In the context of atherosclerosis, specific immune molecules and pathways do indeed play varying roles at different stages of disease progression. In the early stages, modified endogenous molecules such as oxidized low-density lipoprotein (oxLDL) become crucial, providing antigens for antigen-presenting cells and promoting the activation of adaptive immunity, particularly through T helper cells that release pro-inflammatory cytokines like interferon (IFN)-γ [17]. Cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 also play significant roles in early inflammation, facilitating the recruitment of immune cells to the plaque site. As atherosclerosis advances, macrophages become dominant in the lesions, and their function shifts depending on the local microenvironment and the type of signals they receive, influencing plaque stability or vulnerability [18,19]. In Fig. 1, we summarized the stages and key features of these stages of atherosclerosis development.

During plaque rupture and cardiovascular events, the dynamics change as other immune cells, including T lymphocytes and neutrophils, contribute to the inflammatory milieu and can promote lesion instability [20,21]. For instance, cytotoxic T cells and natural killer T (NKT) cells release pro-atherogenic cytokines and participate in apoptosis within the plaque, reinforcing the risk of rupture. Neutrophils, while contributing to early endothelial dysfunction, are implicated in late-stage events, such as thrombosis and inflammation at the site of ruptured plaques, through mechanisms including the formation of neutrophil extracellular traps (NETs) [22,23].

The TLR4/NF-κB pathway plays a stage-specific role in atherosclerosis. During early disease, TLR4 activation promotes pro-inflammatory signaling, monocyte recruitment, and foam cell formation, accelerating plaque development. However, in later stages, controlled NF-κB activity may also contribute to tissue repair and resolution of inflammation. These dual roles suggest that TLR4/NF-κB inhibition may need to be phased or context-specific, with early suppression likely beneficial, whereas late-stage broad inhibition could impair healing, indicating the need for targeted or time-dependent approaches [24].

Cytokines such as IL-1β also gain prominence in later stages, as the immune response can pivot toward a more destructive path, culminating in acute cardiovascular events. Thus, the interplay of cytokines and immune cells reflects a complex balance where specific immunological factors are pivotal at various stages, emphasizing the need for targeted therapeutic strategies that take into account the stage of atherosclerosis when addressing immune involvement [25,26].

Canakinumab is a human monoclonal Ab that is used in auto-immune disorders for neutralization of IL-1β signaling. CANTOS study investigated the hypothesis that this drug can considerably decrease the occurrence of detrimental CV events in subjects with a history of heart attack [58,59]. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) was a landmark clinical trial designed to investigate the role of inflammation in cardiovascular disease, specifically targeting IL-1β with the monoclonal antibody canakinumab. This randomized, double-blind, placebo-controlled study enrolled 10,061 patients who had a history of myocardial infarction and elevated levels of high-sensitivity C-reactive protein (hs-CRP), indicative of ongoing inflammation [60,61]. Participants were randomly assigned to receive either canakinumab or placebo, with treatment administered in three different doses (50, 150, or 300 mg) every three months over an average follow-up period of approximately 4 years. The primary outcome was the occurrence of major adverse cardiovascular events (MACE), which included non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death [62,63]. The findings were significant; canakinumab treatment was associated with a 15% reduction in MACE compared to placebo, particularly demonstrating a 24% reduction in cardiovascular death among those in the higher dose groups. These results not only underscored the role of inflammation in atherosclerosis but also suggested that targeting inflammatory pathways could provide a novel approach to reducing cardiovascular risk, marking a critical shift in the management of coronary artery disease and challenging traditional risk factor-based treatment paradigms [6,64].

While the CANTOS study underscores the significant benefits of the IL-1β inhibitor canakinumab in reducing cardiovascular events, it is essential to consider the limitations that may impact its clinical applicability. The study demonstrated a 15% reduction in major adverse cardiovascular events (MACE) among patients with a history of myocardial infarction and elevated high-sensitivity C-reactive protein levels when treated with canakinumab [59]. This reduction included a notable 24% decrease in cardiovascular deaths, highlighting its potential as a groundbreaking therapy for targeting inflammation in coronary artery disease. However, the practical use of canakinumab is constrained by several notable drawbacks. Firstly, the high cost associated with canakinumab may limit accessibility for many patients, particularly given that long-term treatment could be necessary for optimal benefit [65]. Secondly, the treatment was associated with an increased risk of serious infections, as IL-1β plays a critical role in the body’s immune response. Patients receiving canakinumab may experience heightened susceptibility to infections, which necessitates careful patient selection and monitoring. Thus, while canakinumab offers promising therapeutic potential, its cost and safety profile must be balanced against the benefits to ensure responsible and effective clinical application [66,67].

