT 
Srinivasan et al,32  2006 RCT Australia Metformin 1000 mg BID (10) Placebo (12) Obesity with insulin resistance 9–18 y, (prepubertal + pubertal + postpubertal) GI side effects 
Kay et al,35  2001 Double-blind RCT United States Metformin 850 mg BID + low-calorie diet (12) Placebo + low-calorie diet (12) Obesity uncomplicated, 14–16 y (pubertal + postpubertal) Wt, FPG, total cholesterol, triglycerides, GI side effects 
Freemark and Bursey,26  2001 Double-blind RCT United States Metformin 500 mg BID (14) Placebo (15) Obesity with insulin resistance, 12–19 y (pubertal + postpubertal) BMI, FPG, HOMA-IR, HbA1c, total cholesterol, triglycerides, GI side effects 

ALT, alanine transaminase; AST, aspartate transaminase; BID, twice daily; HbA1c, hemoglobin A1c; ITT, intention-to-treat analysis; QD, once daily; WC, waist circumference; XR, extended release.

Of the 24 included RCTs, 14 were of low to moderate quality (Supplemental Table 5). Nine trials had some concern of bias in the randomization process. A total of 14 RCTs had some concern for bias due to the selection of the reported outcomes. Concerns of high risk of bias were observed for deviations from the intended interventions in 11 trials and missing outcome data as a result of high rates of loss to follow-up in 6 trials. Although the authors of individual RCTs reported similar rates of loss to follow-up across treatment arms, the rates of loss to follow-up across studies ranged from 5% to 80% among subjects randomly assigned to metformin and from 5% to 50% among those randomly assigned to a placebo.

The effect of metformin on our primary efficacy outcomes is reported in Table 2. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (range of mean changes: −1.12 to 1.90). The mean difference in the treatment effect between the metformin and the placebo arms ranged from −2.72 to 0.70, and the 95% CI ranged from −4.43 to 0.31. However, results across studies were heterogeneous, with 11 RCTs suggesting that metformin decreases BMI and 3 RCTs suggesting that it increases BMI (Fig 2). Furthermore, the mean change in BMI was not larger in studies that included children with a higher mean BMI at baseline. Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials. Among the 7 RCTs in which BMI z score was reported, metformin consistently resulted in a decrease in the BMI z score (range of mean changes: −0.37 to −0.03) compared with a placebo (range of mean changes: −0.22 to 0.15) (Fig 3). The mean difference in the treatment effect between the metformin and the placebo arms ranged from −0.15 to −0.07, and the 95% CI ranged from −0.51 to 0.05 (Fig 3). The largest decrease in BMI z score was observed in children and adolescents with NAFLD.39  In addition, among 11 RCTs in which insulin resistance was examined, metformin resulted in modest but favorable effects on insulin resistance (range of mean changes: −3.74 to 1.00) compared with a placebo (range of mean changes: −1.40 to 2.66). The mean difference in the treatment effect between the metformin and the placebo arms ranged from −3.54 to 2.03, and the 95% CI ranged from −6.80 to 8.22 (Fig 4). Although heterogeneity was present, metformin appeared to reduce HOMA-IR in 8 RCTs; as with BMI, some trials were inconclusive because of wide 95% CIs (Fig 4).

TABLE 2

Obesity Measures and Insulin Resistance at Maximum Follow-up in RCTs in Which Metformin Is Examined in Children and Youth

