The underlying mechanisms of metformin on abdominal aortic aneurysms A translational approach

Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with risk of life-threatening rupture. Surgical intervention remains the only definitive treatment, as there is no conclusive evidence for the effectiveness of pharmacological therapies in preventing AAA growth. Previous studies have reported that patients with type 2 diabetes (T2D) treated with metformin exhibit slower AAA growth rates and a reduced risk of AAA-related events. Therefore, we aimed to explore the underlying mechanisms through which metformin may influence AAA.
In this thesis, metformin-associated mechanisms were investigated through analyses of cultured smooth muscle cells (SMCs), aortic tissue, plasma samples, and clinical data from control individuals, non-diabetic (ND) AAA patients, and AAA patients with T2D, with stratification by metformin use where possible. Complementary in vitro metformin stimulation experiments were conducted to differentiate metformin-specific effects from those attributable to T2D itself.
Our findings suggest that metformin induces a metabolic shift from aerobic to anaerobic metabolism, leading to activation of the AMPK and NRF2 signaling pathways. Activation of AMPK promotes mitochondrial biogenesis, whereas activation of NRF2 enhances the antioxidant defense against oxidative stress. Collectively, activation of the AMPK–NRF2 axis may contribute to improved mitochondrial function and underlie the altered SMC phenotype observed following metformin treatment. This phenotype is characterized by increased contractility and metabolic activity together with reduced proliferation, migration and inflammatory responses, and may also be associated with extracellular matrix stabilization. These alterations are reflected in aortic tissue and are also detectable systemically in plasma proteomic and lipidomic profiles.
These findings provide insight into the underlying mechanisms of metformin in AAA and provide a foundation for future analyses of samples from ongoing trials evaluating its effects in ND-AAA patients.