The major adverse CV events involve such harmful conditions as heart attack (MI), ischemic stroke, CV death, as was reported by Ridker and colleagues [68]. Moreover, Everett and colleagues revealed that the subjects who were treated with canakinumab showed a reduction in hospital admission as well as in CV mortality related to cardiac failure [69]. Although therapy with this drug has a high cost. It is also connected to an elevated risk of various infections by different pathogens, which can turn out to be peripheral or systemic.

Furthermore, as was found by Morton and colleagues, anakinra is a suppressant of IL-1α and IL-1β [70]. Anakinra efficiently inhibits the IL-1α and IL-1β signaling, thus reducing the genesis of C-reactive protein and decreasing the occurrence of major adverse CV events [71].

Canakinumab and Anakinra are IL-1 inhibitors that play a significant role in modulating inflammation associated with CAD. Canakinumab is a human monoclonal antibody that selectively inhibits IL-1β, a key pro-inflammatory cytokine involved in the inflammatory response. By neutralizing IL-1β, canakinumab effectively dampens the inflammatory cascade that contributes to atherosclerosis [72,73]. Anakinra works similarly by blocking both IL-1α and IL-1β, preventing their signaling through the IL-1 receptor. Clinical studies have demonstrated that these therapies can significantly reduce levels of CRP and other inflammatory markers, resulting in a decreased incidence of MACE in patients with elevated hs-CRP levels following myocardial infarction [74,75].

Methotrexate, a drug traditionally used in the treatment of malignancies and autoimmune diseases, has garnered attention for its potential role in preventing and treating CAD. Its effectiveness in this context largely stems from its anti-inflammatory properties, which target mechanisms that contribute to the progression of atherosclerosis and cardiovascular events [94]. Methotrexate suppresses the pro-inflammatory cytokines. Among such cytokines are TNF-α, IL-1β, and IL-6. These pro-inflammatory cytokines play a huge role in the progression of AS and other inflammatory diseases mediated by immunity, as was reported by Van Breukelen-van der Stoep and colleagues [95].

Methotrexate, originally used for cancer and autoimmune diseases, serves as another therapeutic option by suppressing the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines play a pivotal role in the progression of atherosclerosis [96–98]. Methotrexate has also been shown to have effects on the adenosine A2A receptor (ADORA2A), promoting reverse cholesterol transport and preventing atherogenesis. Although studies on methotrexate’s efficacy in CAD have shown mixed results, it has potential atheroprotective effects, particularly in patients with inflammatory conditions such as rheumatoid arthritis [99].

Methotrexate works by inhibiting the production of pro-inflammatory cytokines, such as TNF-α and IL-6. By suppressing these inflammatory mediators, methotrexate helps reduce the inflammatory response that can exacerbate vascular pathology. This effect is particularly relevant in patients with conditions characterized by systemic inflammation, such as rheumatoid arthritis, who have a notably higher risk of cardiovascular disease [100,101].

Clinical studies investigating the efficacy of methotrexate in CAD have yielded mixed results. Some trials suggest that low-dose methotrexate can lower levels of inflammatory markers like hs-CRP, which is a biomarker associated with an increased risk of cardiovascular events. For instance, the Cardiovascular Inflammation Reduction Trial (CIRT) studied the impact of methotrexate on patients with a history of myocardial infarction and elevated hs-CRP levels [102–104]. While the trial found that methotrexate treatment did not significantly reduce major adverse cardiovascular events compared to placebo, it did succeed in lowering hs-CRP levels, suggesting some anti-inflammatory efficacy [105].