Study, yFollow-up, moBMI, Mean ± SDBMI z Score, Mean ± SDHOMA-IR, Mean ± SD
BaselineMean ChangeBaselineMean ChangeBaselineMean Change
Warnakulasuriya et al,41  2018 12       
 Metformin (n = 68)  27.44 ± 2.96 −0.85 ± 1.56 2.54 ± 0.59 −0.37 ± 0.29 2.63 ± 1.21 −1.77 ± 3.35 
 Placebo (n = 82)  27.44 ± 2.7 −0.05 ± 1.55 2.51 ± 0.42 −0.22 ± 0.30 2.34 ± 1.46 −0.79 ± 3.49 
van der Aa et al,33  2016 18       
 Metformin (n = 23)  29.8 ± 4.74 −0.35 ± 2.74 3.10 ± 0.59 −0.12 ± 0.42 4.00 ± 3.00 −0.65 ± 3.33 
 Placebo (n = 19)  30.5 ± 7.33 0.82 ± 2.00 3.38 ± 0.81 0.04 ± 0.12 4.85 ± 2.50 −0.07 ± 2.14 
Evia-Viscarra et al,12  2012       
 Metformin (n = 14)  33.44 ± 5.82 −0.73 ± 0.98 NA NA 7.84 ± 3.66 −0.88 ± 4.23 
 Placebo (n = 12)  32.82 ± 6.37 −0.72 ± 0.85 NA NA 5.52 ± 3.35 2.66 ± 4.22 
Gómez-Díaz et al,13  2012       
 Metformin (n = 28)  31.10 ± 6.30 NA NA NA 7.50 ± 22.00 −0.67 ± 0.97 
 Placebo (n = 24)  27.10 ± 5.90 NA NA NA 6.50 ± 13.18 0.12 ± 0.26 
Mauras et al,30  2012       
 Metformin (n = 35)  32.00 ± 1.00 −2.40 ± 2.95 NA NA 4.80 ± 0.40 0.34 ± 4.49 
 Placebo (n = 31)  33.20 ± 0.70 −1.12 ± 2.78 NA NA 5.20 ± 0.60 1.6 ± 4.45 
Lavine et al,39  2011 24       
 Metformin (n = 57)  34.00 ± 5.00 1.30 ± 2.69 2.35 ± 0.30 −0.25 ± 0.32 7.90 ± 5.40 −0.50 ± 8.85 
 Placebo (n = 58)  33.00 ± 6.00 1.90 ± 3.10 2.35 ± 0.26 0.15 ± 0.27 11.00 ± 17.60 −1.40 ± 27.00 
Rynders et al,19  2012       
 Metformin (n = 7)  33.60 ± 7.2 −2.70 ± 2.38 NA NA 5.30 ± 1.60 NA 
 Placebo (n = 6)  33.60 ± 3.40 −1.00 ± 1.01 NA NA 4.90 ± 3.20 NA 
Yanovski et al,42  2011       
 Metformin (n = 53)  34.20 ± 6.80 −0.78 ± 2.84 2.56 ± 0.27 −0.11 ± 0.20 4.50 ± 2.20 NA 
 Placebo (n = 47)  34.60 ± 6.20 −1.09 ± 3.00 2.58 ± 0.24 −0.04 ± 0.21 4.90 ± 3.30 NA 
Rezvanian et al,31  2010       
 Metformin (n = 45)  26.40 ± 3.35 0.9 ± 0.1 2.40 ± 0.06 NA NA NA 
 Placebo (n = 45)  26.20 ± 4.20 0.2 ± 0.04 2.40 ± 0.13 NA NA NA 
Wiegand et al,38  2010       
 Metformin (n = 34)  33.06 ± 4.64 0.69 ± 3.69 2.72 ± 0.49 −0.03 ± 0.02 4.90 ± 1.54 NA 
 Placebo (n = 29)  32.93 ± 6.56 0.07 ± 0.51 2.79 ± 0.60 −0.02 ± 0.07 4.58 ± 3.00 NA 
Wilson et al,34  2010 12       
 Metformin (n = 39)  35.90 ± 5.70 −0.9 ± 3.12 2.28 ± 0.31 −0.09 ± 0.25 3.80 ± 2.80 −0.10 ± 4.99 
 Placebo (n = 38)  35.90 ± 4.70 0.2 ± 3.08 2.31 ± 0.21 −0.04 ± 0.24 5.00 ± 3.50 −0.80 ± 4.31 
Clarson et al,28  2009       
 Metformin (n = 14)  36.40 ± 6.73 −1.80 ± 2.99 2.41 ± 0.22 −0.16 ± 0.26 5.23 ± 1.94 −0.53 ± 3.58 
 Placebo (n = 11)  33.90 ± 3.64 0.50 ± 099 2.34 ± 0.19 −0.02 ± 0.09 6.54 ± 1.92 −0.50 ± 4.07 
Atabek and Pirgon,17  2008       
 Metformin (n = 90)  28.50 ± 3.40 −2.08 ± 5.56 NA NA 4.95 ± 3.34 −3.74 ± 3.80 
 Placebo (n = 30)  28.00 ± 3.40 0.65 ± 3.49 NA NA 3.98 ± 1.81 −1.05 ± 2.30 
Burgert et al,15  2008       
 Metformin (n = 15)  41.00 ± 6.00 −0.90 ± 4.30 NA NA 8.80 ± 2.10 1.00 ± 1.00 
 Placebo (n = 17)  40.00 ± 6.00 1.10 ± 4.68 NA NA 6.20 ± 3.00 1.20 ± 1.21 
Love-Osborne et al,36  2008       
 Metformin (n = 48)  39.40 ± 6.50 −0.16 ± 1.89 4.60 ± 1.80 NA NA NA 
 Placebo (n = 16)  39.30 ± 7.20 0.63 ± 1.29 6.20 ± 8.90 NA NA NA 
Study, yFollow-up, moBMI, Mean ± SDBMI z Score, Mean ± SDHOMA-IR, Mean ± SD
BaselineMean ChangeBaselineMean ChangeBaselineMean Change
Warnakulasuriya et al,41  2018 12       
 Metformin (n = 68)  27.44 ± 2.96 −0.85 ± 1.56 2.54 ± 0.59 −0.37 ± 0.29 2.63 ± 1.21 −1.77 ± 3.35 
 Placebo (n = 82)  27.44 ± 2.7 −0.05 ± 1.55 2.51 ± 0.42 −0.22 ± 0.30 2.34 ± 1.46 −0.79 ± 3.49 
van der Aa et al,33  2016 18       
 Metformin (n = 23)  29.8 ± 4.74 −0.35 ± 2.74 3.10 ± 0.59 −0.12 ± 0.42 4.00 ± 3.00 −0.65 ± 3.33 
 Placebo (n = 19)  30.5 ± 7.33 0.82 ± 2.00 3.38 ± 0.81 0.04 ± 0.12 4.85 ± 2.50 −0.07 ± 2.14 
Evia-Viscarra et al,12  2012       
 Metformin (n = 14)  33.44 ± 5.82 −0.73 ± 0.98 NA NA 7.84 ± 3.66 −0.88 ± 4.23 
 Placebo (n = 12)  32.82 ± 6.37 −0.72 ± 0.85 NA NA 5.52 ± 3.35 2.66 ± 4.22 
Gómez-Díaz et al,13  2012       
 Metformin (n = 28)  31.10 ± 6.30 NA NA NA 7.50 ± 22.00 −0.67 ± 0.97 
 Placebo (n = 24)  27.10 ± 5.90 NA NA NA 6.50 ± 13.18 0.12 ± 0.26 
Mauras et al,30  2012       
 Metformin (n = 35)  32.00 ± 1.00 −2.40 ± 2.95 NA NA 4.80 ± 0.40 0.34 ± 4.49 
 Placebo (n = 31)  33.20 ± 0.70 −1.12 ± 2.78 NA NA 5.20 ± 0.60 1.6 ± 4.45 
Lavine et al,39  2011 24       
 Metformin (n = 57)  34.00 ± 5.00 1.30 ± 2.69 2.35 ± 0.30 −0.25 ± 0.32 7.90 ± 5.40 −0.50 ± 8.85 
 Placebo (n = 58)  33.00 ± 6.00 1.90 ± 3.10 2.35 ± 0.26 0.15 ± 0.27 11.00 ± 17.60 −1.40 ± 27.00 
Rynders et al,19  2012       
 Metformin (n = 7)  33.60 ± 7.2 −2.70 ± 2.38 NA NA 5.30 ± 1.60 NA 
 Placebo (n = 6)  33.60 ± 3.40 −1.00 ± 1.01 NA NA 4.90 ± 3.20 NA 
Yanovski et al,42  2011       
 Metformin (n = 53)  34.20 ± 6.80 −0.78 ± 2.84 2.56 ± 0.27 −0.11 ± 0.20 4.50 ± 2.20 NA 
 Placebo (n = 47)  34.60 ± 6.20 −1.09 ± 3.00 2.58 ± 0.24 −0.04 ± 0.21 4.90 ± 3.30 NA 
Rezvanian et al,31  2010       
 Metformin (n = 45)  26.40 ± 3.35 0.9 ± 0.1 2.40 ± 0.06 NA NA NA 
 Placebo (n = 45)  26.20 ± 4.20 0.2 ± 0.04 2.40 ± 0.13 NA NA NA 
Wiegand et al,38  2010       
 Metformin (n = 34)  33.06 ± 4.64 0.69 ± 3.69 2.72 ± 0.49 −0.03 ± 0.02 4.90 ± 1.54 NA 
 Placebo (n = 29)  32.93 ± 6.56 0.07 ± 0.51 2.79 ± 0.60 −0.02 ± 0.07 4.58 ± 3.00 NA 
Wilson et al,34  2010 12       
 Metformin (n = 39)  35.90 ± 5.70 −0.9 ± 3.12 2.28 ± 0.31 −0.09 ± 0.25 3.80 ± 2.80 −0.10 ± 4.99 
 Placebo (n = 38)  35.90 ± 4.70 0.2 ± 3.08 2.31 ± 0.21 −0.04 ± 0.24 5.00 ± 3.50 −0.80 ± 4.31 
Clarson et al,28  2009       
 Metformin (n = 14)  36.40 ± 6.73 −1.80 ± 2.99 2.41 ± 0.22 −0.16 ± 0.26 5.23 ± 1.94 −0.53 ± 3.58 
 Placebo (n = 11)  33.90 ± 3.64 0.50 ± 099 2.34 ± 0.19 −0.02 ± 0.09 6.54 ± 1.92 −0.50 ± 4.07 
Atabek and Pirgon,17  2008       
 Metformin (n = 90)  28.50 ± 3.40 −2.08 ± 5.56 NA NA 4.95 ± 3.34 −3.74 ± 3.80 
 Placebo (n = 30)  28.00 ± 3.40 0.65 ± 3.49 NA NA 3.98 ± 1.81 −1.05 ± 2.30 
Burgert et al,15  2008       
 Metformin (n = 15)  41.00 ± 6.00 −0.90 ± 4.30 NA NA 8.80 ± 2.10 1.00 ± 1.00 
 Placebo (n = 17)  40.00 ± 6.00 1.10 ± 4.68 NA NA 6.20 ± 3.00 1.20 ± 1.21 
Love-Osborne et al,36  2008       
 Metformin (n = 48)  39.40 ± 6.50 −0.16 ± 1.89 4.60 ± 1.80 NA NA NA 
 Placebo (n = 16)  39.30 ± 7.20 0.63 ± 1.29 6.20 ± 8.90 NA NA NA 

