Time to Consider Pharmacologic Management of Unruptured Intracranial Aneurysms?

Article information

J Stroke. 2025;27(3):302-312

Publication date (electronic) : 2025 September 17

doi : https://doi.org/10.5853/jos.2025.01662

Yeon Soo Kim ¹^,², Sungbin Hwang ¹^,², Mi Hyeon Kim ¹^,², Boseong Kwon ², Yunsun Song ², Deok Hee Lee^,¹^,²

¹Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea

²Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: Deok Hee Lee Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-5944 E-mail: dhlee@amc.seoul.kr

Received 2025 April 8; Revised 2025 May 27; Accepted 2025 June 13.

Abstract

The increasing detection rate of unruptured intracranial aneurysms (UIAs) using advanced imaging underscores the need for alternative management strategies beyond surgical and endovascular interventions. Although these procedures have improved substantially, they still carry procedural risks, high costs, and psychological burdens related to continuous surveillance. This review aimed to suggest the potential role of pharmacological therapy in mitigating aneurysm progression and the risk of rupture. We first reviewed the key pathophysiological mechanisms—endothelial dysfunction, hemodynamic stress, inflammation, and thrombosis—contributing to UIA growth and instability. We then listed and examined a range of pharmacological agents, including antihypertensives, lipidlowering drugs, anti-inflammatory compounds, antioxidants, and novel candidates, summarizing both the preclinical and observational evidence supporting their use. While these findings are encouraging, current clinical data do not support broad, standardized treatment guidelines. Further prospective or randomized studies are required to clarify the safety, efficacy, and feasibility of using these agents in routine practice. By highlighting the rationale for pharmacological interventions and identifying key knowledge gaps, this review underscores the importance of an integrative management approach, encompassing medication, lifestyle modification, and vigilant monitoring, to better address patient needs and ultimately improve outcomes in UIA care.

Keywords: Unruptured intracranial aneurysm; Pharmacologic management; Aneurysm stabilization

Introduction

Over the past decades, the reported prevalence of cerebral aneurysms has surged, probably due to the widespread adoption of high-resolution, non-invasive imaging modalities such as magnetic resonance angiography [1-3]. This increased detection of unruptured intracranial aneurysms (UIAs) has created a paradox in modern neurovascular care. While earlier diagnosis offers the potential for timely intervention, it simultaneously imposes significant clinical challenges and psychological burdens. Patients diagnosed with UIA often experience heightened anxiety and stress, a phenomenon that can adversely affect overall health outcomes [4,5].

Advances in endovascular and microsurgical treatments have markedly improved the safety profile of UIA patient management [6,7]; however, these invasive interventions are not without drawbacks. The procedural risks, high costs, and uncertainty in predicting aneurysm behavior necessitate judicious patient selection. Consequently, many clinicians opt for a conservative strategy and periodic radiologic surveillance to avoid the inherent hazards of intervention. However, repeated imaging not only contributes to cumulative financial costs, but also exacerbates patient anxiety and may eventually lead to overtreatment [8].

Emerging research surrounding the pathobiology of UIAs has highlighted several key processes that underlie aneurysm formation and progression, including endothelial dysfunction, hemodynamic stress, chronic inflammation, and thrombosis [4]. A growing body of evidence suggests that these underlying mechanisms may be amenable to pharmacological modulation. In theory, targeted drug therapies, integrated with robust risk factor control and lifestyle modifications, can stabilize aneurysm growth, delay or prevent rupture, and potentially obviate the need for invasive procedures.

Non-surgical management should begin by controlling modifiable risk factors such as hypertension and smoking, complemented by healthy lifestyle changes, including regular exercise and a balanced diet. However, an equally important question is whether pharmacological therapy can prevent aneurysm growth and rupture [9].

In this context, pharmacological management represents a promising, non-invasive complement to current therapeutic strategies. By mitigating vascular insults that drive aneurysm evolution, a systematic pharmacological approach can transform the clinical landscape of UIA management.

The purpose of this review is to explore the pharmacological agents and compounds proposed in preclinical and observational studies, highlighting both practical candidates ready for investigation and novel substances that hold promise for future clinical applications in UIA patient management.

Non-surgical management principles in UIAs

Table 1 summarizes the general principles guiding the non-surgical management of UIAs. This framework was designed to address the multifactorial nature of aneurysm pathophysiology using a comprehensive integrative approach.

