HbA1c, daily insulin dose requirement also found to benefit from treatment.
In individuals with type 1 diabetes (T1DM), cardiovascular disease (CVD) is a major issue and the primary cause of death. Vascular changes can be detected years before progression to CVD. Targeting blood sugar regulation early in patients at high risk of developing T1DM and in those already diagnosed with T1DM, could potentially help reduce vascular dysfunction risk and even reverse changes already made in vascular function. Past studies have shown that in adults with T1DM, metformin reduces HbA1c, BMI, and required insulin doses. It has also been suggested that metformin leads to reduced cardiovascular events and better blood sugar regulation in patients with type 2 diabetes. Studies conducted on children with T1DM suggest the same benefits. However, there is currently no research on how metformin affects vascular function in children with T1DM.
A double blind, randomized, placebo-controlled trial was conducted to evaluate the association between metformin and vascular health in children with T1DM over a 12-month period. The study included a total of 90 children from a Women’s and Children’s Hospital in South Australia. Children were eligible to enroll if they had been diagnosed with T1DM for at least 6 months before the beginning of the study, had a daily insulin dose of greater than 0.5 units/kg, a BMI above the 50th percentile for age and sex, and were 8 to 18 years of age. Children were randomly divided into two groups to receive either the metformin intervention or the placebo intervention. Children who weighed 60kg or greater received 1gm of metformin twice daily and those who weighed less than 60kg received 500mg twice daily. Doses were then increased to the complete dose over a period of 2 to 6 weeks.
Follow-up was conducted at 3, 6, and 12 months from the start of the study. Vascular function was obtained at baseline and at every follow-up visit using the brachial artery ultrasound (flow mediated dilation (FMD)/glyceryl trinitrate mediated dilation (GTN)). HbA1C, insulin dose, and BMI were among some of the other outcomes measured. To assess safety and toleration, participants received questionnaires over the phone every 2 weeks for up to 3 months, then every month to obtain information on side effects and to assess the need for therapy adjustments. To assess patient compliance to therapy, a pill count was conducted at follow-up visits along with the use of a Medication Event Monitoring System (MEMS).
Results show that vascular function defined by GTN improved over the 12-month period by 3.3% in the metformin intervention group regardless of HbA1c when compared to the placebo group (95% CI 0.3 to 6.3; P=0.03). GTN was found to be the highest in the metformin group at 3 months when compared to placebo. Children in the metformin group also experienced significant improvement (P=0.001) in HbA1c levels at 3 months (8.4%; 95% CI 8.0 to 8.8) (68mmol/mol; 95% CI 64 to 73) when compared to the placebo group (9.3%; 95% CI 9.0 to 9.7). At 12 months, the overall difference between HbA1c improvement between the two groups was lower but remained a significant 1.0% (95% CI 0.4 to 1.5) 10.9mmol/mol (95% CI 4.4 to 16.4), P=0.001. In addition, it was found that children in the metformin group had a decreased insulin dose requirement of 0.2 units/kg/day throughout the 12-month period compared to those in the placebo group (95% CI 0.1 to 0.3, P=0.001).
The following study determined that children with T1DM with above average BMIs and taking metformin saw a significant improvement in vascular smooth muscle function compared to those not taking metformin. The study suggested that in addition to vascular health, metformin also improved HbA1c levels and reduced total daily insulin dose. It was found that improvements in both vascular function and HbA1c were the highest at 3 months. This is most likely due to medication adherence being the highest around 3 months. The study did provide important clinical findings but limitations should be considered. The 12-month duration of the study was only long enough to identify changes in vascular function but not those in vascular structure. Also, the study was powered to identify changes in vascular function but did not consider other vascular markers.
- In children with above average weight and who were diagnosed with type 1 diabetes, metformin provides a significant improvement in vascular smooth muscle function.
- Metformin provides a significant improvement in HbA1c levels in children with type 1 diabetes.
- In addition to vascular health and HbA1c benefits, metformin further aids in reducing daily insulin dose in children with type 1 diabetes.
Anderson JJA, Couper JJ, Giles LC, et al. Effect of Metformin on vascular function in children with type 1 diabetes: A 12 month randomized controlled trial. 2017. J Clin Endocrinol Metab. 2017; 0: 1-16.
Graciela Nieto, Pharm. D. Candidate 2018, LECOM School of Pharmacy