Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial.

Background: Inflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes.

Objectives: We assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications.

Methods: This randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end.

Results: Both groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated.

Conclusions: Oral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.