Moreover, the potential atheroprotective effects of methotrexate may also arise from its capability to enhance reverse cholesterol transport, a process crucial for removing excess cholesterol from arterial walls. This mechanism, combined with its ability to stabilize existing plaques and reduce their vulnerability to rupture, posits methotrexate as a beneficial therapy in patients at high risk of acute coronary events [106]. Treatment strategies that involve methotrexate, methotrexate with etanercept, or methotrexate with sulfasalazine and hydroxychloroquine demonstrated amelioration in the high-density lipoprotein profile of RA subjects, as was reported by Charles-Schoeman and colleagues [107]. Furthermore, methotrexate showed an ability to exert atheroprotective effects via activation of ADORA2A. Upon activation, the ADORA2A can curb the foam cell formation, as was reported by Reiss and colleagues [108]. Besides, monotherapy with this drug, as well as this drug in combination with TNF-α suppressants, can decrease the lipoprotein A Lp(a) and endothelial leucocyte adhesion molecule-1 (ELAM-1) concentrations in serum. In comparison to other disease-modifying antirheumatic drugs in randomized clinical trials (RCTs), this drug can control the stiffness of arteries and the increase in blood pressure related to it [109,110]. These findings indicate that methotrexate’s efficiency is likely higher than that of other disease-modifying antirheumatic drugs in the disruption of inflammation pathways, as was reported by Woodman and colleagues [111]. Another double-blind RCT established the efficacy of this drug at low dosage in decreasing the occurrence of CV events in subjects with stable AS. That trial has been terminated after an average observation period of 2.3 years. Although its results demonstrated that this drug was not able to decrease the concentrations of such markers as IL-1, IL-6, and C-reactive protein [112,113]. Occurrence of detrimental CV events was not reduced either in comparison to the placebo group. Furthermore, methotrexate showed such adverse side effects as increased concentrations of hepatic enzymes, decreased number of leukocytes, decreased hematocrit level, and a higher rate of non-basal cell carcinoma (BCC) cancer occurrence in comparison to the placebo group, as was reported by Ridker and colleagues [114].

Despite the complexities in its application, methotrexate embodies a promising avenue in the broader landscape of anti-inflammatory therapies aimed at reducing cardiovascular risk. As the field continues to evolve, its integration into treatment regimens for patients with coronary artery disease may become clearer, particularly for those with underlying inflammatory conditions. Overall, while methotrexate may not represent a definitive solution for CAD management, its potential to modulate inflammation offers valuable insights into the intricate interplay between immune responses and cardiovascular health [115].

Statins exert pleiotropic effects against inflammation. Statins, such as atorvastatin, are widely prescribed as cholesterol-lowering agents but also exhibit significant anti-inflammatory properties that contribute to cardiovascular risk reduction. They work by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, which not only reduces lipid levels but also decreases the production of pro-inflammatory cytokines. Statins improve endothelial function and have been shown to stabilize atherosclerotic plaques. In clinical trials, statin therapy has resulted in reductions in hs-CRP levels and improved cardiovascular outcomes among patients, showcasing their role beyond traditional lipid management [116–118].

They also show fat-decreasing properties. Numerous studies indicated that statins are able to suppress the activation of T lymphocytes that depend on antigens. Statins are also capable of reducing the inflammatory cell count and of stimulating the synthesis of nitric oxide by the endothelium, as was reported by Kwak and colleagues [119–121]. Ridker and colleagues conducted a series of studies that showed the ability of statins to decrease the high-sensitivity C-reactive protein concentrations in plasma in subjects without MACE history [122]. Hereby, statins seem to be able to help down-regulate inflammatory processes, both vascular and systemic. However, further research is necessary since now any evident therapeutic benefits achieved by lowering high-sensitivity C-reactive protein levels are difficult to distinguish from the fat-reducing activity of statins [123,124]. It was reported that in the AVERT trial, atorvastatin therapy resulted in reduced occurrence of hospital admission and ischemic events in subjects with angina pectoris and CAD [125]. Statin usage for CV event prevention could be helpful in subjects with hypertension, DM, tobacco use, coronary artery disease family history, or in subjects with elevated CV risk assessed with the Framingham risk score (FRS). Subjects treated with statins are generally advised to have their C concentrations and hepatic functioning monitored regularly [126].

Statins exert multiple cardiovascular benefits beyond lipid-lowering, including improvement of endothelial function and inhibition of platelet activation. These effects are partly independent of their anti-inflammatory actions, as they can enhance nitric oxide bioavailability and reduce platelet aggregation directly. Additionally, variations exist among statins in anti-inflammatory potency; for instance, rosuvastatin and atorvastatin both reduce hs-CRP, but rosuvastatin may exhibit slightly greater anti-inflammatory efficacy at equivalent lipid-lowering doses [127].

