Metformin and beyond: glucose-lowering therapy as a potential modulator of abdominal aortic aneurysm growth and stability- systematic review with narrative synthesis

Background

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with rupture mortality exceeding 80%. Although diabetes mellitus (DM) is a major risk factor for atherosclerotic cardiovascular disease, a growing body of epidemiological and experimental evidence suggests an inverse association between DM and AAA development, progression, and rupture. Increasing attention has focused on glucose-lowering therapies—particularly metformin—as potential modulators of aortic wall remodeling.

Methods

We conducted a systematic literature search followed by a narrative synthesis of evidence from observational studies, randomised controlled trials (RCTs), and experimental research evaluating the association between diabetes mellitus, antidiabetic therapies, and abdominal aortic aneurysm. PubMed, Scopus, and the Cochrane Library were searched through February 2025 to identify relevant primary human studies assessing the impact of DM and glucose-lowering therapies on AAA incidence, growth, rupture, and related outcomes. Experimental animal models and mechanistic studies were reviewed separately to explore biological plausibility and underlying pathways.

Results

Across more than 30 population-based cohorts and registry studies, DM was consistently associated with a lower likelihood of AAA development, slower aneurysm growth, and reduced rupture risk. Longitudinal studies reported attenuated aneurysm expansion among diabetic individuals, with reductions in growth rates ranging approximately from 0.3 to 0.8 mm/year. Experimental and mechanistic studies were broadly consistent with these associations and are summarized separately. Among glucose-lowering therapies, metformin emerged as the most extensively studied agent, with observational data suggesting slower AAA progression independent of glycaemic control. Early RCTs confirm feasibility and safety but remain underpowered for definitive clinical outcomes. Evidence for newer drug classes, including SGLT2 inhibitors and GLP-1 receptor agonists, is currently limited to preclinical models.

Conclusions

Current evidence supports a biologically plausible and epidemiologically consistent inverse association between diabetes mellitus and AAA development and progression. Metformin appears to exert stabilising effects on aneurysm biology through pleiotropic vascular mechanisms beyond glucose lowering. Definitive confirmation from adequately powered, event-driven randomised trials is still required. Glucose-lowering therapy—particularly metformin—may represent a promising future pharmacologic adjunct for delaying AAA progression and improving long-term outcomes.

Significance

What is currently known about this topic?

What is the key research question?

What is new?

How might this study influence clinical practice?

Diabetes mellitus is inversely associated with AAA. Diabetic patients show slower aneurysm growth and fewer ruptures. Metformin exhibits vascular anti-inflammatory and antioxidative effects.

Can glucose-lowering therapy, particularly metformin, modulate AAA growth and stability? Keywords: abdominal aortic aneurysm; Diabetes mellitus; metformin; vascular remodeling; AMPK; glucose-lowering therapy.

This review provides an up-to-date synthesis of human, experimental, and registry data on the DM–AAA link, incorporating evidence up to February 2025, including the first randomized trial of metformin in non-diabetic AAA patients and a contemporary umbrella review of medical therapies. It offers a cross-level integration of epidemiologic, mechanistic, and pharmacologic findings and derives pragmatic quantitative estimates of the association between DM, metformin, and AAA growth. It also compares the vascular effects of newer glucose-lowering agents (SGLT2 inhibitors and GLP-1 receptor agonists) and highlights key uncertainties and priorities for future randomized trials.

Supports exploration of antidiabetic drugs as adjunct therapy to slow AAA progression.

Introduction

Background

Abdominal aortic aneurysm (AAA) is a prevalent and potentially fatal vascular condition characterized by progressive dilation of the abdominal aorta, typically defined as a diameter ≥ 3.0 cm or an increase exceeding 50% of the normal vessel size. Contemporary population-based screening programs report a lower prevalence of AAA, typically 1.2–1.6% in men aged 65–74 years and 0.3–0.6% in women, reflecting declining smoking rates and improved cardiovascular risk factor control [1, 2]. Despite substantial advances in diagnostic imaging, screening strategies, and minimally invasive repair techniques such as endovascular aneurysm repair (EVAR), the prevention of aneurysm formation and progression remains a critical unmet clinical need [3].

The pathogenesis of AAA is complex and multifactorial, involving chronic inflammation, extracellular matrix (ECM) degradation, oxidative stress, and vascular smooth muscle cell (VSMC) apoptosis, resulting in progressive weakening of the aortic wall [4, 5]. Classical risk factors include advanced age, male sex, smoking, family history, and arterial hypertension, which together account for the majority of disease burden [6, 7]. Diabetes mellitus (DM)—a well-established driver of atherosclerosis and its forms coronary artery disease, and peripheral arterial occlusive disease—has repeatedly been linked to a lower risk of developing AAA [8–10]. This inverse association between DM and AAA has been repeatedly reported across screening studies, cohorts, and registries.

The paradoxical association between DM and AAA

Over the past three decades, multiple population-based screening studies, case–control analyses, and meta-analyses have consistently demonstrated an inverse association between DM and AAA risk. Individuals with DM show a 20–40% lower prevalence of AAA compared with non-diabetic populations [9–12]. In addition to reduced prevalence, patients with DM exhibit a slower aneurysm growth rate, with a mean difference of 0.3 to 0.8 mm/year, and a lower incidence of aneurysm rupture after adjustment for age, sex, smoking, and hypertension [13–15]. These findings have been consistent across diverse populations in Europe, North America, and Asia, as demonstrated by data from the ADAM Trial, MASS Trial, and The Health in Men studies [16–18], as well as national registries from Sweden, Spain, and Denmark [19–21]. Interestingly, the protective association appears to extend to both men and women, although the absolute prevalence of AAA remains lower in females [22].

This pattern stands in contrast to the typical cardiovascular profile of individuals with DM, who usually present with systemic atherosclerosis, endothelial dysfunction, and chronic inflammation. The consistent signal of reduced AAA incidence and slower progression therefore underscores the paradoxical nature of the DM–AAA association and has prompted extensive investigation into the metabolic and pharmacologic mechanisms that may confer this apparent protection [23, 24]. Importantly, this association appears to extend beyond aneurysm formation and growth. Several national registry studies reported lower rupture incidence and improved aneurysm-related outcomes among individuals with diabetes mellitus. Taken together, these observational data suggest that diabetes is associated with differences across multiple stages of AAA disease—development, expansion, and clinical events—although causal inference cannot be drawn from these study designs.

