Table_2_Effect and Safety of Adding Metformin to Insulin Therapy in Treating Adolescents With Type 1 Diabetes Mellitus: An Updated Meta-Analysis of 10 Randomized Controlled Trials.docx

BackgroundThe role of metformin in the treatment of adolescents with type 1 diabetes mellitus (T1DM) remains controversial. We conducted this updated meta-analysis to generate a comprehensive assessment regarding the effect and safety of metformin in treating adolescents with T1DM.
MethodsWe systematically searched PubMed, Embase, and the Cochrane Central Registry of Controlled Trials (CENTRAL) from their inception to November 2021 to identify randomized controlled trials evaluating the efficacy of metformin in the treatment of adolescents with T1DM. The primary outcome was the HbA1c level, and secondary outcomes included the body mass index (BMI), total insulin daily dose (TIDD) (unit/kg/d), hypoglycemia events, diabetes ketoacidosis (DKA) events, and gastrointestinal adverse events (GIAEs). Statistical analysis was conducted using RevMan 5.4 and STATA 14.0.
ResultsTen studies enrolling 539 T1DM adolescents were included. Results suggested that metformin significantly decreased the HbA1c level at 12 months (mean difference [MD])=-0.50, 95% confidence interval [CI]=-0.61 to -0.39, P < 0.01); BMI (kg/m2) at 3 months (MD=-1.05, 95%CI=-2.05 to -0.05, P=0.04); BMI z-score at 6 months (MD=-0.10, 95%CI=-0.14 to -0.06, P<0.01); and TIDD at 3 (MD=-0.13, 95%CI=-0.20 to -0.06, P<0.01), 6 (MD=-0.18, 95%CI=-0.25 to -0.11, P<0.01), and 12 (MD=-0.42, 95%CI=-0.49 to -0.35, P<0.01) months but significantly increased the risk of hypoglycemia events (risk ratio [RR]=3.13, 95%CI=1.05 to 9.32, P=0.04) and GIAEs (RR=1.64, 95%CI=1.28 to 2.10, P<0.01). For remaining outcomes at other time points, no statistical difference was identified. Sensitivity analysis confirmed the robustness of all pooled results.
ConclusionsThe use of metformin might result in decreased BMI (kg/m2), BMI z-score, and TIDD and increased risk of hypoglycemia events and GIAEs in adolescents with T1DM. However, future studies are required to further confirm the optimal dose and duration of metformin therapy.

背景
二甲双胍（metformin）在青少年1型糖尿病（Type 1 Diabetes Mellitus, T1DM）治疗中的应用价值仍存在争议。本研究开展此项更新版meta分析，旨在全面评估二甲双胍用于青少年T1DM治疗的疗效与安全性。
方法
本研究系统检索了PubMed、Embase及Cochrane对照试验中心注册库（Cochrane Central Registry of Controlled Trials, CENTRAL）自建库至2021年11月的文献，以筛选评估二甲双胍治疗青少年T1DM疗效的随机对照试验（randomized controlled trial, RCT）。本研究的主要结局指标为糖化血红蛋白（HbA1c）水平，次要结局指标包括体重指数（body mass index, BMI）、每日总胰岛素剂量（total insulin daily dose, TIDD，单位：unit/kg/d）、低血糖事件、糖尿病酮症酸中毒（diabetes ketoacidosis, DKA）事件及胃肠道不良事件（gastrointestinal adverse events, GIAEs）。统计分析采用RevMan 5.4与STATA 14.0软件完成。
结果
本研究共纳入10项研究，涉及539名青少年T1DM患者。结果显示，二甲双胍可显著降低12个月时的糖化血红蛋白（HbA1c）水平（均差（mean difference, MD）=-0.50，95%置信区间（95% confidence interval, CI）=-0.61~-0.39，P<0.01）、3个月时的体重指数（body mass index, BMI，kg/m²，均差（mean difference, MD）=-1.05，95%置信区间（95% confidence interval, CI）=-2.05~-0.05，P=0.04）、6个月时的BMI z评分（MD=-0.10，95%CI=-0.14~-0.06，P<0.01），以及3个月（均差（mean difference, MD）=-0.13，95%置信区间（95% confidence interval, CI）=-0.20~-0.06，P<0.01）、6个月（均差（mean difference, MD）=-0.18，95%置信区间（95% confidence interval, CI）=-0.25~-0.11，P<0.01）和12个月（均差（mean difference, MD）=-0.42，95%置信区间（95% confidence interval, CI）=-0.49~-0.35，P<0.01）时的每日总胰岛素剂量（total insulin daily dose, TIDD）；但同时显著升高了低血糖事件（相对危险度（risk ratio, RR）=3.13，95%置信区间（95% confidence interval, CI）=1.05~9.32，P=0.04）与胃肠道不良事件（gastrointestinal adverse events, GIAEs）的发生风险（相对危险度（risk ratio, RR）=1.64，95%置信区间（95% confidence interval, CI）=1.28~2.10，P<0.01）。其余时间点的其余结局指标均未观察到统计学差异。敏感性分析证实所有合并结果的稳健性良好。
结论
对于青少年T1DM患者，二甲双胍的使用可降低其体重指数（body mass index, BMI，kg/m²）、BMI z评分及每日总胰岛素剂量（total insulin daily dose, TIDD），同时升高低血糖事件与胃肠道不良事件（gastrointestinal adverse events, GIAEs）的发生风险。但未来仍需开展进一步研究以明确二甲双胍治疗的最优剂量与疗程。