Does metformin improve vascular health in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial

Abstract

BackgroundCardiovascular disease is the leading cause of mortality in Type 1 diabetes (T1D). Vascular dysfunction is an early and critical event in the development of cardiovascular disease. Children with T1D have vascular dysfunction therefore early interventions to improve vascular health are essential to reduce cardiovascular mortality in T1D. Metformin is an insulin sensitising agent which is known to improve vascular health outcomes in type 2 diabetes (T2D) and other individuals with insulin resistance. It has been used safely in children and adolescents with T2D for over 10 years. This study aims to assess the effect of metformin on vascular health in children with T1D.Methods/DesignThis study is a 12 month, double blind, randomised, placebo controlled trial to determine the effect of metformin on vascular health in children (age 8–18) with T1D. The sample size is 76 with 38 children in the metformin group and 38 children in the placebo group. Vascular health and biochemical markers will be measured at baseline, 3, 6 and 12 months. Vascular function will be measured using flow mediated dilatation and glyceryl trinitrate mediated dilatation of the brachial artery and vascular structure will be measured with carotid and aortic intima media thickness, using standardised protocols.DiscussionThis study will be the first to investigate the effect of metformin on vascular health in children with T1D. It will provide important information on a potential intervention to improve cardiovascular morbidity and mortality in this population at high risk from cardiovascular disease.Trial registrationAustralia New Zealand Clinical Trials Registry ACTRN12611000148976

Prevalence of cardiovascular risk factors in youth with type 1 diabetes and elevated body mass index

“…Our findings highlight the importance of obesity prevention for all youth and the need for more aggressive measures to prevent CVD in adulthood. Ongoing clinical trials with metformin on obese youth with T1D may improve CVD risk factors that are related to insulin resistance [28,29].…”

Efficacy and Safety of Metformin for Patients with Type 1 Diabetes Mellitus: A Meta-Analysis

“…28 Another double-blind, randomized, placebo-controlled trial will provide important information on a potential intervention of metformin to improve cardiovascular morbidity and mortality in children with T1DM at high risk from cardiovascular disease. 29 In order to reduce gastrointestinal AEs, medication (metformin or placebo) in all studies was taken during or at the end of meals. Although a higher gastrointestinal AE risk was shown in the metformin treatment group in patients with T1DM, only four patients in the metformin group in all eight studies were withdrawn because of digestive symptoms.…”

Early atherosclerosis is associated with retinal microvascular changes in adolescents with type 1 diabetes

“…Ninety adolescents aged 8‐18 years with type 1 diabetes were recruited consecutively from August 2011 to June 2015 and all were part of a randomized placebo‐controlled trial evaluating the effects of metformin on vascular function as the primary outcome . The study was approved by the Human Research Ethics Committees of the recruitment sites (Women's and Children's Hospital HREC 2327/12/13 and Flinders Medical Centre HREC 443.12).…”

“…However, there are no studies evaluating the relationship between early changes in the macro and microvascular beds in children with type 1 diabetes before clinical retinopathy develops. We therefore aimed to investigate changes in atherosclerosis (cIMT and aIMT) and retinal microvascular structure both cross‐sectionally and longitudinally in adolescents with type 1 diabetes who were studied over 12 months in a clinical trial [ACTRN12611000148976] . We hypothesized that those adolescents with type 1 diabetes who have thicker IMT have greater structural changes in their retinal vasculature.…”