Effect of Metformin on Vascular Function in Children With Type 1 Diabetes: A 12-Month Randomized Controlled Trial

Context: Children with type 1 diabetes have vascular dysfunction preceding atherosclerosis. Early interventions are needed to reduce cardiovascular disease. Objective: To evaluate the effect of metformin on vascular function in children with type 1 diabetes. Design: Twelve-month double-blind, randomized, placebo-controlled trial. Setting: Tertiary pediatric diabetes clinic. Participants: Ninety children (8 to 18 years of age), >50th percentile body mass index (BMI), with type 1 diabetes. Intervention: Metformin (up to 1 g twice a day) or placebo. Main Outcome Measure: Vascular function measured by brachial artery ultrasound [flow-mediated dilatation/glyceryl trinitrate-mediated dilatation (GTN)]. Results: Ninety participants were enrolled [41 boys, 13.6 (2.5) years of age, 45 per group], 10 discontinued intervention, and 1 was lost to follow-up. On metformin, GTN improved, independent of glycosylated hemoglobin (HbA1c), by 3.3 percentage units [95% confidence interval (CI) 0.3, 6.3, P = 0.03] and insulin dose reduced by 0.2 U/kg/d (95% CI 0.1, 0.3, P = 0.001) during 12 months, with effects from 3 months. Metformin had a beneficial effect on HbA1c at 3 months (P = 0.001) and difference in adjusted HbA1c between groups during 12 months was 1.0%; 95% CI 0.4, 1.5 (10.9 mmol/mol; 95% CI 4.4, 16.4), P = 0.001. There were no effects on carotid/aortic intima media thickness, BMI, lipids, blood pressure, or other cardiovascular risk factors. Median (95% CI) adherence, evaluated by electronic monitoring, was 75.5% (65.7, 81.5), without group differences. More gastrointestinal side effects were reported on metformin (incidence rate ratio 1.65, 95% CI 1.08, 2.52, P = 0.02), with no difference in hypoglycemia or diabetic ketoacidosis. Conclusions: Metformin improved vascular smooth muscle function and HbA1c, and lowered insulin dose in type 1 diabetes children. These benefits and good safety profile warrant further consideration of its use.