Effect of metformin in a novel experimental model of peripheral artery disease

Limited drug therapies for peripheral artery disease (PAD)-related walking impairment exist. There has been recent in repurposing the diabetes medication metformin to treat PAD. Animal studies designed to develop new PAD drug therapies have mainly used a model of temporary hind limb ischemia (HLI). The aim of this study was to test whether metformin improved blood supply and ambulation in a novel mouse model with ongoing HLI. Stable HLI was created in apolipoprotein E deficient mice by a two-stage surgical procedure. Five days after HLI was induced, mice were randomly allocated to receive metformin (n=16; 300mg/kg/day) or vehicle control (n=15) by oral gavage for four weeks. The primary outcome was hind limb blood supply assessed by laser Doppler. Other outcomes included treadmill performance and molecular changes in the ischemic limb. Metformin improved hind limb blood supply (p<0.001), but not physical performance, associated with increased phosphorylation of 5' adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase (p<0.05), reduced expression of thioredoxin interacting protein (p<0.05) and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (p<0.05) in the ischemic muscles and increased circulating nitric oxide levels (p<0.05). Metformin improved blood supply in a novel model of limb ischemia associated with molecular changes previously linked with promoting angiogenesis but these changes did not translate to improved physical performance. The findings suggest that laser Doppler hind limb blood supply may not be an ideal outcome measure to gauge the success of a drug in patients with PAD-related walking impairment.