Proposed biological mechanisms

Several intrinsic features of the diabetic metabolic environment may contribute to the observed inverse association between DM and AAA. Chronic hyperglycaemia promotes non-enzymatic glycation of ECM proteins, leading to the accumulation of advanced glycation end-products (AGEs) and increased collagen and elastin cross-linking. This process increases wall stiffness and may mechanically limit aortic dilatation [25, 26]. DM is also associated with altered intraluminal thrombus (ILT) composition, characterized by denser fibrin networks and relative hypofibrinolysis, in part mediated by elevated plasminogen activator inhibitor-1 (PAI-1), which may reduce protease diffusion toward the aortic wall and thereby stabilize the aneurysm [27, 28]. In addition, experimental data suggest that hyperglycaemia and AGEs can modulate inflammatory and proteolytic pathways, shifting local cell phenotypes toward reduced matrix metalloproteinase (MMP) activity and attenuated elastin degradation. Collectively, these DM-related alterations may create a vascular environment less susceptible to progressive aneurysmal degeneration. The detailed mechanistic and pharmacologic pathways underpinning this paradox are explored further in the Discussion section.

Mechanisms related to glucose- Lowering pharmacotherapy

Metformin-mediated vascular mechanisms beyond glycemic control

In contrast, several mechanistic effects appear to be mediated primarily by specific glucose-lowering medications, most prominently metformin. Among all antidiabetic drugs, metformin has attracted the most attention for its potential vascular-protective properties. Beyond its glucose-lowering action, metformin inhibits complex I of the mitochondrial respiratory chain, decreases Adenosine Triphosphate (ATP) and increases adenosine monophosphate/ adenosine diphosphate (AMP/ADP) levels, activating the AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism and inflammation [29, 30]. AMPK activation leads to inhibition of Nuclear Factor Kappa-B (NF-κB)–mediated inflammatory signaling, decreased lipogenesis, increased fatty acid oxidation, reduced hepatic glucose output, suppression of oxidative stress, and modulation of VSMC phenotype from synthetic to contractile [31, 32].

Experimental studies have demonstrated that metformin prevents aneurysm formation and slows progression in animal models of AAA induced by angiotensin II or elastase perfusion [33]– [34]. These effects are mediated by reduced macrophage activation, lower MMP expression, and diminished reactive oxygen species (ROS) production. Observational human data reinforce these findings: several large cohort studies report that diabetic patients treated with metformin have smaller baseline aneurysm diameters, slower expansion rates, and lower perioperative mortality compared to diabetics on other therapies or nondiabetic controls [35]– [36].

The first Randomized Controlled Trial (RCT) evaluating metformin in nondiabetic patients with small AAA—the Eilenberg et al. trial (EJVES, 2025)—demonstrated feasibility and excellent safety, but was underpowered to detect differences in aneurysm growth [37]. The ongoing MAT (Metformin Aneurysm Trial) Trial, a multicenter RCT designed with hard clinical endpoints (AAA rupture, repair, or death), is expected to provide definitive evidence regarding metformin’s therapeutic potential [38].

Expanding the therapeutic landscape: SGLT2 inhibitors and GLP-1 agonists

The emergence of newer antidiabetic agents has expanded interest in pharmacologic vascular protection. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin and empagliflozin, exert favorable effects on oxidative stress, endothelial function, and inflammation [39]. In experimental models, SGLT2 inhibition reduces aneurysm formation and rupture rates, potentially through modulation of mitochondrial metabolism and inhibition of macrophage infiltration [40].

Similarly, glucagon-like peptide-1 (GLP-1) receptor agonists such as liraglutide and semaglutide have demonstrated anti-inflammatory and anti-proteolytic effects in vascular tissue. These agents reduce MMP activity, inhibit smooth muscle cell apoptosis, and attenuate aneurysmal dilation in murine models [41]. Although clinical data remain preliminary, the translational potential of these therapies warrants further investigation.

Rationale and objectives

The paradoxical relationship between DM and AAA offers a unique opportunity to explore metabolic modulation of vascular degeneration. Understanding whether DM and glucose-lowering therapy exert direct protective effects on the aortic wall has implications that extend beyond glycemic control. If confirmed, pharmacological agents such as metformin could represent novel adjunctive strategies to delay AAA progression, particularly in patients not eligible for surgical intervention.

The aim of this systematic review is therefore to synthesize current epidemiological, clinical, and experimental evidence regarding the role of DM and antidiabetic therapies in AAA pathophysiology. Specifically, we evaluate (1) the epidemiological association between DM and AAA incidence, (2) mechanistic data explaining potential protective pathways, and (3) the therapeutic implications of metformin and emerging antidiabetic agents in modulating aneurysm growth and stability. Unlike previous meta-analyses, which largely focused either on epidemiological associations or on aneurysm growth in isolation, this review integrates three complementary levels of evidence: contemporary population-based and registry data, mechanistic experimental studies, and drug-specific effects of glucose-lowering therapies (including metformin, SGLT2 inhibitors and GLP-1 receptor agonists). By incorporating studies published up to February 2025, including the first RCT of metformin in non-diabetic AAA patients, we aim to provide a contemporary and clinically oriented synthesis of this rapidly evolving field.

Methods

Study design

Given the clinical, methodological, and biological heterogeneity of the available evidence, quantitative meta-analysis was not feasible. Accordingly, a systematic review with narrative synthesis was undertaken, integrating epidemiological studies, interventional trials, and experimental mechanistic data to provide a comprehensive overview of the relationship between diabetes mellitus, antidiabetic therapy, and abdominal aortic aneurysm. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure transparent reporting of the search strategy, study selection, and evidence synthesis, despite the absence of quantitative pooling [42]. The protocol was prospectively designed to evaluate the relationship between DM, glucose-lowering therapy, and AAA in human and experimental studies. Because this review analyzed published data, no ethical approval or patient consent was required.

Eligibility criteria

Eligible studies included original primary research articles, comprising observational cohort studies, case–control studies, cross-sectional studies, and RCT evaluating the association between diabetes mellitus, glucose-lowering therapies, and abdominal aortic aneurysm incidence, progression, or related outcomes. Systematic reviews and meta-analyses were not formally included in the evidence synthesis but were used to support contextual discussion and to identify additional primary studies through citation screening. Studies were included if they involved adults (≥ 18 years) or relevant animal models with diagnosed AAA, assessed the presence of DM (definition of DM-fasting plasma glucose ≥ 7.0 mmol/L or diagnosis documented via medical record), included a comparator group without DM or without glucose-lowering therapy, and reported at least one relevant outcome: AAA incidence or prevalence, growth rate, rupture, AAA-related mortality, or mechanistic/molecular changes related to aneurysm pathophysiology. (Table 1) Exclusion criteria comprised case reports or small case series (< 10 patients), conference abstracts without full data, editorials, expert opinions, narrative reviews, studies lacking quantitative AAA outcomes, and studies exclusively focusing on thoracic aortic aneurysm or aortic dissection.

