Effects of Metformin Added to Insulin in Adolescents with Type 1 Diabetes: An Exploratory Crossover Randomized Trial

Background. To comprehensively assess the effects of metformin added to insulin on metabolic control, insulin sensitivity, and cardiovascular autonomic function in adolescents with type 1 diabetes. Materials and Methods. This was an exploratory, crossover, randomized trial conducted in adolescents with type 1 diabetes aged 12-18 years old. Participants were randomly received metformin (≤1000 mg/d) added to insulin for 24 weeks followed by insulin monotherapy for a subsequent 24 weeks or vice versa. Blood pressure, body mass index, insulin dose, estimated insulin sensitivity, glycated hemoglobin A1c (HbA1c), and lipid profiles were measured, with a 72-hour continuous glucose monitoring and 24-hour Holter monitoring performed at baseline, 24, and 50 weeks for the assessments of glucose variability and heart rate variability. Results. Seventeen patients with <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mtext>mean</a:mtext> <a:mo>±</a:mo> <a:mtext>SD</a:mtext> </a:math> age <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"> <c:mn>14.4</c:mn> <c:mo>±</c:mo> <c:mn>2.3</c:mn> <c:mtext> </c:mtext> <c:mtext>years</c:mtext> </c:math> , body mass index <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"> <e:mn>18.17</e:mn> <e:mo>±</e:mo> <e:mn>1.81</e:mn> <e:mtext> </e:mtext> <e:mtext>kg</e:mtext> <e:mo>/</e:mo> <e:msup> <e:mrow> <e:mtext>m</e:mtext> </e:mrow> <e:mrow> <e:mn>2</e:mn> </e:mrow> </e:msup> </e:math> , median (IQR) diabetes duration 4.50 (3.58, 6.92) years, and HbA1c 9.0% (8.5%, 9.4%) were enrolled. The between-group difference in HbA1c of 0.28% (95% CI -0.39 to 0.95%) was not significant ( <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"> <g:mi>P</g:mi> <g:mo>=</g:mo> <g:mn>0.40</g:mn> </g:math> ). Changes in body mass index, insulin dose, blood pressure, lipid profiles, and estimated insulin sensitivity were similar for metformin add-on vs. insulin monotherapy. Glucose variability also did not differ. Compared with insulin monotherapy, metformin add-on significantly increased multiple heart rate variability parameters. Conclusions. Metformin added to insulin did not improve metabolic control or glucose variability in lean/normal-weight adolescents with type 1 diabetes. However, metformin added to insulin significantly increased heart rate variability, suggesting that metformin might improve cardiovascular autonomic function in this population.