Diabetes mellitus is a common metabolic disorder that is associated with multiple vascular dysfunctions. Despite the detrimental vascular consequences of diabetes, there is consistent evidence that diabetes is associated with lower incidence and less severity of abdominal aortic aneurysms (AAAs).
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On the basis of retrospective studies and meta-analysis of human data,5
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a compelling hypothesis is that metformin, a drug that is commonly used to treat diabetes, improves AAAs. Several animal studies have also reported that metformin prevents AAA formation in mice.8
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However, it remains unknown whether metformin protects against AAAs when it is already formed. The publication by Xu et al1
determined the effect of metformin on pre-existing AAAs in mice.In the study by Xu et al, AAAs were induced by intra-infrarenal aortic perfusion of porcine pancreatic elastase in adult male C57BL/6J mice. Maximal luminal diameters of infrarenal aortas were monitored by ultrasound imaging before the surgery and 3 days after the surgery to confirm that all mice had luminal dilatation for >50% at 3 days after the surgery. Four days after the surgery, mice were allocated into four groups and provided with vehicle, metformin alone, metformin with an AMP-activated protein kinase (AMPK) antagonist, or an AMPK agonist alone for 10 days. The dose of metformin was 250 mg/kg/d. The authors noted that this dose represents the maximal dose for treating type 2 diabetes in a patient with 70 kg of body weight. The inclusion of an AMPK agonist or antagonist was to determine whether metformin has effects on AAAs via its interaction with AMPK.
The authors made several major findings. First, as measured by ultrasound imaging 3 or 10 days after drug administration, namely, 7 or 14 days after the surgery, metformin led to smaller luminal diameters of infrarenal aortas, compared with vehicle. This beneficial effect was modestly attenuated by the combination of metformin and an AMPK antagonist, supporting the notion that metformin interacting with AMPK contributes to reduced progression of AAAs. The involvement of AMPK was also supported by the finding that AMPK agonism alone mitigated AAA dilatations, compared with vehicle. This study compared the four groups at each interval but did not determine differences in luminal diameters at different intervals within each group. Therefore, it is unclear whether metformin halted or regressed AAA progression. The authors also took efforts to explore possible molecular mechanisms by which metformin diminished the progression of pre-existing AAAs. The authors found that in mice administered metformin, the percent of interferon-γ-expressing T cells was lower in spleens, whereas the percent of monocytes was higher in peripheral blood and spleens, implicating that metformin regulated immune responses. However, whether this is causative to the improved AAA progression by metformin is unclear.
Overall, this study provides solid evidence that metformin mitigates pre-existing AAA progression that is induced by intra-aortic perfusion of elastase. This study started drug administration 4 days after surgery (initiation stage of AAAs). It would be important that future studies determine whether metformin can alleviate AAAs in more advanced stages. It is worth noting that AAAs have complex pathogenesis and heterogeneous pathologies. In future studies, it will also be helpful for metformin to be investigated in a mouse model that has frequent aortic rupture to determine whether metformin is beneficial to this fatal consequence of human AAAs.
The opinions or views expressed in this commentary are those of the authors and do not necessarily reflect the opinions or recommendations of JVS: Vascular Science or the Society for Vascular Surgery.
References
- Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysm.JVS Vasc Sci. 2023;
- The effect of diabetes on abdominal aortic aneurysm growth over 2 years.J Vasc Surg. 2022; 75: 1211-1222.e1
- Diabetes and abdominal aortic aneurysms.Eur J Vasc Endovasc Surg. 2014; 47: 243-261
- The aneurysm detection and management study screening program: validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators.Arch Intern Med. 2000; 160: 1425-1430
- Metformin prescription and aortic aneurysm: systematic review and meta-analysis.Heart. 2019; 105: 1351-1357
- Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population.J Vasc Surg. 2019; 69: 710-716.e3
- Association between metformin prescription and growth rates of abdominal aortic aneurysms.Br J Surg. 2017; 104: 1486-1493
- Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE(-/-) mice.Cell Biosci. 2019; 9: 68
- Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E-deficient mice.JVS Vasc Sci. 2021; 2: 33-42
- Metformin protects against abdominal aortic aneurysm by Atg7-induced autophagy.Adv Clin Exp Med. 2022; 31: 59-69
Article info
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Published online: March 13, 2023
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The authors’ research work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL139748 and R35HL155649) and the American Heart Association SFRN in Vascular Disease (18SFRN33960163). The content in this editorial is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS-Vascular Science policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
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