Table 1.

Eligibility criteria-inclusion criteria

Population	Adults (≥ 18 years) or experimental animal models with diagnosed AAA
Exposure	Fasting plasma glucose ≥ 7.0 mmol/L or diagnosis documented via medical record
Control Group	Non-diabetic subjects or those not receiving glucose-lowering therapy
Outcomes	AAA incidence, prevalence, growth rate, rupture rate, mortality, or relevant molecular mechanisms.
Study design	RCTs, cohort, case-control, registry analyses, and experimental animal studies.

AAA = Abdominal aortic aneurysm, RCT = Randomized controlled trials

Information sources

We systematically searched three electronic databases: PubMed (MEDLINE), Scopus, and the Cochrane Library (Cochrane Database of Systematic Reviews) from their inception to 28 February 2025. In addition, we screened the reference lists of all included studies and relevant systematic reviews to identify additional eligible publications. We also performed citation tracking using Scopus (“cited-by” function). To identify ongoing or unpublished studies, we searched ClinicalTrials.gov and international trial registries.

Search strategy

For PubMed (MEDLINE), the following strategy was applied: (“abdominal aortic aneurysm“[MeSH] OR AAA OR aortic aneurysm) AND (“DM“[MeSH] OR DM OR hyperglycemia) AND (metformin OR “glucose-lowering therapy” OR “glucose-lowering therapy” OR “hypoglycemic agents” OR insulin OR SGLT2 inhibitor OR GLP-1 agonist OR DPP-4 inhibitor). For Scopus, the search string was: TITLE-ABS-KEY (“abdominal aortic aneurysm” OR AAA) AND TITLE-ABS-KEY (DM OR “DM mellitus” OR hyperglycemia) AND TITLE-ABS-KEY (metformin OR “antidiabetic drugs” OR “glucose lowering” OR insulin OR SGLT2 OR GLP-1 OR DPP-4). For the Cochrane Library, the strategy used was: (abdominal aortic aneurysm OR AAA) AND (DM OR DM mellitus) AND (metformin OR antidiabetic OR glucose lowering). Filters were applied for English-language publications and for studies involving human subjects or experimental animal models. Eligible study designs included RCTs, cohort studies, case–control studies, registry analyses, and experimental mechanistic studies.

Study selection

Two independent authors (A1 et A2) performed the search and screening process. Titles and abstracts were assessed for relevance, followed by full-text evaluation of potentially eligible articles. Disagreements were resolved through discussion and consensus. The initial search retrieved 524 records; after removal of 170 duplicates, 354 records underwent title and abstract screening, of which 56 studies met the inclusion criteria and were incorporated into the final qualitative synthesis. These comprised 32 epidemiological and registry-based studies, 6 randomized or interventional trials, and 18 experimental or mechanistic studies. During full-text screening, systematic reviews and meta-analyses were excluded from formal inclusion after primary studies had been identified, in order to avoid overlap and duplication of data (Table 2).

Table 2.

Study selection

	32 epidemiological studies (cohort and case–control)
Final Dataset	6 randomized or interventional trials
	18 experimental and mechanistic studies on animal or cellular models.

Data extraction and quality assessment

Data extraction was independently conducted by two authors using a predefined template, as presented in Table 3.

Table 3.

Data extraction

Study characteristics	author, year, country, design, population, sample size
Definition of DM and AAA	DM- Fasting plasma glucose ≥ 7.0 mmol/L or diagnosis documented via medical record AAA-abdominal aorta with diameter of 3 cm or greater
Type and duration of glucose-lowering therapy	Metformin, intake duration at least 1 year
Primary outcomes	AAA incidence, diameter, growth rate, rupture, mortality
Secondary outcomes	MMP levels, inflammatory markers, ECM remodeling, AMPK activation

DM = DM Mellitus, AAA = Abdominal aortic aneurysm, MMP = Matrix metalloproteinase, ECM = Extracellular Matrix, AMPK = AMP-activated protein kinase

Quality (risk of bias) assessment

The methodological quality and risk of bias of all included studies were evaluated using standardized, design-specific assessment tools to ensure transparency and consistency. For observational studies (cohort and case–control designs), the Newcastle–Ottawa Scale (NOS) was applied. This instrument assesses three key domains: (1) Selection of study groups (representativeness of exposed cohort or case definition, selection of controls, and ascertainment of exposure), (2) Comparability of groups based on design or analysis (control of confounding variables), and (3) Outcome assessment (or exposure assessment for case–control studies), including adequacy of follow-up and objectivity of outcome determination. Each study could receive a maximum of nine stars, and studies scoring ≥ 7 were considered low risk of bias, 5–6 moderate risk, and ≤ 4 high risk of bias. Only studies with low or moderate risk of bias were included in the core evidence synthesis, while high-risk studies were retained for narrative discussion only.

For RCTs, risk of bias was evaluated using the Cochrane Risk of Bias Tool version 2.0 (RoB 2.0). This framework assesses five domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurement of the outcome, and (5) bias in selection of the reported result. Each domain was rated as “low risk,” “some concerns,” or “high risk of bias,” leading to an overall judgment for each trial. Only RCTs classified as low risk or with minor concerns were considered suitable for interpretative weighting in the main conclusions.

For experimental animal studies, the SYRCLE Risk of Bias Tool was applied, evaluating selection bias, performance bias, detection bias, attrition bias, and reporting bias specific to preclinical research. This ensured appropriate appraisal of mechanistic evidence.

All assessments were performed independently by two authors ( A1 and A2), with discrepancies resolved through discussion and consensus. This structured approach ensured methodological rigor while allowing balanced inclusion of high-quality evidence across study designs.

Data synthesis and analysis

Given heterogeneity in study designs, populations, exposures, and outcome definitions, formal quantitative pooling was not undertaken. Therefore, we performed a narrative (qualitative) synthesis structured across epidemiological, interventional, and mechanistic domains, emphasizing consistency, directionality, and biological plausibility of observed associations.

For transparency, we extracted and reported effect estimates (e.g., odds ratios, hazard ratios, relative risks, and mean differences in aneurysm growth) from the included primary human studies where available, and these are tabulated in Table 5. Systematic reviews and meta-analyses identified during screening were not included as units of evidence in the Results; instead, they were used for citation tracking and to provide contextual interpretation in the Introduction and Discussion. Where relevant, we also noted summary estimates reported in high-quality published meta-analyses to facilitate comparison with our primary-study synthesis; however, these secondary syntheses were not used for study counting, risk-of-bias assessment, or primary results reporting.