Table 1.

General principles in the non-surgical management of unruptured cerebral aneurysms

Risk factor management

Controlling modifiable risk factors is paramount. The use of antihypertensive agents to stabilize blood pressure plays a critical role [10], while managing menopausal changes is equally important given the hormonal influence on vascular integrity [11]. Together, these measures help reduce the hemodynamic stress that can contribute to aneurysm formation and progression [9].

Lifestyle modification

Adopting healthy lifestyle practices is also essential to complement pharmacological interventions. Recommendations include smoking cessation, moderation of alcohol consumption, engagement in regular aerobic exercise, and avoiding excessive physical exertion [12]. These behavioral modifications diminish systemic inflammation and improve endothelial function, thereby reducing the risk of aneurysmal growth.

Maintaining a healthy arterial wall

Preservation of arterial wall integrity is fundamental. Strategies to maintain endothelial stability, ensure structural robustness, and preserve vascular integrity and elasticity are crucial in preventing pathological remodeling [13]. Measures that support collagen and elastin synthesis or inhibit matrix degradation may fortify vessel walls, thereby mitigating the risk of aneurysm growth and rupture.

Anti-inflammatory strategy

Chronic inflammation is increasingly recognized as a key factor in the pathogenesis and rupture of UIA. Effective management of inflammatory conditions, prompt treatment of infections, and overall recuperation from poor physical condition are important measures [14,15]. These interventions help curb the inflammatory milieu that compromises arterial wall stability.

Other considerations

Additional supportive measures may be employed to complement the aforementioned strategies, thereby providing a holistic and patient-tailored approach that considers various patient-specific factors for UIA management [16].

Targets of pharmacological intervention

To identify potential pharmacological candidates for stabilizing or treating UIAs, it is essential to understand the mechanisms underlying aneurysm formation, growth, and rupture (Figure 1) [17]. The next step is to evaluate substances that exhibit protective or therapeutic effects against these mechanistic pathways [18,19].

Figure 1.

Pathophysiologic mechanisms of intracranial aneurysm formation and progression. This cartoon representation summarizes key factors contributing to aneurysm formation, growth, and rupture: (A) Hemodynamic stress and aneurysm formation—flow impingement and high wall shear stress drive endothelial dysfunction and maladaptive vascular remodeling; (B) Endothelial dysfunction and vascular instability—increased permeability, oxidative stress, and inflammation compromise vascular integrity; (C) Connective tissue degradation and aneurysm wall weakening—excessive matrix metalloproteinase activity leads to extracellular matrix breakdown; (D) Intraluminal thrombosis and vascular remodeling—mural thrombi promote inflammation and progressive wall weakening; (E) Local vascular inflammation and aneurysm wall destabilization—chronic inflammatory responses contribute to aneurysm growth and rupture risk. Understanding these mechanisms provides a better foundation for targeted pharmacologic interventions.

Hemodynamic stress and aneurysm formation

Hemodynamic stress is the principal initiator of intracranial aneurysm formation and remains a key driver of its progression. At arterial bifurcations and curvatures, flow impingement generates focal areas of high wall shear stress and spatial shear stress gradients, leading to endothelial dysfunction and maladaptive vascular remodeling. These regions of sustained mechanical stress mark the initial sites of aneurysmogenesis, where the arterial wall undergoes structural weakening due to endothelial injury, inflammatory cell infiltration, and extracellular matrix (ECM) remodeling [14,20]. Once an aneurysm has formed, ongoing hemodynamic stimuli exacerbate pathological changes, promote aneurysm growth, and increase the risk of rupture. Localized flow disturbances within the aneurysmal sac, such as oscillatory shear stress and intra-aneurysmal vortices, sustain a chronic pro-inflammatory state, drive phenotypic changes in smooth muscle cells, and accelerate ECM degradation. These biomechanical forces compromise vessel integrity, thereby predisposing aneurysms to further expansion and future rupture [15,20]. As hemodynamic stress governs both the initiation and progression of aneurysms, pharmacological strategies should prioritize its mitigation. Agents that reduce excessive shear forces, reduce flow impingement, and enhance vascular resilience may provide significant therapeutic benefits. Additionally, targeting the downstream effects of hemodynamic stress, such as inflammation and ECM remodeling, may offer complementary stabilization strategies [19,21]. Given the central role of hemodynamic stress in aneurysm pathophysiology, future research should focus on interventions that directly modulate biomechanical forces to prevent aneurysm formation and progression.