Statins, widely prescribed for lowering cholesterol, are increasingly recognized for their anti-inflammatory properties that contribute to cardiovascular risk reduction. They exert their effects by inhibiting HMG-CoA reductase, leading to reduced cholesterol synthesis, which in turn decreases the production of pro-inflammatory cytokines and improves endothelial function. Statins have been shown to lower levels of hs-CRP, a marker of inflammation, independently of their cholesterol-lowering effects [116,128]. Clinical evidence supporting the anti-inflammatory benefits of statins comes from numerous large-scale trials, such as the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, which demonstrated that rosuvastatin significantly reduced cardiovascular events in individuals with elevated hs-CRP but normal LDL levels. Additionally, statins are associated with stabilization of atherosclerotic plaques, making them less likely to rupture and lead to acute cardiovascular events. The clinical implications of statin therapy extend beyond lipid management; their ability to modulate the immune response suggests a role in the comprehensive management of patients at high cardiovascular risk, particularly those with inflammatory conditions like rheumatoid arthritis or metabolic syndrome [129,130].

Colchicine is a drug that exhibits activity directed against inflammation. It is applied in cases of gout for prophylaxis and therapy [131]. Imazio and colleagues conducted trials on the application of colchicine for AS cardiac disorders management [132]. Given the anti-inflammation effect of this drug, it suppresses the synthesis of IL-1β and inhibits ELAM-1 expression, which is required for adhesion of neutrophils in endothelial cells (ECs). Furthermore, this drug abolishes cryopyrin inflammasome complex (NLRP3 inflammasome) activation, inhibiting the expression of IL-1β and IL-6 synthesized after the signals of danger [72,133].

Colchicine, a drug traditionally used for gout, has emerged as a promising therapy for CAD due to its anti-inflammatory properties. Colchicine inhibits microtubule polymerization, which is essential for the inflammatory response, particularly in inhibiting the activation and migration of neutrophils. It also directly suppresses the synthesis of IL-1β by inhibiting the activation of the inflammasome complex, particularly the cryopyrin inflammasome. These actions lead to a significant reduction in MACE, especially in stable CAD patients, by lowering inflammatory markers and resulting in decreased risk of unstable angina and myocardial infarctions [134–136].

Huang et al. discovered that administration of this drug to rats with elevated cholesterol levels considerably decreased concentrations of C-reactive protein and Lp-related phospholipase A2 (PLA2) in blood [137]. Moreover, this therapy has been proven to enhance the synthesis of NO, which implies that there has been a significant amelioration of the functioning of the endothelium. Results of a proteomics research showed that subjects with coronary artery disease who received colchicine therapy showed notably decreased expression of cryopyrin pathway cascade (IL-18, IL-6) as well as the acquired immunity response via suppression of CCL17, CD-40 [138,139]. Silvis and colleagues reported that median concentrations of high-sensitivity C-reactive protein and EV cryopyrin were considerably decreased as well after treatment with colchicine [140].

The RCT LoDoCo (Low-Dose Colchicine), which was focused on the secondary prevention of CV events, involved 532 subjects with stable CAD, as was reported by Nidorf and colleagues [141]. Following a median of 3 years, the observation demonstrated that therapy with colchicine was able to considerably decrease the occurrence of CV mortality, noncardioembolic stroke, acute coronary syndrome (ACS), and sudden cardiac arrest (SCA). The decrease in ACS was seventy-two percent, where more than fifty percent of the decrease was accounted for by the decreased incidence of unstable angina pectoris [142,143]. Nidorf and colleagues indicated that the LoDoCo-2 study has validated these discoveries, demonstrating a remarkable reduction in MACE in subjects with stable CAD following the colchicine therapy [141]. The median follow-up time in this study was reported to be 28.6 months.

The COLCOT (COLchicine Cardiovascular Outcomes Trial) trial was large-scale and involved investigation of the positive effects of colchicine therapy for secondary prevention of adverse CV events [144]. This trial involved 4745 subjects who had previously had ischemic stroke or myocardial infarction (MI) not long before the trial. These subjects were divided into two groups, where the first group was administered colchicine at a low dosage and the second group received a placebo. According to Tardif and colleagues, the results from the first group showed that the colchicine therapy decreased the adverse CV events by 23%, e.g., MI, ischemic stroke, SCA with resuscitation, hospital admission for angina resulting in re-vascularisation, and CV mortality [145]. Bouabdallaou and colleagues discovered that early administration of this drug within the first three days of MI showed notable positive effects, with a forty-eight percent relative risk decrease in the primary outcome [144]. These discoveries indicate that administration of this drug in hospitals to subjects with MI has great potential and exhibits a powerful positive impact.