Table 5.

Summary of included primary human studies (observational and interventional) evaluating diabetes status and glucose-lowering therapies in relation to AAA outcomes

Author (Year)	Country / Design	Population (n)	Exposure	Primary Outcome	Quantitative Effect Estimate	Risk of Bias
Yang et al. (2017)	China – Mouse (Ang II AAA)	48	Metformin	AAA formation	–50% incidence	Low
Liu et al. (2022)	China – Mouse	40	Dapagliflozin	AAA formation	~ 60% reduction in AAA	Low
Zhang et al. (2021)	China – Rat model	36	Liraglutide	AAA size	Reduced dilation by ~ 30–50%	Low
Miyama et al. (2012)	Japan – ApoE−/− mice	30	Hyperglycemia	AAA development	Hyperglycemia ↓ AAA by 40–55%	Miyama et al. (2012)
Kunath et al. (2021)	Germany – Murine model	60	Metformin	AAA size	Reduced dilation by ~ 40%	Low

Outcome measures

The primary and secondary outcomes are summarized in Table 4.

Table 4.

Primary and secondary outcomes

	Relative risks (RRs), odds ratios (ORs), and hazard ratios (HRs) of AAA among diabetic vs. non-diabetic individuals.
Primary Outcomes	Annual aneurysm growth rate (mm/year).
	Risk of rupture or AAA-related mortality.
	Biomolecular correlates (CRP, MMP-2, MMP-9, IL-6)
Secondary outcomes	Effects of individual antidiabetic agents (metformin, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors) on aneurysm development and progression.

RR = relative risk, OR = odds ratio, CRR = C reactive protein, MMP-2 = Matrix metalloproteinse-2, MMP-9 = Matrix metalloproteinase-9, IL-6 = Interleukin-6, SGLT2 = Sodium-Glucose Cotransporter-2, GLP-1 = glucagon-like peptide-1, DPP-4 = Dipeptidyl peptidase 4

Registration

This systematic review was conducted according to PRISMA 2020 guidelines. A review protocol was prospectively developed defining the objectives, eligibility criteria, database search strategy, study selection process, data extraction procedures, and risk-of-bias assessment methodology. Although the protocol followed PRISMA methodological standards, it was not registered in PROSPERO due to its integration within a doctoral dissertation project.

Results

Study selection

A total of 524 records were identified through database searching. After removal of 170 duplicates, 354 records were screened by title and abstract. Of these, 56 studies met the eligibility criteria and were included in the final qualitative synthesis. These consisted of 32 epidemiological/registry studies, 6 randomized or interventional trials, and 18 experimental mechanistic studies. Most observational studies achieved Newcastle–Ottawa scores ≥ 7, and the few available RCTs showed low risk of bias.Systematic reviews and meta-analyses identified during screening were excluded from formal inclusion after primary studies had been identified, to avoid overlap and duplication of data.

A PRISMA flow diagram summarizing the selection process is presented in Fig. 1.

Fig. 1.

A PRISMA flow diagram summarizing the selection process

Study characteristics

The characteristics of all included primary human studies are summarized in Table 5. The final dataset comprised 32 epidemiological cohort and case–control studies, 6 randomized or interventional trials, and 18 experimental animal or cellular studies. Study sample sizes ranged from small mechanistic studies to national registry datasets involving > 100,000 participants. Most observational studies evaluated the association between DM and AAA prevalence, growth rate, or rupture, while interventional and experimental studies focused on mechanistic pathways or pharmacologic effects of antidiabetic therapies.

Experimental animal studies (Table 6) and mechanistic cellular or tissue-based investigations (Table 7) were analysed separately to explore biological plausibility and underlying mechanisms.

Table 6.

Experimental animal studies evaluating glucose-lowering therapies in AAA models

Author (Year)	Country / Design	Population (n)	Exposure	Primary Outcome	Quantitative Effect Estimate	Risk of Bias
Lederle et al. (2000, 2012)	USA – ADAM trial, screening cohort	> 70,000	DM vs. non-DM	AAA ≥ 3 cm	OR 0.60–0.70	Low
Norman et al. (2007)	Australia – Cross-sectional	12,203 men	DM vs. non-DM	AAA prevalence	43% lower prevalence of AAA in DM	Low
Wanhainen et al. (2016)	Sweden – Swedvasc registry	25,000	DM status	AAA rupture	HR 0.64 (95% CI 0.52–0.78)	Low
De Rango et al. (2012)	Europe – Registry	> 30,000	DM vs. non-DM	AAA prevalence	Lower prevalence in DM (13%)	Moderate
Simoni et al. (2013)	Italy – Screening	1,601	DM status	AAA diameter	DM had smaller AAAs (mean − 2.1 mm)	Moderate
Blanchard et al. (2012)	France – Case-control	742	DM vs. non-DM	AAA > 4 cm	OR 0.32 (95% CI 0.15–0.68)	Low
Kang et al. (2014)	Korea – Screening	478	DM vs. non-DM	AAA prevalence	21.9% vs. 9.2% (p = 0.002)	Low
Golledge et al. (2021)	Australia – Cohort	11,500	DM status	AAA growth	MD − 0.37 mm/year	Low
Spain Registry (2003–2012)	Spain – National registry	> 100,000	DM prevalence	AAA rupture	DM: lower rupture rate (exact effect not reported)	Moderate
Eilenberg et al. (2025)	Austria – RCT	58	Metformin 2 g/d	AAA growth	No significant change (MD − 0.08 mm/year)	Low
MAT Trial (Ongoing)	International – RCT	> 500	Metformin vs. placebo	AAA events	Results pending	—

Table 7.

Mechanistic and translational studies investigating diabetes and glucose-lowering therapy in AAA biology

Author (Year)	Country / Design	Population (n)	Exposure	Primary Outcome	Quantitative Effect Estimate	Risk of Bias
Dunn et al. (2014)	UK – In vitro	—	DM plasma	Thrombus structure	Denser fibrin clots; ↓ lysis time (+ 35%)	Moderate
Arapoglou et al. (2017)	Greece – Human tissue	42	DM vs. non-DM	Macrophage phenotype	DM → less proteolytic profile	Moderate
Death et al. (2003)	Australia – Endothelial cells	—	High glucose	MMP expression	MMP-3 ↓ by 50%	Low
van Merrienboer et al. (2025)	Netherlands – Human SMC study	—	Metformin	Oxidative stress, contractility	AMPK↑, ROS↓	Low

Risk of bias within studies

Most observational studies achieved Newcastle–Ottawa Scale (NOS) scores ≥ 7, indicating low risk of bias. The available randomized controlled trials demonstrated low or moderate risk according to Cochrane RoB 2.0. Experimental animal studies generally showed low risk using the SYRCLE tool. No studies were excluded based solely on risk of bias rating, but lower-quality studies were weighted less in the narrative synthesis.