Endothelial dysfunction and vascular instability

The integrity of the arterial wall is critically dependent on endothelial cells, which form the innermost vascular lining and regulate vascular homeostasis. Endothelial dysfunction, which is characterized by increased permeability of the arterial wall, oxidative stress, and inflammatory activation, compromises vascular stability and may contribute to aneurysm formation. Persistent hemodynamic stress exacerbates endothelial injury, further promoting vascular remodeling and aneurysm progression [11,22]. Pharmacological interventions that enhance endothelial function, such as statins and endothelial-stabilizing agents, may mitigate these deleterious effects. Additionally, agents that improve vascular healing could be beneficial in counteracting endothelial damage induced by abnormal hemodynamic forces [23].

Connective tissue degradation and aneurysm wall weakening

Beyond endothelial dysfunction, the ECM plays pivotal roles in maintaining the structural integrity of the aneurysm wall. Collagen and elastin, which are essential components of the ECM, provide tensile strength and elasticity to the arterial wall. However, their degradation leads to wall thinning and increased susceptibility to rupture. Excessive activity of matrix metalloproteinases (MMPs) accelerates ECM breakdown, contributing to abnormal vascular remodeling and aneurysm destabilization [13,22]. Pharmacological strategies targeting ECM preservation, such as MMP inhibitors and collagen stabilizers, may help maintain the integrity of the aneurysm wall. Furthermore, drugs that promote vascular healing and suppress excessive ECM degradation may offer additional benefits in stabilizing UIAs [24].

Intraluminal thrombosis and vascular remodeling

Thrombosis within the sac plays a critical role in aneurysmal progression and instability. Turbulent or abnormal blood flow, particularly in regions with locally circulating flow [25], can promote mural thrombosis, leading to localized inflammation and progressive weakening of the aneurysm wall. The presence of an intraluminal thrombus exacerbates the inflammatory response by recruiting immune cells and releasing proteolytic enzymes that degrade the ECM, further compromising the structural integrity of the arterial wall. Persistent thrombosis and subsequent vascular remodeling may contribute to aneurysm growth and increase the risk of rupture [19]. Pharmacological strategies targeting thrombosis may help stabilize aneurysms by reducing thrombus formation and mitigating inflammation. Antiplatelet agents, such as aspirin, may limit platelet aggregation and the pro-inflammatory effects of mural thrombi. In addition, anticoagulants and other antithrombotic agents prevent excessive clot formation and promote a more stable vascular environment. However, the potential risk of bleeding complications must be carefully considered when considering long-term antithrombotic therapy in patients with UIAs [26].

Local vascular inflammation and aneurysm wall destabilization

Local inflammation within the aneurysm wall is a key contributor to aneurysmal instability and subsequent rupture. Inflammation can originate from local thrombus formation or from intrinsic immune responses triggered by endothelial dysfunction and hemodynamic stress. The persistent presence of inflammatory mediators, including cytokines and MMPs, leads to vascular remodeling, smooth muscle cell depletion, and ECM degradation. These pathological processes weaken the aneurysmal wall, making it more susceptible to expansion and rupture. Additionally, localized inflammatory responses promote fibroblast proliferation and atherosclerotic changes, further contributing to aneurysm destabilization [27]. Pharmacological strategies targeting inflammation may play a critical role in aneurysm stabilization [27,28]. Anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and selective cytokine inhibitors, can help suppress chronic inflammatory responses and preserve vascular integrity [29]. Immunomodulatory therapies that regulate macrophage activity and inflammatory signaling pathways may also offer potential benefits. However, given the complex interplay between inflammation and aneurysm pathology, further research is needed to determine the most effective anti-inflammatory interventions that minimize adverse systemic effects.

Oxidative stress and other contributory mechanisms

Oxidative stress plays a significant role in aneurysm progression by promoting endothelial dysfunction, smooth muscle cell apoptosis, and ECM degradation. Overproduction of reactive oxygen species contributes to chronic inflammation and vascular remodeling, further destabilizing aneurysm walls. Additionally, oxidative stress can activate inflammatory pathways, exacerbate mural cell dysfunction, and increase rupture risk [19]; pharmacologic interventions targeting oxidative stress and its related mechanisms may help mitigate aneurysm instability [30,31]. Antioxidants, including coenzyme Q10 and resveratrol, have been suggested to reduce oxidative damage and improve endothelial function. Metabolic modulators that enhance vascular resilience may also have potential benefits. However, further studies are required to determine the efficacy and safety of these approaches in stabilizing aneurysms.