NA, not available.

FIGURE 2

Mean differences and CIs from 14 RCTs in which change in BMI was compared between metformin treatment and a placebo among children and adolescents with obesity.

FIGURE 2

Mean differences and CIs from 14 RCTs in which change in BMI was compared between metformin treatment and a placebo among children and adolescents with obesity.

Close modal
FIGURE 3

Mean differences and CIs from 7 RCTs in which change in BMI z score is compared between metformin treatment and a placebo among children and adolescents with obesity.

FIGURE 3

Mean differences and CIs from 7 RCTs in which change in BMI z score is compared between metformin treatment and a placebo among children and adolescents with obesity.

Close modal
FIGURE 4

Mean differences and CIs from 11 RCTs in which mean change in HOMA-IR is compared between metformin treatment and a placebo among children and adolescents with obesity.

FIGURE 4

Mean differences and CIs from 11 RCTs in which mean change in HOMA-IR is compared between metformin treatment and a placebo among children and adolescents with obesity.

Close modal

Compared with a placebo, metformin had heterogeneous effects on other efficacy end points. Among 7 RCTs, metformin was associated with greater weight loss (range of mean changes: −5.1 to 12 kg) compared with a placebo (range of mean changes: −1.7 to 12.7 kg), resulting in an overall decrease in weight in 6 RCTs (Supplemental Fig 6). Metformin’s effects on waist circumference, FPG, total cholesterol, or triglycerides were heterogeneous and inconclusive (Supplemental Figs 610).

In 16 RCTs, authors reported adverse effects during follow-up. Metformin treatment was associated with a higher report rate of adverse GI effects (rate range: 2% to 74%) compared with a placebo (rate range: 0% to 42%) (Table 3, Fig 5). Evidence regarding a potential increased risk of liver toxicity was inconclusive, with potential liver toxicity reported in only 4 RCTs and heterogeneous results across studies (Supplemental Fig 11). Adverse effects were not stratified by ethnicity in the included RCTs. The occurrence of adverse effects was not reported in 7 RCTs, with 6 studies conducted in the United States and 1 study conducted in Mexico.