Results of individual studies

Association between diabetes mellitus and AAA incidence or prevalence

Findings from epidemiological and interventional human studies are summarized below. Across included population-based studies, diabetes mellitus was inversely associated with AAA prevalence and/or incidence. Early screening studies, including the ADAM Trial and the Health in Men Study, reported lower AAA prevalence among individuals with DM compared with non-diabetic controls (approximately 30–40% lower) [16, 18]. Subsequent analyses from national vascular registries in Sweden, Denmark, and Spain reported similar associations, with adjusted hazard ratios ranging from 0.56 to 0.72 after controlling for major cardiovascular risk factors [19–21].

Effect of DM on AAA growth rates

The observation that DM might influence the biological course of established AAA is equally well supported. Several longitudinal cohort studies reported that diabetic patients experience a slower rate of aneurysm expansion compared with non-diabetics. Sweeting et al., in an analysis of the UK Small Aneurysm Trial, showed that DM was associated with a 0.26 mm/year reduction in aneurysm growth rate after adjustment for smoking and blood pressure [2]. Norman and colleagues corroborated these results in the Health in Men study, where median aneurysm expansion was 1.3 mm/year among diabetics compared to 1.9 mm/year in non-diabetics (p < 0.01) [18].

Association between diabetes mellitus and AAA rupture or AAA-related outcomes

The protective pattern also extends to the risk of rupture and AAA-related mortality. Data from the Swedish Vascular Registry (Swedvasc), encompassing more than 15,000 patients with diagnosed AAA, showed that diabetics had a significantly lower incidence of rupture (adjusted HR 0.64, 95% CI 0.52–0.78) [19]. A nationwide Danish registry yielded comparable results, with an adjusted HR of 0.69 (95% CI 0.54–0.88) [20]. Collectively, epidemiological and registry data suggest that DM not only reduces the likelihood of developing AAA but also attenuates the rate of enlargement and decreases the risk of rupture, thereby contributing to improved long-term survival.

Effect of metformin on AAA progression

Several observational studies reported an association between metformin use and slower AAA growth compared with diabetic patients treated without metformin. In a large cohort study, metformin use remained associated with reduced AAA growth after adjustment for baseline aneurysm size and cardiovascular risk factors [35].

Evidence from randomised trials remains limited. The first completed double-blind, placebo-controlled randomised trial evaluating metformin in patients with small AAA included 58 participants randomised to metformin 2 g/day or placebo [37]. After 18 months, no statistically significant difference in aneurysm growth rate was observed between groups. Metformin was well tolerated and demonstrated an acceptable safety profile. The ongoing MAT trial is designed to evaluate metformin using clinical endpoints including aneurysm growth, rupture, repair, and mortality [38].

Evidence for other glucose-lowering agents

Experimental studies have evaluated the effects of newer glucose-lowering drug classes on abdominal aortic aneurysm biology. In animal models of AAA, sodium–glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin and empagliflozin, were associated with reduced aneurysm formation and changes in inflammatory and proteolytic markers [39, 40]. In angiotensin II–infused ApoE−/− mice, dapagliflozin administration was associated with lower aneurysm incidence and reduced expression of matrix metalloproteinase-9 (MMP-9) [40]. Empagliflozin has been reported in vascular experimental studies to reduce oxidative stress, improve nitric oxide signaling, and decrease macrophage infiltration within the aortic wall [39].

Glucagon-like peptide-1 (GLP-1) receptor agonists have also been investigated in experimental AAA models. In murine studies, agents such as liraglutide were associated with reduced inflammatory cell recruitment, suppression of NF-κB signaling, decreased MMP-9 expression, and preservation of collagen and elastin architecture within the aortic wall [41]. In elastase-induced AAA models, liraglutide treatment was associated with a reduction in maximal aortic diameter, although reported effect sizes varied across experimental systems [43].

No clinical studies evaluating SGLT2 inhibitors or GLP-1 receptor agonists in human AAA populations were identified.

Experimental and mechanistic evidence from animal and cellular models

Experimental animal studies are summarized in Table 6 and mechanistic cellular/tissue studies in Table 7. Across models, diabetes induction or exposure to glucose-lowering agents was associated with reduced aneurysm formation and/or smaller maximal aortic diameters, and mechanistic studies reported differences in extracellular matrix composition, inflammatory markers, and proteolytic enzyme expression.

Discussion

Pathobiological interpretation of the DM–AAA paradox

The present synthesis underscores a paradox that continues to refine our understanding of aneurysm biology: the inverse association between DM and AAA formation and progression. Beyond AAA prevalence/incidence, the included longitudinal cohorts also reported an association between DM and slower expansion of established aneurysms, indicating potential links between diabetic status and AAA natural history. The review focuses on interpreting the findings within a broader scientific and clinical framework, emphasizing their mechanistic underpinnings, translational relevance, and implications for contemporary vascular practice.

It is critical to distinguish between mechanisms driven by the diabetic metabolic environment (e.g. hyperglycaemia-induced ECM cross-linking and altered thrombus structure) and those resulting from pharmacologic intervention, particularly metformin, which exerts its effects through AMPK activation and anti-inflammatory signaling independent of glucose levels. Mechanistic and experimental studies have provided plausible biological explanations for this phenomenon. Experimental animal studies evaluating the effects of diabetes and glucose-lowering therapies on aneurysm biology are summarised in Table 6, and mechanistic cellular and tissue-based studies are summarised in Table 7. In murine and rat models of AAA, induction of diabetes or administration of glucose-lowering agents was associated with reduced aneurysm formation, smaller maximal aortic diameters, and preservation of aortic wall structure. Mechanistic studies using human vascular cells and aneurysm tissue reported differences in extracellular matrix composition, inflammatory markers, and proteolytic enzyme expression. One major hypothesis concerns the chronic hyperglycemic state characteristic of DM, which leads to non-enzymatic glycation of ECM proteins and accumulation of AGEs. These AGEs induce cross-linking of collagen and elastin fibers, enhancing the structural stiffness and tensile strength of the aortic wall. Norman and colleagues reported lower circulating levels of carboxymethyl-lysine—a soluble AGE—among diabetic patients with AAA compared to diabetics without AAA, suggesting increased local deposition of AGEs in the vessel wall [44]. In animal models, AGE accumulation has been shown to decrease circumferential wall stress and protect against elastin degradation. Astrand et al. observed thicker intima–media complexes and a 20% reduction in wall stress in diabetic compared to non-diabetic aortas, supporting the hypothesis that glycation-driven stiffening of the ECM reduces susceptibility to aneurysmal dilation [45].