Considering these pharmacological targets, we reviewed the existing literature to identify substances with potential protective or therapeutic properties. The resulting list of candidate drugs, presented in Table 2, serves as a foundation for the further exploration of pharmacological management strategies for UIAs. Adopting a systematic framework similar to the one used by the National Institute on Aging (NIA) Interventions Testing Program [32] could help identify and evaluate novel compounds for long-term aneurysm stabilization.

Table 2.

Potential candidate substances for stabilization of unruptured intracranial aneurysms

Strategies of pharmacologic intervention

Deciding to manage UIAs conservatively often entails a lifelong commitment to observation and control. As an aneurysm represents an irreversible focal bulge in the cerebral artery, the principal goal is to prevent further growth and future rupture. Consequently, prolonged and potentially lifelong pharmacological interventions are required.

Duration of pharmacotherapy

When determining treatment duration, both indefinite and short-term approaches are valid. For example, patients requiring continuous blood pressure control or vascular wall reinforcement may benefit from continuous drug administration. Conversely, if an aneurysm is deemed temporarily unstable, such as a newly developed mural enhancement on vessel wall magnetic resonance imaging (MRI), interval growth, or morphological changes detected during radiological surveillance, aneurysm repair interventions are generally considered. Alternatively, targeted pharmacological intervention confined to a specific high-risk period may be considered a potential strategy to promote lesion stabilization [33].

Selecting agents with secondary benefits

Given that many UIA patients also present with comorbid conditions, it is advantageous to prioritize drugs that address both aneurysm stabilization and other medical issues. For instance, in cases in which hypertension is a risk factor, various antihypertensive agents may be considered and angiotensin II receptor blockers are often recommended. This is because they not only lower systemic blood pressure, but also suppress inflammation and pathological remodeling of the aneurysm wall by blocking the angiotensin II type 1 receptor, thus concurrently addressing both the hemodynamic and biological mechanisms of aneurysm progression [23].

Safety considerations and dosing strategies

Regardless of the treatment timeframe, potential adverse effects of long-term medications must be carefully considered. Agents with robust safety profiles are particularly important for lifelong drug administration. Similarly, short-term therapies should also demonstrate efficacy for aneurysm stabilization with minimal side effects. As many patients with UIAs are otherwise healthy, identifying safe substances such as nutraceuticals or dietary supplements may offer a promising pharmacological approach [34]. Moreover, employing low- or ultra-low-dose regimens may help mitigate adverse effects, and combining multiple agents at minimal effective doses may enhance aneurysm stabilization while minimizing toxicity [35].

Future directions for novel compounds

Beyond established pharmacotherapies, newer investigational agents show promise in preclinical models for slowing or halting aneurysm progression. These novel compounds often target specific molecular pathways ranging from advanced anti-inflammatory molecules to cutting-edge gene-based therapies. However, rigorous validation through randomized clinical trials is necessary before these agents can be adopted in standard clinical practice. Owing to the time-intensive and highly regulated nature of such trials, a detailed examination of these therapies is beyond the scope of this review [28,29,36].

Additional considerations for commonly used agents

Although none of these medications are formally indicated for UIA prophylaxis, several widely prescribed drugs originally developed for other conditions have shown potential stabilizing effects on cerebral aneurysms in addition to the antihypertensive medications previously discussed. Among the many compounds that fit the previously discussed pharmacological strategies, we have highlighted a subset supported by preclinical and/or observational data. In the following sections, we examine these potential candidates focusing on their mechanisms of action and how they may offer ancillary benefits in mitigating aneurysm progression and rupture risk.

Statins: anti-inflammatory and endothelial-stabilizing properties

Originally prescribed for their lipid-lowering effects, statins also exert anti-inflammatory and endothelial-stabilizing effects that may help slow UIA progression [37]. Observational studies have indicated a possible association between statin therapy and reduced aneurysm growth or rupture [38,39]. With a generally favorable safety profile and established cardiovascular benefits, statins represent a viable long-term option for patients who may benefit from the management of dyslipidemia. An ongoing trial (NCT04943783) targeting unruptured aneurysms with wall enhancement on vessel wall MRI is investigating the long-term effects of low-dose atorvastatin and is expected to yield intriguing results [38].

