Efficacy and safety of variable-dose metformin as adjunctive therapy to insulin in adolescents with type 1 diabetes mellitus: a systematic review and network meta-analysis.

Background: Adolescent Type 1 Diabetes (T1D) is complicated by insulin resistance, dyslipidemia, and heightened cardiovascular risk. As adjunctive metformin therapy lacks optimized dosing, we conducted a network meta-analysis (NMA) to rigorously assess the dose-dependent efficacy and safety of metformin combined with insulin in this population.

Methods: Totally 764 adolescents (aged 10-19 years) met inclusion criteria were involved. We assessed five metformin regimens: 1.0 g/day, 1.7 g/day, 2.0 g/day, weight-based (≤ 60 kg:1.0 g/day;≥60 kg:2.0 g/day), and multi-tiered weight-based (< 50 kg:1.0 g;50-75 kg:1.5 g;≥75 kg:2.0 g). Outcomes included HbA1c, BMI/BMI-Z, insulin dose, lipid profile, and adverse events. A Bayesian NMA was performed using R 4.4.1, with effect sizes reported as mean differences (MD) or relative risks (RR) with 95% confidence intervals (CI). Surface under the cumulative ranking curve (SUCRA) values ranked interventions.

Results: Consequently, metformin 2.0 g/day significantly reduced BMI (MD=-0.6 kg/m², 95%CI:-0.68, -0.52) and LDL-C (MD=-12.78 mg/dL, 95%CI:-21.17, -0.49) versus placebo. Doses of 1.0 g/day, 2.0 g/day, and the 60 kg weight-based regimen significantly reduced daily insulin requirements. Metformin 2.0 g/day and the 50 kg weight-based regimen reduced total cholesterol. No regimen significantly lowered HbA1c or triglycerides versus placebo. All doses demonstrated safety profiles comparable to placebo regarding gastrointestinal events, hypoglycemia, diabetic ketoacidosis (DKA), and transaminase elevations (RRs not significant).

Conclusion: To sum up, adjunctive metformin at 2.0 g/day offers significant benefits in weight management, insulin dose reduction, and lipid improvement (LDL-C, total cholesterol) for adolescents with T1D, with a favorable safety profile across all doses, which will represent a viable therapeutic option.