Another key mechanistic insight involves suppression of MMPs, particularly MMP-2 and MMP-9, which are central to ECM remodeling and aneurysm progression. In several in vitro studies hyperglycemia alone tends to increase MMP-2 and MMP-9 expression and activity supported in vascular biology and diabetic vasculopathy literature [31, 43]. Some specific MMPs (e.g., MMP-3) can be decreased in high glucose in certain cell lines. Death et al. observed that exposure of endothelial cells to high glucose concentrations (25 mmol/L) decreased MMP-3 expression by nearly 50% [31]. Metformin, in particular, appears to enhance this inhibitory effect via activation of AMPK, which downregulates NF-κB-mediated inflammatory signaling and reduces oxidative stress. In animal models of DM, suppressed MMP expression correlates with decreased elastin fragmentation and smaller aneurysm diameters, indicating that downregulation of proteolytic enzymes constitutes one of the central protective mechanisms [33].

Inflammation represents another critical pathway modulated by DM. Studies using apolipoprotein E-deficient mice infused with angiotensin II demonstrated that hyperglycemia alone does not reliably reduce inflammation; however DM induced with insulin-deficient state does reduce AAA formation in these models аnd lead to expression of pro-inflammatory cytokines, leading to smaller aneurysms [40]. Interestingly, other investigations in human aneurysm tissue found higher macrophage counts in diabetic specimens, yet these cells displayed a less destructive phenotype characterized by diminished proteolytic potential and reduced MMP secretion [46]. Overall, the diabetic state appears to generate a less aggressive inflammatory milieu within the aortic wall, distinguishing proteolytic, M2-like states by attenuated TNF-α and IL-6 activity and evidence of a phenotypic shift toward less.

Changes in thrombotic–fibrinolytic balance may also contribute to the protective effects of metformin. ILT plays a dual role in AAA biology—acting as a biochemical source of proteases while also providing a biomechanical buffer between blood flow and the wall. Multiple studies show that ILT can enhance periwall proteolysis, in part by harboring fibrinolytic activity and proteases, yet its structure also moderates diffusion toward the media. Studies reported denser fibrin clot structure and reduced fibrinolysis in diabetic plasma [47]. In addition, DM is commonly associated with elevated PAI-1, producing hypofibrinolysis that stabilizes thrombus. Together, these features plausibly promote a more stable ILT and reduced protease delivery to the underlying wall, helping to explain reports of a less degradative, more fibrotic aneurysm milieu in diabetic contexts. Collectively, these findings provide a coherent biological context for the epidemiological observations that diabetes mellitus is associated with lower AAA prevalence, slower aneurysm growth, and reduced rupture risk.

Beyond intrinsic metabolic effects, pharmacological therapies used in DM management may contribute to the attenuated aneurysm phenotype. Among these, metformin has the strongest mechanistic support. Through activation of AMPK, metformin exerts multiple vascular actions, including reduced oxidative stress, modulation of endothelial nitric oxide bioavailability, and suppression of NF-κB–driven inflammatory signaling. In AngII-infused ApoE−/− mouse models, metformin treatment reproducibly reduces aneurysm incidence and limits aortic dilation, typically in the range of 30–60% compared with untreated controls [48]. Findings in elastase-induced models are more variable but generally support a protective trend [34]. Histologic analyses commonly demonstrate reduced macrophage accumulation, lower MMP-2 and MMP-9 expression, and better preservation of medial elastin architecture in metformin-treated animals.

In contrast to prior reviews that examined epidemiological associations or individual drug classes separately, our synthesis explicitly links population-based data, mechanistic experiments, and early interventional trials into a single conceptual framework that connects the diabetic milieu, specific glucose-lowering agents, and AAA biology. AAA represents a disease of medial and adventitial matrix degeneration, characterized by chronic inflammation, proteolysis, and loss of structural integrity. In contrast, DM appears to reprogram this pathological environment toward a more fibrotic and biomechanically stable phenotype. Hyperglycemia-driven non-enzymatic glycation enhances collagen and elastin cross-linking, conferring increased tensile strength and resistance to enzymatic degradation [25, 26]. Concurrently, metabolic signaling through AMPK activation attenuates NF-κB–mediated inflammatory cascades, suppresses matrix metalloproteinase activity, and mitigates oxidative stress [32, 33]. The net effect is a vessel wall less susceptible to progressive dilatation and rupture.

Importantly, current evidence suggests that while DM itself contributes to structural stabilization of the aortic wall through metabolic and biomechanical mechanisms, the most potent anti-inflammatory and anti-proteolytic effects appear to be drug-specific, particularly associated with metformin, and not universally characteristic of all diabetic states.

Beyond intrinsic metabolic influences, the thrombotic–fibrinolytic imbalance characteristic of DM may further stabilize the aneurysmal wall. Denser, less porous intraluminal thrombus formation, combined with elevated plasminogen activator inhibitor-1 levels, could limit protease diffusion and periwall degradation [28]. This integrated pathophysiological framework provides biological coherence to the consistently slower aneurysm growth observed in diabetic individuals and those receiving metformin therapy.

Despite the predominantly protective epidemiological signal, DM may also exert opposing effects that could theoretically impair aneurysm wall integrity. Chronic hyperglycaemia and accumulation of AGEs, while increasing matrix stiffness, may at the same time render collagen and elastin more brittle and less capable of adaptive remodeling, potentially predisposing to focal tears under haemodynamic load [26, 27]. DM is also characterized by endothelial dysfunction, increased oxidative stress, and low-grade inflammation, which in some experimental settings are associated with upregulation of selected MMPs and impaired balance between proteolytic enzymes and their inhibitors [28, 31]. In addition, diabetic microangiopathy of the vasa vasorum may promote mural hypoxia and vascular smooth muscle cell apoptosis, thereby compromising medial support [49]. Finally, advanced atherosclerosis, medial calcification, and prothrombotic changes typical of diabetic vasculopathy can alter local wall biomechanics and stress distribution in complex ways that might unfavourably affect aneurysm stability in individual patients. These potential deleterious pathways underline the “double-edged sword” concept of DM in AAA and may partly explain residual heterogeneity across clinical and experimental studies.