TABLE 3

GI Adverse Effects Reported During Follow-up in RCTs in Which Metformin Is Examined in Children and Youth

Study, yFollow-up, moDaily Dose, mgGI Adverse Effects ReportedMetformin Cases/n (%)Placebo Cases/n (%)
Warnakulasuriya et al,41  2018 12 1000–2000 GI adverse effects and anorexia 25/68 (37) 22/82 (27) 
Pastor-Villaescusa et al,40  2017 1000 Diarrhea 9/68 (13) 6/72 (8) 
van der Aa et al,33  2016 18 2000 Nausea and diarrhea 17/23 (74) 8/19 (42) 
Clarson et al,27  2014 12 500–2000 Diarrhea 1/50 (2) 0/59 (0) 
Evia-Viscarra et al,12  2012 1000 Epigastric pain 2/14 (14) 1/12 (8) 
Gómez-Díaz et al,13  2012 1700 Diarrhea 10/28 (36) 0/24 (0) 
Kendall et al,14  2013 500 or 1000 Diarrhea, nausea, abdominal pain 20/74 (27) 8/77 (10) 
Yanovski et al,42  2011 2000 Loose stool, vomiting 21/53 (40) 8/47 (17) 
Rezvanian et al,31  2010 1500 Abdominal pain, loose stool 3/41 (7) 0/42 (0) 
Wiegand et al,38  2010 1000 GI adverse effects 5/36 (14) 9/34 (26) 
Wilson et al,34  2010 12 2000 Nausea, vomiting 9/39 (23) 3/38 (8) 
Nadeau et al,37  2009 1700 Nausea, diarrhea, abdominal pain 10/37 (27) 3/13 (23) 
Atabek and Pirgon,17  2008 1000 Vomiting 2/90 (2) 0/30 (0) 
Love-Osborne et al,36  2008 1700 GI adverse effects 14/48 (29) 3/16 (19) 
Srinivasan et al,32  2006 2000 Nausea 2/10 (20) 0/12 (0) 
Kay et al,35  2001 1700 Nausea, loose stool 5/12 (42) 0/12 (0) 
Study, yFollow-up, moDaily Dose, mgGI Adverse Effects ReportedMetformin Cases/n (%)Placebo Cases/n (%)
Warnakulasuriya et al,41  2018 12 1000–2000 GI adverse effects and anorexia 25/68 (37) 22/82 (27) 
Pastor-Villaescusa et al,40  2017 1000 Diarrhea 9/68 (13) 6/72 (8) 
van der Aa et al,33  2016 18 2000 Nausea and diarrhea 17/23 (74) 8/19 (42) 
Clarson et al,27  2014 12 500–2000 Diarrhea 1/50 (2) 0/59 (0) 
Evia-Viscarra et al,12  2012 1000 Epigastric pain 2/14 (14) 1/12 (8) 
Gómez-Díaz et al,13  2012 1700 Diarrhea 10/28 (36) 0/24 (0) 
Kendall et al,14  2013 500 or 1000 Diarrhea, nausea, abdominal pain 20/74 (27) 8/77 (10) 
Yanovski et al,42  2011 2000 Loose stool, vomiting 21/53 (40) 8/47 (17) 
Rezvanian et al,31  2010 1500 Abdominal pain, loose stool 3/41 (7) 0/42 (0) 
Wiegand et al,38  2010 1000 GI adverse effects 5/36 (14) 9/34 (26) 
Wilson et al,34  2010 12 2000 Nausea, vomiting 9/39 (23) 3/38 (8) 
Nadeau et al,37  2009 1700 Nausea, diarrhea, abdominal pain 10/37 (27) 3/13 (23) 
Atabek and Pirgon,17  2008 1000 Vomiting 2/90 (2) 0/30 (0) 
Love-Osborne et al,36  2008 1700 GI adverse effects 14/48 (29) 3/16 (19) 
Srinivasan et al,32  2006 2000 Nausea 2/10 (20) 0/12 (0) 
Kay et al,35  2001 1700 Nausea, loose stool 5/12 (42) 0/12 (0) 
FIGURE 5

Risk ratios and CIs from 16 RCTs in which risk of GI adverse effects is compared between metformin treatment and a placebo among children and adolescents with obesity.

FIGURE 5

Risk ratios and CIs from 16 RCTs in which risk of GI adverse effects is compared between metformin treatment and a placebo among children and adolescents with obesity.

Close modal

Our study was designed to examine the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity. We found that metformin has modest but favorable effects on BMI, BMI z score, and HOMA-IR relative to a placebo. However, the available evidence is of varying quality, with high drop-out rates, and higher-quality studies had smaller estimated treatment effects, suggesting some uncertainty in its clinical benefits. Metformin was also associated with almost a doubled rate of GI adverse effects compared with a placebo, and the currently available evidence is inconclusive for liver toxicity.