Colchicine has emerged as a promising anti-inflammatory therapy for the secondary prevention of cardiovascular events, as highlighted in the LoDoCo and COLCOT trials. In the LoDoCo trial, colchicine significantly reduced the occurrence of major adverse cardiovascular events (MACE) by 72%, primarily by lowering the risk of unstable angina pectoris, while the COLCOT trial demonstrated a 23% reduction in cardiovascular events among patients who had experienced a recent myocardial infarction [146]. These findings underscore colchicine’s potential to exert beneficial effects by modulating inflammatory pathways involved in atherosclerosis and thrombosis. However, the clinical utility of colchicine must be tempered by an awareness of its potential side effects, which can include gastrointestinal disturbances, such as diarrhea, nausea, and abdominal pain. More seriously, colchicine has the potential to cause myelosuppression, which could lead to leukopenia and increase the risk of infections [147,148]. Furthermore, colchicine’s narrow therapeutic index means that careful dosing and monitoring are required to avoid toxicity, especially in patients with renal impairment or those taking medications that can interact with colchicine and affect its metabolism. Therefore, while colchicine offers a novel approach to managing cardiovascular risk through inflammation reduction, clinicians must consider both its efficacy and safety profile in order to optimize patient outcomes and minimize adverse effects [149,150].

Evidence suggests that integrating immune suppression with statin therapy can amplify the overall effects on cardiovascular health. Studies have demonstrated that statins not only lower lipid levels but also possess pleiotropic effects, including anti-inflammatory properties. Combining these with targeted immune suppressors may provide a dual mechanism: statins can reduce lipid accumulation and stabilize plaques, while immune suppressors can mitigate the inflammatory processes that contribute to plaque instability and cardiovascular events [153,154].

However, while there are promising preliminary findings regarding the benefits of such combination therapies, comprehensive clinical data specifically targeting high-risk groups are still emerging. Some studies, such as those examining Canakinumab, have shown reductions in cardiovascular events in patients with elevated hs-CRP levels, suggesting that targeting inflammation can be beneficial in addition to standard lipid management. Yet, more extensive clinical trials are needed to provide robust evidence and clarify long-term outcomes, safety, and optimal treatment protocols for combining these therapies [155–157].

In summary, while there is a rationale for combining immune suppression therapies with lipid-lowering drugs to further reduce cardiovascular risks, particularly in high-risk patients, further research is necessary to establish conclusive clinical guidelines and evidence supporting this approach. This combination could ultimately lead to more effective strategies for managing cardiovascular disease [158,159].

The potential of immune suppressors like Tocilizumab and Canakinumab in reducing cardiovascular risk has garnered significant interest, particularly due to their anti-inflammatory properties. Long-term data supporting the effectiveness of these drugs in cardiovascular risk reduction is still emerging. For example, the CANTOS trial demonstrated that Canakinumab reduced the risk of cardiovascular events in patients with a history of myocardial infarction and elevated hs-CRP levels [160,161]. However, while these findings are promising, the duration of follow-up in such studies may not yet be sufficient to fully assess the long-term benefits and risks associated with these therapies. Further studies are needed to evaluate the long-term cardiovascular outcomes and overall safety of these agents across diverse populations [162–164].

Assessing the risks associated with long-term use of immune suppressors is crucial, particularly in elderly patients who may present with multiple comorbidities. Immune suppressive therapy can increase the risk of infections, malignancies, and other adverse effects due to its mechanism of action, which dampens the immune response. For elderly patients, who often have age-related immune senescence and may already be at heightened risk for infections, this aspect is particularly concerning. Moreover, the use of these medications can complicate the management of existing health conditions and may interact with other medications, potentially affecting patient safety and adherence to therapy [165,166].