Low-dose aspirin: anti-platelets and anti-inflammatory actions

Low-dose aspirin exerts both anti-platelet and anti-inflammatory effects, potentially mitigating aneurysm wall weakening by reducing platelet aggregation and vascular inflammation [26,40]. Observational data suggest that patients taking low-dose aspirin may experience a lower risk of aneurysm progression, although additional research is needed to determine whether these benefits are dose-dependent or vary across patient subgroups [26,40]. While aspirin is generally well-tolerated at low doses, bleeding risk remains a concern during long-term administration. Overall, aspirin remains a promising non-surgical option for UIA stabilization. The results of the ongoing large prospective trial (NCT03063541), which evaluates low-dose aspirin combined with intensive blood pressure control, are highly anticipated.

Metformin: anti-inflammatory and vascular protective effects

Originally used primarily for type 2 diabetes, metformin also reduces oxidative stress and inflammation by activating AMP-activated protein kinase (AMPK)-based mechanisms that may help preserve endothelial function in patients with UIA [31]. These actions could retard aneurysm growth and lower the risk of rupture, even in non-diabetic individuals [41]. This observational study indicates that metformin may help reduce the risk of aneurysm rupture, possibly by regulating cellular energy balance and suppressing inflammation. However, further randomized trials are required to confirm this protective effect. Given its favorable safety profile and broad clinical availability, metformin is an appealing candidate for long-term prophylaxis, especially in patients in need of hyperglycemic control, pending additional robust evidence. A prospective trial (NCT06405971), which specifically targets unruptured vertebrobasilar dissecting aneurysms, is currently underway to evaluate the protective effects of metformin.

Doxycycline and minocycline: MMP inhibition and aneurysm wall protection

Doxycycline and minocycline are tetracycline derivatives that may stabilize aneurysms by inhibiting MMPs, enzymes responsible for degrading the ECM of the aneurysm wall [24]. Notably, this study suggests that tetracycline antibiotics offer more pronounced UIA protection than selective MMP inhibitors, indicating that additional mechanisms may contribute to their effects. Although preclinical data are encouraging, clinical evidence remains limited. Concerns regarding long-term antibiotic use, including side effects and drug resistance, imply that short-term or intermittent regimens might be preferable over indefinite therapy [42].

Natural antioxidants (e.g., resveratrol, curcumin)

Various natural antioxidants, including resveratrol and curcumin, exhibit anti-inflammatory and antioxidative properties that may help preserve arterial integrity [43,44]. These compounds have the potential to stabilize aneurysm walls by mitigating oxidative stress and improving endothelial function, although direct evidence specific to patients with UIA remains evolving. Both agents appear relatively safe for long-term use; however, the limited bioavailability of curcumin may necessitate enhanced formulations to maximize its therapeutic benefits. Overall, the broad vascular advantages and generally favorable safety profiles of natural antioxidants make them promising adjuncts to conventional UIA management strategies.

Vitamin D: endothelial support and dual benefits in women

Vitamin D supports endothelial health and modulates inflammation, suggesting its protective role against UIA progression [45]. Clinical studies have linked vitamin D deficiency to increased vascular risk, and vitamin D supplementation is generally well-tolerated, although doses should be monitored to avoid toxicity. Notably, UIAs are more prevalent in women, many of whom are also at a higher risk of osteoporosis, indicating the potential for vitamin D to confer dual benefits in this subgroup [46]. Further research is needed to determine whether improving patient vitamin D status can help limit UIA progression while also supporting bone health.

Coenzyme Q10 (ubiquinol): antioxidant and vascular benefits

Coenzyme Q10 (CoQ10) is integral to mitochondrial energy production and functions as a potent antioxidant, potentially reducing oxidative damage to the aneurysm wall [47]. Other preclinical studies have suggested that CoQ10 may improve endothelial function and alleviate vascular inflammation [48], which could help stabilize UIAs. However, translating these findings into clinical efficacy remains challenging, as it is uncertain whether CoQ10 supplementation in humans would reproduce the vascular benefits observed in preclinical studies, such as enhanced endothelial function and reduced vascular inflammation [49]. Despite limited clinical data specific to UIAs, the broader cardiovascular advantages of CoQ10, coupled with its favorable safety profile, make it an appealing candidate for long-term adjunctive therapies.