The findings of our systematic review add to the existing literature, suggesting that metformin therapy has a modest favorable effect in children and adolescents with obesity. However, the clinical significance and the long-term effects of these beneficial effects in this population remain uncertain. These findings are partially consistent with previously published systematic reviews and meta-analyses.4347  Although in these previous knowledge syntheses, researchers examined metformin therapy for insulin resistance and obesity in children and adolescents, they had important methodologic limitations. In these syntheses, which included 1 recent meta-analysis,46  several systematic reviews, and 1 older meta-analysis,4345,47  researchers focused on absolute BMI, did not examine BMI z score, and did not assess safety outcomes. In the meta-analyses, data were pooled across trials despite substantial heterogeneity in mean age across studies and substantial loss to follow-up.4547  Moreover, the authors pooled data for continuous outcomes at the end of follow-up rather than pooling the mean change from baseline, which is a more accurate estimate of the treatment effect. These previous syntheses also included studies of patients with type 2 diabetes and those of pharmacotherapies in addition to metformin. The inclusion of such studies limits the capability to assess the efficacy and safety of metformin therapy in insulin resistance and obesity. With inclusion restricted to trials with metformin monotherapy and synthesis focused on the qualitative assessment in light of the substantial heterogeneity in the included trials and the examination of mean changes in outcomes from baseline, our systematic review has overcome many of the limitations of the previous studies. Finally, we included BMI z score as an end point, which is the preferred measure for obesity in the pediatric population.48,49 

The observed effects of metformin on changes in BMI and weight were not consistent across trials. Absolute BMI is not the ideal measure for obesity in children and adolescents because BMI varies with sex and age. With metformin-related weight loss superimposed on the naturally occurring weight gain associated with growth, changes in BMI translate differently among prepubertal and pubertal children and adolescents, especially when not compared across an age- and sex-adjusted reference.48,49  To better assess the effects of metformin on BMI, it is crucial to examine changes in BMI z score, a measure of relative weight for height compared to a reference standard that accounts for age and sex, rather than absolute change in BMI.48,49  All trials in which changes in the BMI z score were reported revealed a consistent decrease with metformin, with the largest decrease observed among individuals with NAFLD. Furthermore, improvement in absolute weight, if not adjusted to reference norms accounting for age, sex, and height, may have little clinical value when comparing children of different ages and developmental stages. Consequently, weight loss and changes in absolute BMI may not be as clinically meaningful outcomes in obese children and adolescents as in adults.50  These issues underscore the importance of examining BMI z score as a primary outcome in clinical trials as well as other measures of adiposity, such as insulin resistance; FPG; waist circumference adjusted for age, sex, and height; and the lipid profile.

Insulin resistance measured by HOMA-IR decreased in the metformin treatment arm, indicating modest efficacy. However, these changes must be interpreted carefully because changes in insulin resistance may be different among school-aged children and adolescents because of their different stages of pubertal development and changes in other hormones.51  The majority of trials included prepubertal and pubertal children and adolescents, but results were not stratified by age or developmental stage. The measurement of developmental stage varied, assessed by either a trained endocrinologist and/or nurse or reported by caregivers, further limiting the clinical interpretation of the results. Furthermore, metformin’s primary mechanism of action is through lowering hepatic glucose production, with much smaller effects on insulin resistance.10,46,52  However, a mediation analysis to quantify how much of the observed effect on insulin resistance can be attributed to weight loss versus a direct drug effect is not possible with the aggregated nature of the data. Finally, the effect of metformin on both weight loss and insulin resistance was consistent only among individuals with NAFLD; however, the trial of patients with NAFLD had a longer follow-up time (2 years) than other included trials, and it is unclear if this difference is due to differences in patient populations or long-term adherence to therapy.

The number of studies in which researchers assessed changes in the FPG level, waist circumference, and lipid profile was small. For the FPG level, the studies revealed an overall decrease, whereas the effects on waist circumference and the lipid profile were heterogeneous and inconclusive. In most trials, the mean change in waist circumference was not adjusted for age, sex, and height, and therefore the results have little applicability in the clinical setting.2  The heterogeneity in the observed treatment effects in our systematic review may also be attributed to differences in adherence, large percentages of loss to follow-up, intensity of concurrent lifestyle modifications, comedications, and tolerance of adverse effects.

Metformin is approved for use in children and adolescents for type 2 diabetes only, and the prescribing of metformin for insulin resistance, prediabetes, and obesity remains controversial. In a study of adults aged at least 25 years with prediabetes, metformin plus lifestyle interventions, compared with lifestyle interventions and a placebo, resulted in a lower cumulative incidence of type 2 diabetes after 3 years of follow-up.53  Lifestyle interventions were more effective than metformin in people aged ≥60 years, less effective than metformin in adults aged 45 to 59 years old, and as effective in adults aged ≤44 years. These beneficial effects in adults with prediabetes and glucose intolerance are not observed in children and adolescents.5456  In our systematic review, the efficacy of metformin in children and adolescents with prediabetes was assessed in 3 RCTs.13,14,38  These trials revealed a modest decrease in the BMI z score and no change in insulin resistance and the FPG level, suggesting that metformin is not as effective in the treatment of prediabetes in children and adolescents. In children and adolescents, prediabetes is often a transient condition, and the determinants of progression to overt type 2 diabetes remain uncertain in this population.5456  Results from our study do not allow us to conclude whether metformin treatment in children and adolescents with prediabetes is beneficial to prevent the progression to overt type 2 diabetes.

Generally, in adults and adolescents, clinically significant responses to metformin are not seen at doses <1500 to 2000 mg/day among patients with type 2 diabetes.57  The metformin dose used in trials included in our systematic review ranged from 500 to 2000 mg/day, and there was no clear trend regarding a potential dose-response effect on BMI, BMI z score, and HOMA-IR. Furthermore, the rate of GI adverse effects was slightly lower with doses of up to 1000 mg/day as opposed to doses of 1500 to 2000 mg/day. However, included trials had relatively high rates of loss to follow-up (5% to 80% among patients randomly assigned to metformin), and authors did not report the specific doses of metformin at which patients had discontinued use because of GI adverse effects.