Patient compliance is another significant factor in the long-term use of these drugs. Adherence to treatment regimens can be influenced by the complexity of medication schedules, potential side effects, and the perceived benefits of therapy. Ensuring that patients understand the rationale behind the treatment, the importance of adherence for cardiovascular risk reduction, and the management of any arising side effects is critical. Regular follow-up and monitoring can help address concerns and modify treatment as necessary, improving compliance and overall satisfaction with the treatment plan [167,168].

In summary, while there is emerging evidence on the effectiveness of immune suppressors like Tocilizumab and Canakinumab in reducing cardiovascular risk, long-term data is still required to substantiate their use, particularly concerning safety in elderly patients. Careful risk assessment, patient education, and ongoing monitoring are vital to optimize therapy and enhance adherence to treatment in this vulnerable population [169,170].

Allopurinol (ALP) and oxipurinol serve as a substrate for the enzyme xanthene oxidase. Xanthene oxidase contributes to the conversion of hypoxanthine into xanthine, which is followed by the xanthine transformation into uric acid (UA). Suppressants of xanthene oxidase notably decrease oxidative stress (OS) and downregulate the synthesis of UA [171,172]. Research has suggested that allopurinol’s effects on oxidative stress and endothelial function may contribute to its protective role in CAD, although further studies are warranted to better understand its efficacy in this context. Hereby, they contribute to the decrease of the risk of endothelium function impairment as well as of the inflammatory process, which facilitate the development of atheromatous plaques and CV disease.

ALP was proved to exert 3 major effects which account for its powerful CV activity. The first is the ability to decrease circulating UA concentrations since it has proinflammatory properties. The second is its capacity of suppressing the synthesis of ROS, which stimulates endothelium function impairment and affects the stability of atheromatous lesions. The third is the ability to curb AS, as well as to protect from ischemia/reperfusion injury (IRI) [173–175].

The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial group of authors performed a trial on subjects with stable coronary artery disease. The authors discovered that even though the subjects received optimal treatment and re-vascularization, they showed life quality reduction and exhibited symptoms [176,177]. Weintraub and colleagues concluded that it should be advised that ALP and similar agents are better used as an additional treatment of angina because of their capacity of alleviating endothelium function impairment by reducing the synthesis of UA and free radicals [178].

Another research was performed by Baldus and colleagues on subjects with coronary artery disease with no history of ALP therapy [179]. The subjects were administered with acetylcholine (ACh). The researchers assessed the coronary vaso-constrictor response of the subjects to this compound as well as alterations of coronary artery circulation following administering of ALP metabolite oxipurinol. Oxipurinol did not influence ACh-dependent alterations in subjects with preserved functioning of the coronary endothelium. Although in subjects with endothelium functioning impairment, administering oxipurinol led to a considerable amelioration in artery MLD and coronary artery circulation. The trial results showed that free radicals obtained from XO diminished the availability of NO. Suppression of oxipurinol might ameliorate the functioning of the endothelium in coronary vessels in subjects with coronary artery disease [180,181].

Another research of angina pectoris involved sixty subjects. The subjects had stable angina and received treatment with pentaerythritol tetranitrate (PETN) and ALP. The results showed that this combined treatment is much more efficient than the PETN treatment alone. After the treatment, the subjects showed a considerable decrease in serum and urine concentrations of UA [182,183]. Kaliakin and Mit’kin observed that this therapy resulted in a reduction of lipid peroxidation (LPO) and anti-oxidative system functioning as well as in a significant amelioration of central haemodynamics [184].

Another RCT evaluated the application of ALP in the elevation of the exercise ability of sixty-five subjects with CAD, stable angina pectoris, and positive exercise tolerance. The results of the trial showed that ALP therapy was able to considerably decrease concentrations of UA as well as to elevate the St depression time, time of the physical activity, as well as time to angina pectoris. The results resemble those of several presently used anti-anginal agents [185,186]. The researchers indicated that ALP has a good safety profile, is sufficiently tolerated, and has acceptable cost as an antiischemic compound for subjects with angina. Noman and colleagues theorized that endogenous XO action might account for the coronary ischemia caused by exercise [185].

ALP upregulates synthesis of adenosine triphosphate and elevates exercise ability, retaining the supply of oxygen to the myocardium even at the peaks of exercise. ALP was also proved to ameliorate the functioning of the endothelium and to decrease coronary artery vasoconstriction parameters, as was reported by Stone and colleagues [187]. Recent research was performed on eighty subjects with CAD. The results showed that ALP therapy considerably ameliorated vasorelaxation depending on the endothelium, as well as inhibited OS in subjects with CAD [188].