Omega-3 fatty acids: anti-inflammatory and antithrombotic benefits

Omega-3 fatty acids (notably eicosapentaenoic acid and docosahexaenoic acid) exhibit potent anti-inflammatory and antithrombotic properties that can improve endothelial function and reduce hemodynamic stress on the arterial wall [50]. By curbing inflammation and platelet aggregation, they may help stabilize existing UIAs and potentially slow aneurysm progression. Although direct evidence of their protective effects against UIAs is limited, the broader cardiovascular advantages of omega-3 fatty acids make them an appealing long-term option [51]. These agents are well-tolerated, and are thus, suitable for sustained preventive strategies; however, further research is needed to confirm their specific role in UIA management.

Other substances undergoing or planned for clinical trials

Apart from the agents discussed above, ongoing trials of dimethyl fumarate (NCT05959759) and the selective β1-blocker nebivolol (NCT06249802) are designed to assess their roles in modulating inflammation and hemodynamics, potentially expanding the pharmacologic options available for UIA stabilization.

Summary

The growing recognition of UIAs as a significant clinical concern calls for a shift in management strategies beyond traditional surgical and endovascular interventions. While conservative approaches such as radiological surveillance play a role in monitoring UIAs, they may be overly passive and insufficient to address the psychological burden associated with the uncertainty of disease progression. Pharmacological management presents a promising avenue to address the underlying pathophysiological mechanisms, offering potential benefits in preventing aneurysm growth and rupture while minimizing the risks associated with invasive procedures. Although current evidence highlights several candidate agents with protective effects, robust clinical trials are required to establish their efficacy and safety. In the future, research should not only refine existing therapeutic options but also explore novel compounds that may further enhance the pharmacological management of patients with UIA.

Notes

Funding statement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (grant number: RS-2023-00280269).

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Conceptualization: DHL. Study design: BK, YS, DHL. Methodology: YSK, DHL. Data collection: SH, MHK. Investigation: SH, MHK, DHL. Writing—original draft: YSK, DHL. Writing—review & editing: BK, YS, YSK, DHL. Funding acquisition: DHL. Approval of final manuscript: all authors.

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Category	Method
Risk factor management	Antihypertensives
Managing menopause
Lifestyle modification	Smoking cessation
Moderation in drinking
Regular aerobic exercise
Avoiding overexertion
Maintaining healthy arterial wall	Endothelial integrity
Structural stability of the wall
Maintaining vascular elasticity
Anti-inflammatory scheme	Management of known inflammatory conditions
Recuperation of poor physical condition
Management of any infectious condition
Others	Additional supportive measures

Table 2.

Potential candidate substances for stabilization of unruptured intracranial aneurysms