Our study has several potential limitations. First, we aimed to assess high-quality evidence from RCTs, and although our systematic review included 24 RCTs, changes from baseline were not reported in many, preventing the assessment of treatment effects of metformin for many studies. We focused on assessing the mean change and its variance from baseline. Although the exclusion of trials may have reduced the precision of our range of estimates, it likely resulted in more valid treatment effect estimates. Second, substantial heterogeneity was present in the RCTs. Given this heterogeneity and the varying quality of this literature, we focused on a qualitative review and assessed the quality of the RCTs and did not perform a meta-analysis. Third, for most of our secondary end points, there was substantial heterogeneity in observed treatment effects, and results were inconclusive for waist circumference, FPG, the lipid profile, and liver toxicity. Fourth, in the studies, loss to follow-up ranged between 5% and 80% in the metformin arm and between 5% and 50% in the placebo arm. Although the authors of most studies reported similar drop-out rates across treatment arms, drop-out analyses were conducted in only 3 studies.14,27,34  Substantial loss to follow-up may result in biased results.58  In addition, adherence rates to metformin varied across studies from 60% to 90%, which may also result in attenuated treatment effects and reveals the challenges of drug adherence among this population. Fifth, the majority of trials had a high risk of bias, which may have resulted in some bias in estimated treatment effects. Sixth, there was substantial heterogeneity in lifestyle interventions across the studies, which may have resulted in different treatment effects of metformin, depending on the nature of the implemented diet and exercise regimen. Seventh, we were unable to assess treatment effects of metformin across different age groups and developmental stages, which may have been beneficial for the clinical interpretation of results. However, the treatment effects in trials that included only school-aged children or adolescents were fairly consistent for the primary outcomes. Eighth, although a mediation analysis may have been useful, we were unable to quantify how much of the observed effect on insulin resistance could be attributed to weight loss versus a direct drug effect with the aggregated nature of the data. Finally, our study was restricted to the use of metformin monotherapy; therefore, the generalizability of our findings to its use in combination with other therapies is unknown.

There is some evidence that metformin therapy plus lifestyle interventions has a modest favorable effect on BMI z score and insulin resistance and a tolerable safety profile in children and adolescents with obesity. However, the available evidence is of varying quality, and results from higher-quality studies revealed smaller treatment effects, suggesting some uncertainty in its benefits. Nonetheless, metformin may be considered for use as a pharmacologic therapy in this pediatric population because of its modest efficacy, availability, cost, and safety profile. Future RCTs with standardized lifestyle interventions and real-world studies are required to characterize pediatric patients who may benefit most from metformin monotherapy and metformin in combination with other drugs for the treatment of insulin resistance and obesity.

Dr Masarwa developed the study question, conducted the literature search, screening, data extraction, and quality assessments, and wrote the manuscript; Dr Aloe contributed to the conceptualization of the study question, participated in the screening and data extraction, interpreted the data, and critically reviewed the manuscript for important intellectual content; Ms Brunetti conducted data extraction and quality assessment, interpreted the data, and critically reviewed the manuscript for important intellectual content; Drs Henderson and Platt interpreted data and critically reviewed the manuscript for important intellectual content; Dr Filion is the guarantor and supervised the study, conceived the study question, interpreted data, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) (identifier CRD42019126099).

FUNDING: Dr Masarwa is supported by a postdoctoral bursary from the Fonds de Recherche du Québec – Santé (Quebec Foundation for Health Research) and a training stipend from the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program. Ms Brunetti is supported by a doctoral bursary from the Fonds de Recherche du Québec – Santé and a Drug Safety and Effectiveness Cross-Disciplinary Training award. Dr Henderson is supported by a junior II salary support award from the Fonds de Recherche du Québec – Santé. Dr Filion is supported by a senior salary support award from the Fonds de Recherche du Québec – Santé and a William Dawson Scholar award from McGill University.