Pharmacologic implications and translational relevance

Clinically, these insights invite a reconsideration of risk stratification and therapeutic paradigms in AAA management. From a preventive perspective, DM may represent a biological modifier that confers relative protection rather than risk, suggesting the need to refine screening algorithms and surveillance intervals accordingly. From a therapeutic standpoint, metformin has emerged as the most promising candidate for pharmacologic modulation of aneurysm progression. However, the strength of evidence differs by study design. Observational cohorts consistently report associations between metformin exposure and slower aneurysm expansion, whereas the first completed randomized controlled trial demonstrated feasibility and safety but was not powered to detect modest differences in aneurysm growth. This discrepancy highlights the need for adequately powered, event-driven trials before clinical recommendations can be made. Its pleiotropic vascular effects—anti-inflammatory, antioxidative, and anti-proteolytic—extend beyond glycemic regulation and provide a mechanistic rationale for its repurposing as a disease-modifying agent in AAA. While early randomized trials have demonstrated safety and feasibility, adequately powered studies with standardized imaging protocols and clinical endpoints remain essential to establish efficacy. In this context, our review deliberately reports the key quantitative estimates from the largest cohorts with a particular focus on pooled mean differences in AAA growth associated with metformin, so that clinicians can judge the likely magnitude of benefit in a transparent and reproducible manner (Table 4). Existing RCTs, such as the Eilenberg et al. pilot trial, were primarily designed to assess feasibility and short-term safety rather than aneurysm-related outcomes [37]. Achieving sufficient statistical power to detect modest differences in AAA growth requires large sample sizes and long follow-up periods, making such trials logistically and financially challenging. Variability in imaging modalities, growth-rate measurement techniques, and patient selection criteria further complicates trial design and comparability across studies. While metformin remains the most extensively studied agent, its precise contribution to aneurysm stabilization relative to other metabolic or pharmacologic factors remains uncertain. Evidence is largely observational, and distinguishing metformin’s independent effects from broader DM-related alterations remains a critical research need.

To improve comparability and interpretability, future clinical trials should adopt standardized definitions of aneurysm growth (e.g., ≥ 1 mm/year), uniform imaging intervals, and clearly defined composite clinical endpoints including rupture, elective repair, and aneurysm-related mortality. Harmonization of inclusion criteria—such as baseline aneurysm size, diabetic status, and concurrent pharmacotherapy—will be essential to facilitate meta-analytic synthesis and evidence translation.

Comparative effects of glucose-lowering agents on AAA biology

In comparison with other glucose-lowering therapies, metformin exhibits the most consistent and well-supported vascular effects relevant to aneurysm stabilization. Its actions include inhibition of mitochondrial complex I, activation of AMPK, reduction of oxidative stress, and suppression of inflammatory signaling pathways such as NF-κB—mechanisms extensively demonstrated in murine and cellular models [29–33, 48]. Metformin also decreases MMP-2 and MMP-9 activity, thereby limiting extracellular matrix degradation [27, 48, 50]. These mechanistic actions align with epidemiological findings, where metformin is the only glucose-lowering agent repeatedly associated with attenuated AAA growth in clinical cohorts [35, 51].

SGLT2 inhibitors, such as dapagliflozin, also demonstrate protective effects in experimental aneurysm models, primarily through modulation of mitochondrial metabolism, reduction of oxidative stress, and suppression of macrophage infiltration and inflammatory cytokines [39, 40, 52]. However, no human studies to date have evaluated their impact on AAA incidence or progression, and all available evidence remains preclinical.

GLP-1 receptor agonists (e.g., liraglutide) exert potent anti-inflammatory and anti-proteolytic effects, including downregulation of MMP-9, inhibition of smooth muscle cell apoptosis, and preservation of collagen and elastin structure [41, 43]. These actions have been shown to reduce aneurysm growth in elastase and AngII-induced murine models, but, similar to SGLT2 inhibitors, there are currently no clinical data in human AAA patients.

In contrast, DPP-4 inhibitors and insulin therapy have limited mechanistic evidence relating to aneurysm biology and lack any consistent preclinical or clinical data suggesting benefit. Taken together, metformin remains the only glucose-lowering agent with concordant mechanistic and epidemiological support, whereas SGLT2 inhibitors and GLP-1 receptor agonists represent biologically promising but exclusively experimental therapies at this time.

Sources of heterogeneity across included studies

Considerable heterogeneity was observed across the included studies, reflecting intrinsic differences in methodological design, populations, and outcome assessment. One major source of variability was study design, which included data spanning screening programs, hospital-based cohorts, national registries, RCTs clinical trials, and experimental models. Screening studies often included asymptomatic populations with smaller aneurysms, whereas registry-based studies frequently involved advanced disease and surgical cohorts, thereby influencing baseline aneurysm size and event rates.

Population characteristics also contributed significantly to heterogeneity. Included cohorts varied in age distribution, sex ratio, prevalence of smoking, hypertension, dyslipidemia, and ethnicity, all of which influence AAA natural history. Geographical variation further introduced differences in healthcare systems, screening practices, and treatment thresholds.

Diagnostic criteria for both DM and AAA were inconsistently reported. Some studies defined DM based on self-report or medication use, while others used biochemical thresholds (fasting glucose or HbA1c). Similarly, AAA was defined using variable diameter thresholds (≥ 30 mm vs. ≥ 35 mm) and different imaging modalities (ultrasound versus computer tomography), leading to variation in reported prevalence and growth rates.

Across included cohorts, definitions of AAA, DM and glucose-lowering therapy exposure varied substantially. AAA thresholds ranged from ≥ 3.0 cm, > 3 cm, and > 4 cm, with some RCTs restricting inclusion to 3–5 cm AAAs. DM was variously defined by biochemical criteria, medical record diagnosis, or medication use, particularly within large registry datasets. Metformin exposure was inconsistently reported, with some studies defining treatment as ≥ 1-year use, while others relied solely on prescription records without information on dose or duration. These discrepancies limit direct comparability across studies and may introduce measurement heterogeneity.

Measurement of aneurysm expansion demonstrated additional heterogeneity due to differences in imaging intervals, operator dependency, and reporting of growth either as absolute annual increase or percentage change. Furthermore, adjustment for confounders was inconsistent, with some studies controlling for smoking and cardiovascular comorbidities while others did not.

Heterogeneity was also introduced by variability in glucose lowering treatment exposure, including duration of therapy, differences between drug classes (metformin, insulin, SGLT2 inhibitors, GLP-1 receptor agonists), and lack of uniform dosage reporting. This complicates direct comparison of therapeutic effects across cohorts.

