Diabetes mellitus and abdominal aortic aneurysm growth: Clinical evidence and mechanistic insights

Abstract

Background

Diabetes mellitus (DM) has paradoxically been associated with slower abdominal aortic aneurysm (AAA) growth, despite its adverse vascular profile.

Methods

We present a focused synthesis of contemporary longitudinal cohort studies reporting AAA growth rates according to diabetes status and metformin exposure.

Results

Across six independent cohorts, patients with diabetes consistently exhibited slower aneurysm expansion compared with patients without diabetes, with reported differences of approximately 0.5–1.5 mm/year. Three cohorts further demonstrated that metformin use was independently associated with additional attenuation of AAA growth, with an adjusted reduction of approximately 0.3–0.4 mm/year.

Conclusion

Available clinical evidence consistently supports an inverse association between diabetes and AAA growth, with metformin emerging as a potential disease-modifying factor. These findings highlight metabolic modulation as a promising avenue for individualized surveillance strategies and future therapeutic investigation in AAA.

Keywords

abdominal aortic aneurysm diabetes mellitus aneurysm growth rate metformin vascular remodeling

1. Introduction

Abdominal aortic aneurysm (AAA) is a progressive degenerative disease associated with substantial morbidity and mortality.¹ Aneurysm growth rate remains the principal determinant of rupture risk, surveillance intervals, and timing of intervention.² Despite advances in surgical and endovascular repair, no pharmacological therapy has been conclusively shown to slow aneurysm expansion.

Diabetes mellitus (DM) represents a notable paradox in aneurysmal disease. Although diabetes is strongly associated with endothelial dysfunction, inflammation, and accelerated atherosclerosis, epidemiological studies have repeatedly reported a lower prevalence of AAA among patients with diabetes and slower aneurysm growth once AAA is established.^3,4 This inverse association challenges traditional vascular paradigms and has generated increasing interest.

In parallel, attention has focused on antidiabetic therapies, particularly metformin. Beyond glycaemic control, metformin exerts pleiotropic vascular effects, including modulation of inflammatory signaling, oxidative stress, and vascular remodeling. Several contemporary cohort studies suggest that metformin use may be specifically associated with reduced AAA expansion.^5–7

This Short Report summarizes current longitudinal clinical evidence examining the association between DM, metformin use, and AAA growth, and discusses potential mechanisms underlying this paradoxical relationship.

2. Methods

A focused synthesis of longitudinal observational studies was undertaken. Eligible studies included prospective or retrospective cohorts of adult patients with infrarenal AAA undergoing imaging surveillance and reporting aneurysm growth rates stratified by diabetes status and/or metformin exposure. Studies reporting only AAA prevalence, rupture, or cross-sectional diameter were excluded.

Electronic searches of major medical databases (PubMed/MEDLINE, Embase, and the Cochrane Library) were performed to identify contemporary human studies published between 2012 and 2024. Search strategies combined terms related to “abdominal aortic aneurysm,” “diabetes mellitus,” and “metformin.”. Extracted data included cohort characteristics, imaging modality, follow-up duration, diabetes definition, metformin exposure, and reported aneurysm growth rates. Given heterogeneity in study design and outcome reporting, results were synthesized descriptively rather than pooled quantitatively.

3. Results

Six longitudinal cohort studies were identified, comprising 5,901 patients under AAA surveillance (Table 1).^5–10 Study populations were predominantly older males with small-to-medium infrarenal aneurysms, followed for approximately 2–5 years using ultrasound or computed tomography.

Table 1.

Longitudinal cohort studies evaluating diabetes, metformin use, and abdominal aortic aneurysm growth.