Lipid rafts play a prominent role in the pathogenesis of inflammation associated with cardio-metabolic diseases. These cholesterol- and sphingolipid-rich membrane microdomains act as organizing centers for many signaling molecules and are crucial in the initiation and propagation of inflammatory responses [189]. Rafts host a wide range of receptors that regulate innate and adaptive immunity. Toll-like receptor 4 (TLR4), tumor necrosis factor receptor 1 (TNFR1), integrin CD11b, and antigen receptors such as BCR and TCR are recruited into lipid rafts during activation [189]. CD36, a scavenger receptor implicated in the uptake of oxLDL, also localizes to rafts, where it drives foam cell formation and contributes to metabolic inflammation [190]. Given this role, raft abundance strongly influences inflammatory signaling. Augmentation of rafts enhances receptor clustering, potentiates downstream signaling, and promotes cytokine secretion [191], whereas raft disruption attenuates these responses, demonstrating an anti-inflammatory effect [192].

Therapeutic targeting of lipid rafts has therefore emerged as a promising strategy to modulate inflammation in atherosclerosis as well as in other inflammatory diseases [193]. Because rafts depend on cholesterol and sphingolipids for their stability, agents that alter lipid composition or interfere with raft-associated receptors can attenuate pro-inflammatory signaling. Statins not only reduce systemic LDL cholesterol but also disrupt raft cholesterol, thereby reducing TLR4 and TNFR1 signaling in vascular cells [124,194]. MβCD and hydroxypropyl-β-cyclodextrin (HPβCD) extract cholesterol from rafts, reduce foam cell formation, and lower atherosclerotic burden in animal models, though systemic toxicity limits their translational potential [195,196]. Agents targeting sphingolipids, such as inhibitors of sphingomyelin synthesis (e.g., myriocin) or sphingomyelinase inhibitors, destabilize ceramide-rich raft domains and prevent clustering of death and inflammatory receptors [197]. Another therapeutic strategy is to block raft-resident receptors directly: monoclonal antibodies or small molecules targeting CD36 and TLR4 reduce ligand binding, prevent receptor clustering, and inhibit foam cell formation and cytokine release [198]. Novel small molecules and natural compounds also show promise; synthetic oxysterols such as Oxy210 redistribute raft cholesterol and attenuate macrophage inflammation [199], while polyphenols like resveratrol and curcumin weaken raft integrity and reduce inflammatory signaling, though their bioavailability remains a limitation [200,201]. Another promising agent, apolipoprotein A-I binding protein (AIBP), was shown to reduce lipid rafts content, inhibit inflammatory responses to LPS, and confer protection against atherosclerosis in a mouse model [202]. Finally, nanoparticle-based therapeutics are emerging as highly specific approaches to modulate raft composition and signaling. Lipid- and protein-decorated nanoparticles designed to selectively target raft domains reduce systemic toxicity and hold translational potential in cardiovascular disease [203].

Overall, lipid rafts act as central hubs for inflammatory receptor signaling in atherosclerosis, and their abundance and composition directly influence disease progression. Multiple therapeutic classes, including cholesterol modulators, raft disruptors, sphingolipid-targeting agents, receptor-specific inhibitors, oxysterols, natural compounds, and nanoparticles, demonstrate preclinical efficacy, but the challenge remains to translate these raft-targeted therapies into safe and effective treatments for cardiovascular disease.

Suppression of SGLT2 is unanimously acknowledged as an important part of managing DM, cardiac failure, and renal disorders, as was reported by Carnicelli and Mentz [204], Padda [205], Vaduganathan and colleagues [206]. Suppression of sodium-glucose transport protein 2 shows pleiotropic impact, which may be explained by different factors, such as powerful activity directed against inflammation, as was reported by Elrakaybi [207], La Grotta and colleagues [208]. Theofilis and colleagues conducted a number of RCT and revealed a remarkable efficacy of the treatment of cardiac failure with decreased left ventricular ejection fraction (LVEF) [209]. In case of elevated LVEF, the effect of the treatment is yet to be fully discovered. Novel medications, e.g., angiotensin receptor/neprilysin inhibitor (ARNI) and finerenone, might be able to alleviate the burden associated with cardiac failure [210,211].