In experimental studies, heterogeneity derived from differing animal species, AAA induction methods (angiotensin II, elastase, calcium chloride), models of DM (streptozotocin-induced vs. genetic), and variable outcome measures such as histology, biomarker expression, and biomechanical testing.

Synthesis of results

Across primary human observational studies, randomised trials, and experimental models, DM was consistently associated with a lower likelihood of AAA development, slower aneurysm growth, and reduced risk of rupture. Human observational data further suggest that metformin use may confer additional attenuation of aneurysm progression, although definitive evidence from adequately powered randomised trials is still emerging. Experimental and mechanistic studies support these clinical observations by demonstrating biologically plausible pathways through which diabetes and antidiabetic therapies influence aneurysm stability.

In summary, the results of this review highlight the paradoxical yet reproducible relationship between DM and AAA. The consistency across population studies, mechanistic experiments, and pilot therapeutic trials suggests that the diabetic state—particularly in the setting of metformin therapy—may confer measurable attenuation of aneurysm growth. These findings provide a rational foundation for ongoing translational and clinical research aimed at repurposing antidiabetic therapies as adjunct pharmacologic strategies for AAA management.

Limitations of current evidence and trial challenges

Nevertheless, important methodological limitations persist. The predominance of observational data introduces potential residual confounding that cannot be fully eliminated despite multivariable adjustment. Unmeasured or incompletely captured factors—including DM duration, level of metabolic control, treatment indication bias, differential medical surveillance, and variability in imaging modality or follow-up intervals—may partly explain the observed associations. Additionally, heterogeneity in DM definitions, glucose-lowering therapy exposure, and imaging methods limits comparability across cohorts. Mechanistic insights derived from experimental models, although biologically informative, may not fully replicate human pathophysiology, underscoring the need for translational validation. Future research incorporating standardized imaging protocols, molecular biomarkers, and rigorously phenotyped cohorts will be essential to delineate causal pathways and identify therapeutic responders. Therefore, caution is required when inferring causality from the current evidence base.

Future directions and research priorities

Collectively, the convergence of epidemiologic, mechanistic, and early interventional evidence supports a unifying hypothesis: DM and its pharmacologic treatments, particularly metformin, exert a stabilizing influence on aneurysm biology. Should forthcoming trials confirm these effects, pharmacologic modulation of aneurysm growth could redefine the current paradigm of AAA management—transitioning from reactive, diameter-based intervention to proactive, biologically targeted therapy.

Conclusion

DM, though traditionally considered deleterious to the cardiovascular system, has been consistently associated with slower aneurysm progression in observational and experimental contexts. However, current evidence remains insufficient to establish causality, as most data derive from non-randomized designs and mechanistic extrapolations. Across epidemiological, experimental, and pharmacological domains, the evidence consistently demonstrates that diabetic individuals experience a lower incidence of AAA, slower aneurysm expansion, and reduced rupture-related mortality. The underlying mechanisms are multifactorial and biologically plausible, involving increased cross-linking of extracellular matrix proteins through advanced glycation, suppression of matrix metalloproteinase activity, modulation of macrophage-driven inflammation, and stabilization of the intraluminal thrombus.

Among glucose-lowering therapies, metformin stands out as the most compelling agent with vascular-protective properties. Through activation of AMPK and inhibition of NF-κB–mediated inflammation, metformin attenuates oxidative stress and ECM degradation—mechanisms directly implicated in aneurysm formation and growth. Emerging drug classes, including SGLT2 inhibitors and GLP-1 receptor agonists, also demonstrate favorable effects on vascular remodeling in preclinical studies, hinting at a broader pharmacological potential in aneurysm prevention.

Although causality cannot yet be definitively established, the coherence between epidemiological trends and mechanistic data strongly suggests that DM—and particularly its pharmacologic management—modifies the natural history of AAA. The ongoing MAT trial and future event-driven studies are expected to clarify whether these associations can be translated into clinical benefit. If confirmed, repurposing glucose-lowering therapy for aneurysm stabilization could mark a paradigm shift in the management of AAA, transforming a traditionally surgical disease into one amenable to metabolic and pharmacologic modulation.

Ultimately, the inverse association between DM and AAA highlights an important concept in vascular medicine: pathologic metabolic states may, under certain conditions, induce adaptive vascular remodeling that mitigates specific disease pathways. Significant knowledge gaps remain regarding dose–response relationships, potential class effects of non-metformin agents, and long-term clinical benefit. Clarifying these uncertainties through coordinated, standardized, event-driven RCTs should be a research priority. Understanding and harnessing these mechanisms could open a new therapeutic frontier in the prevention of aortic degeneration and aneurysm rupture.

Abbreviations

AAA

Abdominal Aortic Aneurysm

DM

Diabetes Mellitus

RCT

Randomized Controlled Trial

MA

Metformin Aneurysm Trial

SGLT2

Sodium-Glucose Cotransporter-2

GLP-1

Glucagon-Like Peptide-1

EVAR

Endovascular Aneurysm Repair

ECM

Extracellular Matrix

VSMC

Vascular Smooth Muscle Cell

AGEs

Advanced Glycation End-Products

MMP

Matrix Metalloproteinase

IL-6

Interleukin 6

TNF-α

Tumor Necrosis Factor Alpha

ILT

Intraluminal Thrombus

AMPK

AMP-Activated Protein Kinase

NF-κB

Nuclear Factor Kappa-B

ROS

Reactive Oxygen Species

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

NOS

Newcastle–Ottawa Scale

RoB 2.0

Cochrane Risk-of-Bias Tool 2.0

SYRCLE

Systematic Review Centre for Laboratory Animal Experimentation

OR

Odds Ratio

RR

Relative Risk

CRP

C-Reactive Protein

DPP-4

Dipeptidyl Peptidase-4

HR

Hazard Ratio

PAI-1

Plasminogen Activator Inhibitor-1

AngII

Angiotensin II

ApoE−/−

Apolipoprotein E Knockout (mouse model)

HbA1c

Hemoglobin A1c

ACE

Angiotensin-Converting Enzyme

ATP

Adenosinte Triphosphate

AMP/ADP

Adenosine monophosphate/ adenosine diphosphate

Author contributions

M.D has made substantial contributions to the conception and design of the work; the acquisition, analysis, interpretation of data. B.B drafted the work and substantively revised it and approved the submitted version. B.I helped with conceptualizing the research, collecting and analyzing data and editing the manuscript. Y.K Verified the analytical methods and Interpreted the results. M.D. has agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.