Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort

Abstract

Background: Recent reports suggest that the negative association between diabetes mellitus and abdominal aortic aneurysm (AAA) may be driven by metformin, the world's most common antidiabetic drug rather than diabetes per se. We sought to investigate the association among AAA growth rate, chemokine profile, and metformin prescription in a contemporary Swedish cohort. Methods: Patients under surveillance for small AAA were identified at 4 Swedish vascular centers with active AAA screening programs. Annual AAA growth rate, medical history, and prescribed medications were recorded for linear regression analysis. In a subset of patients with AAA and control subjects without AAA or diabetes, plasma samples were available and analyzed for 40 inflammatory chemokines. Results: A total of 526 patients were included for AAA growth analysis: 428 without type 2 diabetes mellitus (T2DM), 65 with T2DM and metformin prescription, and 33 with T2DM but without metformin prescription. Patients were included from 2005 to 2017 with mean follow-up of 3.2 (1.7) years and median annual AAA growth rate 1.6 mm, range À4.8 to 15.4 mm. Mean (standard deviation) annual AAA growth rates were 2.3 (2.2) mm in non-T2DM patients versus 1.1 (1.1) mm in patients with T2DM with metformin prescription and 1.6 (1.4) mm among those with T2DM without metformin prescription. With non-T2DM patients as reference in an unadjusted and 2 adjusted models, metformin prescription was significantly associated with reduced AAA growth rate (P < 0.001, P ¼ 0.005, and P ¼ 0.024, respectively), but not T2DM without metformin prescription (P ¼ 0.137, P ¼ 0.331, and P ¼ 0.479, respectively). Among 240 patients with AAA (152 without T2DM, 51 with T2DM and metformin, and 37 with T2DM without metformin) and 59 without AAA or T2DM, metformin prescription was associated with reduced expression of chemokines representing all classes of leukocytes. Conclusions: Metformin prescription is associated with reduced AAA growth rate, possibly mediated by broad anti-inflammatory effects. A randomized controlled trial is needed to determine what role metformin may play in AAA disease, particularly in the absence of T2DM.

Inhibition of angiotensin-induced aortic aneurysm by metformin in apolipoprotein E–deficient mice

“… 18 , 19 , 20 The results from recent observational studies have suggested that the protective effect of diabetes on AAA is more likely a result of the antidiabetic treatment, specifically metformin. 3 , 4 , 8 …”

“…1 , 2 , 3 , 4 This might, in part, be attributable to the oral hypoglycemic drug metformin, which we, and others, have shown. 5 , 6 , 7 , 8 Metformin is the world's most commonly prescribed drug for type 2 diabetes and has been widely used for >60 years owing to an excellent safety profile, positive metabolic effects such as lowering cholesterol levels, and the ability to reduce cardiovascular events, over and above its effects on glycemic control. 2 , 5 , 9 …”

The Protective Effect of Metformin on Abdominal Aortic Aneurysm: A Systematic Review and Meta-Analysis

“…Studies exploring the mechanism that metformin is beneficial for AAA patients are limited. Although an article claimed that metformin could downregulate serum chemokines in those taking metformin, it demonstrated little correlation between the level of chemokines and aneurysm growth rate ( 26 ). The effect of metformin on AAA in patients without T2DM remained unknown.…”

“…They found there was no significant difference of inflammatory cells and cytokines, such as interferon-g and interleukins, between patients taking metformin or not (28). However, Unosson et al analyzed samples from 240 patients with AAA and discovered chemokine expression was significantly decreased in those using metformin (26), but the correlation between chemokine level and aneurysm growth rate was not clear. More studies need to be done to prove the association between metformin prescription and AAA expansion and inflammation.…”

Increased arterial stiffness in males with abdominal aortic aneurysm

“…Instead, DM seems to have a protective effect on AAA, both through pathophysiological mechanisms and antidiabetics drugs (Raffort et al., 2018). Metformin prescription in AAA patients has also shown to be associated with reduced AAA growth rate (Unosson et al., 2020).…”