CI

confidence interval

FPG

fasting plasma glucose

GI

gastrointestinal

HOMA-IR

homeostatic model assessment of insulin resistance

NAFLD

nonalcoholic fatty liver disease

RCT

randomized controlled trial

1
de Onis
M
,
Blössner
M
,
Borghi
E
.
Global prevalence and trends of overweight and obesity among preschool children
.
Am J Clin Nutr
.
2010
;
92
(
5
):
1257
1264
2
Barlow
SE
;
Expert Committee
.
Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report
.
Pediatrics
.
2007
;
120
(
suppl 4
):
S164
S192
3
Ogden
CL
,
Carroll
MD
,
Lawman
HG
, et al
.
Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014
.
JAMA
.
2016
;
315
(
21
):
2292
2299
4
Skinner
AC
,
Ravanbakht
SN
,
Skelton
JA
,
Perrin
EM
,
Armstrong
SC
.
Prevalence of obesity and severe obesity in US children, 1999-2016. [published correction appears in Pediatrics. 2018;142(3):e20181916]
.
Pediatrics
.
2018
;
141
(
3
):
e20173459
5
Caprio
S
.
Insulin resistance in childhood obesity
.
J Pediatr Endocrinol Metab
.
2002
;
15
(
suppl 1
):
487
492
6
Berenson
GS
,
Srinivasan
SR
,
Bao
W
,
Newman
WP
 III
,
Tracy
RE
,
Wattigney
WA
.
Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study
.
N Engl J Med
.
1998
;
338
(
23
):
1650
1656
7
Must
A
,
Jacques
PF
,
Dallal
GE
,
Bajema
CJ
,
Dietz
WH
.
Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935
.
N Engl J Med
.
1992
;
327
(
19
):
1350
1355
8
Boland
CL
,
Harris
JB
,
Harris
KB
.
Pharmacological management of obesity in pediatric patients
.
Ann Pharmacother
.
2015
;
49
(
2
):
220
232
9
Steinberger
J
,
Daniels
SR
;
American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young)
;
American Heart Association Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism)
.
Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism)
.
Circulation
.
2003
;
107
(
10
):
1448
1453
10.
Bristol-Myers Squibb Company
. GLUCOPHAGE (metformin hydrochloride) tablets.
2017
. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039/021202s021s023lbl.pdf. Accessed April 4, 2019
11
American Diabetes Association
.
Type 2 diabetes in children and adolescents
.
Diabetes Care
.
2000
;
23
(
3
):
381
389
12
Evia-Viscarra
ML
,
Rodea-Montero
ER
,
Apolinar-Jiménez
E
, et al
.
The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial
.
J Pediatr Endocrinol Metab
.
2012
;
25
(
1–2
):
41
49
13
Gómez-Díaz
RA
,
Talavera
JO
,
Pool
EC
, et al
.
Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial
.
Metabolism
.
2012
;
61
(
9
):
1247
1255
14
Kendall
D
,
Vail
A
,
Amin
R
, et al
.
Metformin in obese children and adolescents: the MOCA trial
.
J Clin Endocrinol Metab
.
2013
;
98
(
1
):
322
329
15
Burgert
TS
,
Duran
EJ
,
Goldberg-Gell
R
, et al
.
Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance
.
Pediatr Diabetes
.
2008
;
9
(
6
):
567
576
16
Harden
KA
,
Cowan
PA
,
Velasquez-Mieyer
P
,
Patton
SB
.
Effects of lifestyle intervention and metformin on weight management and markers of metabolic syndrome in obese adolescents
.
J Am Acad Nurse Pract
.
2007
;
19
(
7
):
368
377
17
Atabek
ME
,
Pirgon
O
.
Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial
.
J Pediatr Endocrinol Metab
.
2008
;
21
(
4
):
339
348
18
Luong
DQ
,
Oster
R
,
Ashraf
AP
.
Metformin treatment improves weight and dyslipidemia in children with metabolic syndrome
.
J Pediatr Endocrinol Metab
.
2015
;
28
(
5–6
):
649
655
19
Rynders
C
,
Weltman
A
,
Delgiorno
C
, et al
.
Lifestyle intervention improves fitness independent of metformin in obese adolescents
.
Med Sci Sports Exerc
.
2012
;
44
(
5
):
786
792
20
Moher
D
,
Liberati
A
,
Tetzlaff
J
,
Altman
DG
;
PRISMA Group
.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
.
BMJ
.
2009
;
339
:
b2535
21
Stroup
DF
,
Berlin
JA
,
Morton
SC
, et al
.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group
.
JAMA
.
2000
;
283
(
15
):
2008
2012
22
Ouzzani
M
,
Hammady
H
,
Fedorowicz
Z
,
Elmagarmid
A
.
Rayyan-a web and mobile app for systematic reviews
.
Syst Rev
.
2016
;
5
(
1
):
210
23
Higgins
JP
,
Altman
DG
,
Gøtzsche
PC
, et al.;
Cochrane Bias Methods Group
;
Cochrane Statistical Methods Group
.
The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials
.
BMJ
.
2011
;
343
:
d5928
24
Hozo
SP
,
Djulbegovic
B
,
Hozo
I
.
Estimating the mean and variance from the median, range, and the size of a sample
.
BMC Med Res Methodol
.
2005
;
5
:
13
25
Freemark
M
.
Liver dysfunction in paediatric obesity: a randomized, controlled trial of metformin
.
Acta Paediatr
.
2007
;
96
(
9
):
1326
1332
26
Freemark
M
,
Bursey
D
.
The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes
.
Pediatrics
.
2001
;
107
(
4
). Available at: www.pediatrics.org/cgi/content/full/107/4/e55
27
Clarson
CL
,
Brown
HK
,
De Jesus
S
, et al
.
Effects of a comprehensive, intensive lifestyle intervention combined with metformin extended release in obese adolescents
.
Int Sch Res Notices
.
2014
;
2014
:
659410
28
Clarson
CL
,
Mahmud
FH
,
Baker
JE
, et al
.
Metformin in combination with structured lifestyle intervention improved body mass index in obese adolescents, but did not improve insulin resistance
.
Endocrine
.
2009
;
36
(
1
):
141
146
29
Garibay-Nieto
N
,
Queipo-García
G
,
Alvarez
F
, et al
.
Effects of conjugated linoleic acid and metformin on insulin sensitivity in obese children: randomized clinical trial
.
J Clin Endocrinol Metab
.
2017
;
102
(
1
):
132
140
30
Mauras
N
,
DelGiorno
C
,
Hossain
J
, et al
.
Metformin use in children with obesity and normal glucose tolerance–effects on cardiovascular markers and intrahepatic fat