First author (Year)	Country/cohort/study design	Sample size/mean age/% male	Exposure of interest	Imaging modality	Mean follow-up/AAA growth outcome	Key findings relevant to diabetes/Metformin
Kristensen et al. (2017)	Denmark (VIVA substudy); Prospective cohort	615; 69 years; 76% male	Diabetes mellitus; HbA1c	Ultrasound	3.1 years; Median growth (mm/year)	Patients with diabetes had significantly slower AAA growth than patients without diabetes; higher HbA1c independently associated with reduced growth
De Rango et al. (2012)	Italy (CAESAR surveillance cohort); Prospective cohort (trial subgroup)	360; 71 years; 90% male	Diabetes mellitus	Ultrasound	2.5 years; Growth and probability of expansion	Diabetes independently associated with reduced likelihood of aneurysm growth during surveillance
Betancourt-Garcia et al. (2019)	USA (Hispanic cohort); Retrospective cohort	187; 73 years; 88% male	Diabetes mellitus	Ultrasound	2.2 years; Mean growth (mm/year)	Patients with diabetes demonstrated markedly lower annual AAA growth compared with patients without diabetes
Fujimura et al. (2016)	USA; Retrospective cohort	58; 72 years; 93% male	Metformin use in type 2 DM	CT/Ultrasound	2.4 years; Annual diameter change	Metformin-treated patients exhibited significantly slower aneurysm progression than non-users
Itoga et al. (2019)	USA (Veterans Affairs cohort); Retrospective cohort	3,435; 69 years; 99% male	Metformin prescription	CT/Ultrasound	3.3 years; Mean growth (mm/year); adjusted models	Metformin use associated with reduced AAA growth compared with patients with diabetes not receiving metformin
Gellatly et al. (2024)	United Kingdom (UKAGS); Prospective multicentre cohort	1,246; 74 years; 82% male	Metformin use	Ultrasound	4.0 years; Linear mixed-effects growth model	Metformin independently associated with ∼0.3–0.4 mm/year reduction in AAA growth after multivariable adjustment

3.1. Diabetes and AAA growth

Across all studies evaluating diabetes status, DM was consistently associated with slower aneurysm growth compared with patients without diabetes.^8–10 Reported differences in expansion ranged from approximately 0.5 to 1.5 mm/year after adjustment for baseline aneurysm diameter, age, smoking status, and cardiovascular comorbidities. No study demonstrated faster AAA growth among patients with diabetes.

3.2. Metformin exposure

Three independent cohorts specifically examined metformin use among patients with type 2 diabetes. In each, metformin exposure was independently associated with further attenuation of aneurysm growth compared with patients with diabetes not receiving metformin.^5–7 The largest contemporary cohort demonstrated an adjusted reduction in AAA expansion of approximately 0.3–0.4 mm/year associated with metformin therapy. These associations persisted after multivariable adjustment.

Overall, the direction of effect was uniform across all included cohorts, supporting a robust inverse association between diabetes, metformin use, and AAA progression.

4. Discussion

This Short Report highlights consistent clinical evidence that diabetes mellitus is associated with slower AAA growth and that metformin use may further attenuate aneurysm progression. Although derived from observational data, the uniformity of findings across independent cohorts strengthens the credibility of this association.

Several biological mechanisms may explain this paradox. Chronic hyperglycaemia promotes formation of advanced glycation end-products, leading to collagen and elastin cross-linking that may enhance extracellular matrix stability within the aneurysm wall.¹¹ Diabetes has also been associated with reduced matrix metalloproteinase activity and attenuated inflammatory signaling—key drivers of aneurysm expansion.

Metformin may exert additional protective effects independent of glycaemic control. Activation of AMP-activated protein kinase by metformin suppresses inflammatory pathways, reduces oxidative stress, and modulates vascular smooth muscle cell behavior, processes directly relevant to aneurysm biology.¹² The consistency of reduced growth rates among metformin-treated patients across cohorts supports its potential role as a disease-modifying agent.

From a clinical perspective, differences of 0.5–1.0 mm/year in aneurysm growth are meaningful and may translate into prolonged surveillance intervals and delayed need for intervention. While current guidelines do not incorporate metabolic status into surveillance strategies, these findings suggest that diabetes and antidiabetic therapy may contribute to individualized risk stratification.