Category	Subgroup	Representative substance	Potential protection mechanism
Anti-hypertensive agents	ACE inhibitors	Captopril	Inhibition of local renin-angiotensin signaling and vessel wall stabilization beyond antihypertensive effect [10]
	ARBs	Losartan	Blockade of vascular angiotensin II type 1 receptor signaling and anti-inflammatory wall protection beyond BP control [10,52]
	Beta-blockers	Propranolol	Suppression of sympathetic-driven vascular inflammation and wall remodeling beyond BP effect [53]
	CCBs	Amlodipine	Preservation of elastic lamina and attenuation of inflammatory signaling beyond BP control [54]
Vasodilators	Rho-kinase inhibitors	Fasudil	Inhibition of Rho-kinase–mediated vascular inflammation and medial wall degeneration beyond BP effect [55]
Vasodilators	Direct-acting vasodilators	Hydralazine	Reduction of hemodynamic stress via BP normalization [10]
Lipid-lowering agents	Statins	Simvastatin	Upregulation of eNOS and suppression of NF-κB–mediated inflammation [37-39]
Anti-inflammatory agents	NSAIDs	Aspirin	Suppression of COX-2–mediated inflammation and NF-κB signaling beyond antiplatelet effect [26,40]
	Selective COX-2 inhibitors	Celecoxib	Selective COX-2 inhibition and downstream suppression of NF-κB–mediated inflammation [26]
	DPP-4 inhibitors	Anagliptin	DPP-4 inhibition–induced GLP-1 signaling activation and suppression of vascular inflammation [28]
Antioxidants	Ubiquinones	Coenzyme Q10	Suppression of NF-κB–driven inflammation and oxidative stress contributing to vessel wall stabilization [47]
	iNOS inhibitors	Aminoguanidine	iNOS inhibition and reduction of nitrosative stress and inflammatory vascular damage [56]
	Nrf2 pathway activators	Dimethyl fumarate	Activation of Nrf2 signaling and suppression of oxidative stress and macrophage-driven inflammation [57]
	Tryptophan derivatives	Melatonin	Activation of SIRT1/Nrf2 signaling and modulation of autophagy to stabilize vessel wall
MMP inhibitors	Tetracyclines	Doxycycline, minocycline	Direct MMP inhibition and extracellular matrix preservation [24,42]
Immune-modulating agents	TNF-α inhibitors	Etanercept	TNF-α blockade reducing vascular inflammation and cytokine-driven aneurysm wall damage [58]
Immune-modulating agents	mTOR inhibitors	Sirolimus	mTOR inhibition–induced autophagy activation and suppression of vascular inflammation and degeneration [43]
Metabolic agents	Oral hypoglycemic agents	Metformin	Activation of AMPK signaling and inhibition of NF-κB–mediated inflammation and wall remodeling [41]
Metabolic agents	Oral hypoglycemic agents	Pioglitazone	PPARγ activation suppressing vascular inflammation and extracellular matrix degradation [31]
Anticonvulsants	Sodium channel blockers	Topiramate	Glutamate signaling inhibition and suppression of neuroinflammation around aneurysmal wall [59]
Natural compounds	Polyphenols	Resveratrol	SIRT1/Nrf2 activation and oxidative stress–driven vascular inflammation suppression [43]
	Polyphenols	Curcumin	NF-κB inhibition and antioxidant response contributing to vascular inflammation control [44]
	Isoflavones	Daidzein	Estrogen receptor β–mediated vascular protection via downregulation of inflammation and MMP-9 expression [30]
	Plant alkaloids	Berberine	AMPK and Nrf2 activation suppressing oxidative stress and vascular inflammation [60]
	Sulfur-containing compounds	Sulforaphane	Upregulation of Nrf2-driven antioxidant defense reducing oxidative stress and preserving vascular structure [61]
	Marine polysaccharides	Fucoidan	Inhibition of microglial-mediated neuroinflammation and oxidative stress surrounding the aneurysmal wall [62]
Vitamins and minerals	Vitamins	Vitamin D	Activation of vitamin D receptor signaling reducing inflammatory damage to the aneurysm wall [45]
	Vitamins	Folic acid	Homocysteine reduction and endothelial protection via folate metabolic pathway activation [51]
	Minerals	Magnesium	Improvement of endothelial function and reduction of oxidative stress independent of BP [63]
		Zinc	Induction of A20 expression and suppression of NF-κB–mediated inflammation in aneurysm wall stabilization [64]
		Copper	Promotion of lysyl oxidase–dependent matrix cross-linking to maintain aneurysm wall structural integrity [65]
Fatty acids	Omega-3 fatty acids	Eicosapentaenoic acid	Activation of PPARγ and inhibition of NF-κB–mediated inflammation in aneurysm wall protection [50]
Biological products	Probiotics	-	Modulation of gut–brain axis and suppression of systemic and vascular inflammation [66]

ACE, angiotensin-converting enzyme; AMPK, AMP-activated protein kinase; ARB, angiotensin II receptor blocker; BP, blood pressure; CCB, calcium channel blocker; COX-2, cyclooxygenase-2; DPP-4, dipeptidyl peptidase-4; eNOS, endothelial nitric oxide synthase; GLP-1, glucagon-like peptide-1; iNOS, inducible nitric oxide synthase; LOX, lysyl oxidase; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chainenhancer of activated B cells; Nrf2, nuclear factor erythroid 2–related factor 2; NSAID, non-steroidal anti-inflammatory drug; PDE3, phosphodiesterase type 3; PPARγ, peroxisome proliferator-activated receptor gamma; SIRT1, sirtuin 1; TNF-α, tumor necrosis factor-alpha.