.
J Pediatr Endocrinol Metab
.
2012
;
25
(
1–2
):
33
40
31
Rezvanian
H
,
Hashemipour
M
,
Kelishadi
R
,
Tavakoli
N
,
Poursafa
P
.
A randomized, triple masked, placebo-controlled clinical trial for controlling childhood obesity
.
World J Pediatr
.
2010
;
6
(
4
):
317
322
32
Srinivasan
S
,
Ambler
GR
,
Baur
LA
, et al
.
Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin
.
J Clin Endocrinol Metab
.
2006
;
91
(
6
):
2074
2080
33
van der Aa
MP
,
Elst
MAJ
,
van de Garde
EMW
,
van Mil
EGAH
,
Knibbe
CAJ
,
van der Vorst
MMJ
.
Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial
.
Nutr Diabetes
.
2016
;
6
(
8
):
e228
34
Wilson
DM
,
Abrams
SH
,
Aye
T
, et al.;
Glaser Pediatric Research Network Obesity Study Group
.
Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up
.
Arch Pediatr Adolesc Med
.
2010
;
164
(
2
):
116
123
35
Kay
JP
,
Alemzadeh
R
,
Langley
G
,
D’Angelo
L
,
Smith
P
,
Holshouser
S
.
Beneficial effects of metformin in normoglycemic morbidly obese adolescents
.
Metabolism
.
2001
;
50
(
12
):
1457
1461
36
Love-Osborne
K
,
Sheeder
J
,
Zeitler
P
.
Addition of metformin to a lifestyle modification program in adolescents with insulin resistance
.
J Pediatr
.
2008
;
152
(
6
):
817
822
37
Nadeau
KJ
,
Ehlers
LB
,
Zeitler
PS
,
Love-Osborne
K
.
Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents
.
Pediatr Diabetes
.
2009
;
10
(
1
):
5
13
38
Wiegand
S
,
l’Allemand
D
,
Hübel
H
, et al
.
Metformin and placebo therapy both improve weight management and fasting insulin in obese insulin-resistant adolescents: a prospective, placebo-controlled, randomized study
.
Eur J Endocrinol
.
2010
;
163
(
4
):
585
592
39
Lavine
JE
,
Schwimmer
JB
,
Van Natta
ML
, et al.;
Nonalcoholic Steatohepatitis Clinical Research Network
.
Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial
.
JAMA
.
2011
;
305
(
16
):
1659
1668
40
Pastor-Villaescusa
B
,
Cañete
MD
,
Caballero-Villarraso
J
, et al
.
Metformin for obesity in prepubertal and pubertal children: a randomized controlled trial. [published corrections appear in Pediatrics. 2017;140(5):e20172555 and Pediatrics. 2017;140(6):e20173232]
.
Pediatrics
.
2017
;
140
(
1
):
e20164285
41
Warnakulasuriya
LS
,
Fernando
MMA
,
Adikaram
AVN
, et al
.
Metformin in the management of childhood obesity: a randomized control trial
.
Child Obes
.
2018
;
14
(
8
):
553
565
42
Yanovski
JA
,
Krakoff
J
,
Salaita
CG
, et al
.
Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial
.
Diabetes
.
2011
;
60
(
2
):
477
485
43
Brufani
C
,
Crinò
A
,
Fintini
D
,
Patera
PI
,
Cappa
M
,
Manco
M
.
Systematic review of metformin use in obese nondiabetic children and adolescents
.
Horm Res Paediatr
.
2013
;
80
(
2
):
78
85
44
McDonagh
MS
,
Selph
S
,
Ozpinar
A
,
Foley
C
.
Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger
.
JAMA Pediatr
.
2014
;
168
(
2
):
178
184
45
Park
MH
,
Kinra
S
,
Ward
KJ
,
White
B
,
Viner
RM
.
Metformin for obesity in children and adolescents: a systematic review
.
Diabetes Care
.
2009
;
32
(
9
):
1743
1745
46
Sun
J
,
Wang
Y
,
Zhang
X
,
He
H
.
The effects of metformin on insulin resistance in overweight or obese children and adolescents: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials
.
Medicine (Baltimore)
.
2019
;
98
(
4
):
e14249
47
Al-Shareef
MA
,
Sanneh
AFNS
,
Aljoudi
AS
.
Clinical effect of metformin in children and adolescents with type 2 diabetes mellitus: a systematic review and meta-analysis
.
J Family Community Med
.
2012
;
19
(
2
):
68
73
48
Mühlig
Y
,
Wabitsch
M
,
Moss
A
,
Hebebrand
J
.
Weight loss in children and adolescents
.
Dtsch Arztebl Int
.
2014
;
111
(
48
):
818
824
49
Must
A
,
Anderson
SE
.
Body mass index in children and adolescents: considerations for population-based applications
.
Int J Obes (Lond)
.
2006
;
30
(
4
):
590
594
50
Levri
KM
,
Slaymaker
E
,
Last
A
, et al
.
Metformin as treatment for overweight and obese adults: a systematic review
.
Ann Fam Med
.
2005
;
3
(
5
):
457
461
51
Shalitin
S
,
Phillip
M
.
Role of obesity and leptin in the pubertal process and pubertal growth–a review
.
Int J Obes Relat Metab Disord
.
2003
;
27
(
8
):
869
874
52
Pau
CT
,
Keefe
C
,
Duran
J
,
Welt
CK
.
Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study
.
J Clin Endocrinol Metab
.
2014
;
99
(
5
):
1870
1878
53
Knowler
WC
,
Barrett-Connor
E
,
Fowler
SE
, et al.;
Diabetes Prevention Program Research Group
.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
.
N Engl J Med
.
2002
;
346
(
6
):
393
403
54
Galderisi
A
,
Giannini
C
,
Weiss
R
, et al
.
Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis
.
Lancet Child Adolesc Health
.
2018
;
2
(
10
):
726
735
55
Weiss
R
,
Taksali
SE
,
Tamborlane
WV
,
Burgert
TS
,
Savoye
M
,
Caprio
S
.
Predictors of changes in glucose tolerance status in obese youth
.
Diabetes Care
.
2005
;
28
(
4
):
902
909
56
Kleber
M
,
deSousa
G
,
Papcke
S
,
Wabitsch
M
,
Reinehr
T
.
Impaired glucose tolerance in obese white children and adolescents: three to five year follow-up in untreated patients
.
Exp Clin Endocrinol Diabetes
.
2011
;
119
(
3
):
172
176
57
Copeland
KC
,
Silverstein
J
,
Moore
KR
, et al.;
American Academy of Pediatrics
.
Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents
.
Pediatrics
.
2013
;
131
(
2
):
364
382
58
Akl
EA
,
Briel
M
,
You
JJ
, et al
.
Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review
.
BMJ
.
2012
;
344
:
e2809

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data