Limitations include the observational nature of available studies and potential residual confounders. Study populations were predominantly male, limiting generalizability. Nevertheless, the convergence of epidemiological, mechanistic, and pharmacological evidence supports further investigation.

5. Clinical implications

Diabetes mellitus and metformin use appear to be associated with slower AAA growth and may influence disease trajectory. While metformin cannot yet be recommended solely for aneurysm stabilization, these findings support prospective trials exploring metabolic modulation as a therapeutic strategy in AAA.

6. Conclusion

Contemporary longitudinal evidence consistently demonstrates that diabetes mellitus is associated with slower abdominal aortic aneurysm growth. Metformin use is further associated with additional attenuation of aneurysm expansion. These findings are biologically plausible, clinically relevant, and support metabolic modulation as a promising avenue for future research in AAA management.

Footnotes

ORCID iDs

Margaret Dimova

Boris Ilchev

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Johnston

Rutherford

Tilson

, et al. Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms. J Vasc Surg 1991; 13(3): 452–458, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. https://doi.org/10.1067/mva.1991.26737

Brown

Powell

. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg 1999; 230(3): 289–296, discussion 296-7. https://doi.org/10.1097/00000658-199909000-00002

De Rango

Farchioni

Fiorucci

, et al. Diabetes and abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2014; 47(3): 243–261. https://doi.org/10.1016/j.ejvs.2013.12.007

Takagi

Umemoto

ALICE (All-Literature Investigation of Cardiovascular Evidence) Group . Diabetes and Abdominal Aortic Aneurysm Growth. Angiology 2016; 67(6): 513–525. https://doi.org/10.1177/0003319715602414

Fujimura

Xiong

Kettler

, et al. Metformin treatment status and abdominal aortic aneurysm disease progression. J Vasc Surg 2016; 64(1): 46–54.e8. https://doi.org/10.1016/j.jvs.2016.02.020

Itoga

Rothenberg

Suarez

, et al. Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population. J Vasc Surg 2019; 69(3): 710–716.e3. https://doi.org/10.1016/j.jvs.2018.06.194

Gellatly

Sweeting

Emin

, et al. Influence of cardiometabolic medications on abdominal aortic aneurysm growth in the UK Aneurysm Growth Study: metformin and angiotensin-converting enzyme inhibitors associated with slower aneurysm growth. Br J Surg 2024; 111(1): znad375. https://doi.org/10.1093/bjs/znad375

Kristensen

Dahl

Rasmussen

, et al. Glycated Hemoglobin Is Associated With the Growth Rate of Abdominal Aortic Aneurysms: A Substudy From the VIVA (Viborg Vascular) Randomized Screening Trial. Arterioscler Thromb Vasc Biol 2017; 37(4): 730–736. https://doi.org/10.1161/ATVBAHA.116.308874

De Rango

Cao

Cieri

, et al. Comparison of surveillance vs. Aortic Endografting for Small Aneurysm Repair (CAESAR) investigators group. Effects of diabetes on small aortic aneurysms under surveillance according to a subgroup analysis from a randomized trial. J Vasc Surg 2012; 56(6): 1555–1563. https://doi.org/10.1016/j.jvs.2012.05.078

10.

Betancourt-Garcia

Vatcheva

Thakur

, et al. Diabetes and Its Effect on Abdominal Aortic Aneurysm Growth Rate in Hispanic Patients. Ann Vasc Surg 2019; 61: 254–260. https://doi.org/10.1016/j.avsg.2019.06.004

11.

Miyama

Dua

Yeung

, et al. Hyperglycemia limits experimental aortic aneurysm progression. J Vasc Surg 2010; 52(4): 975–983. https://doi.org/10.1016/j.jvs.2010.05.086

12.

Luo

Nocon

Fry

, et al. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes 2016; 65(8): 2295–2310. https://doi.org/10.2337/db15-1122