SGLT2 inhibitors, such as empagliflozin, have gained attention not only for their glucose-lowering effects in diabetes management but also for their anti-inflammatory and cardioprotective benefits. These agents promote urinary glucose excretion, which can reduce body weight and improve glycemic control. In addition to their metabolic effects, SGLT2 inhibitors have been shown to exert favorable effects on inflammation and oxidative stress, both of which are critical in the pathogenesis of cardiovascular disease [212,213].

Clinical trials demonstrate that SGLT2 inhibitors significantly lower the risk of hospitalization for heart failure and reduce MACE among patients with existing cardiovascular disease or those at high risk [214].

Recent research involved thirty studies which were focused on the impact of sodium-glucose transport protein 2 suppressants on inflammation biomarkers. The results of this research showed that sodium-glucose transport protein 2 suppressants therapy considerably decreased concentrations of IL-6, C-reactive protein, TNF-α, and monocyte chemoattractant protein 1 [215,216]. When empagliflozin was applied, the reduction of C-reactive protein and TNF-α was not as pronounced. Whereas in this trial, mild-to-significant heterogenous property has been observed and publication bias is probable, these results stayed unaltered following sensitivity analysis [217,218]. The trial results indicated that suppression of sodium-glucose transport protein 2 is able to decrease inflammation biomarkers in animals, confirming the theory of anti-inflammation properties of sodium-glucose transport protein 2 suppressants, as was reported by Theofilis and colleagues [18]. Kondo et al. investigated the characteristics of canagliflozin, which has a greater affinity to sodium-glucose transport protein 1 than to sodium-glucose transport protein 2 [219]. This drug showed remarkable anti-oxidant activity. Canagliflozin was able to decrease the activity of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase, making tetrahydrobiopterin more available and ameliorating NO synthase un-coupling via sodium-glucose transport protein 1/AMP activated protein kinase/RAC-1 pathway. This process leads to alleviation of inflammation and inhibition of apoptosis [220,221]. Although more research is necessary to establish the main cause of these positive effects of these agents on CVD occurrence (sodium-glucose transport protein 1 or sodium-glucose transport protein 2). That is a subject of particular interest, as recent trial indicated that nonselective suppression of sodium-glucose transport protein 2 could turn out to be more efficient in decreasing the risk of hospital admission for heart failure and CV mortality [222–224].

SGLT2 inhibitors have garnered attention not only for their glucose-lowering effects in diabetes management but also for their anti-inflammatory and cardioprotective benefits. These agents promote urinary glucose excretion, which has been shown to reduce body weight and improve glycemic control [225]. In addition to these metabolic effects, SGLT2 inhibitors also exert favorable effects on inflammation and oxidative stress, mechanisms that are critical in the pathogenesis of cardiovascular disease. Studies such as EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction) and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) have demonstrated that SGLT2 inhibitors significantly lower the risk of hospitalization for heart failure and reduce major cardiovascular events among patients with existing cardiovascular disease or at high risk [226–229]. The cardiovascular benefits of SGLT2 inhibitors extend beyond their diuretic and antihypertensive effects. Evidence suggests they exert distinct anti-inflammatory and antifibrotic actions, including reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and attenuation of myocardial fibrosis. Moreover, SGLT2 inhibitors modulate myocardial energy metabolism by promoting ketone utilization, improving mitochondrial efficiency, and enhancing ATP production, which collectively contribute to improved cardiac function and reduced heart failure risk [230]. The anti-inflammatory effects of SGLT2 inhibitors may be linked to reduced levels of circulating inflammatory markers and improved myocardial oxygenation. Clinically, the implications of using SGLT2 inhibitors extend beyond glycemic control; they represent a paradigm shift in the management of patients with heart failure and chronic kidney disease, highlighting the importance of a multi-faceted approach that addresses inflammation and cardiovascular risk concurrently [213].

There is growing interest in researching the utilization of markers to evaluate inflammation, and that interest has been increasing for many years now. Elevated concentrations of high-sensitivity CRP and IL-6 were proved to be closely connected to the adverse cardiovascular events. Although C-reactive protein is generated by the liver. C-reactive protein possibly reflects the result of the pathway of activation of IL-1/IL-6 [114,240]. Hereby, it probably does not facilitate the appearance of such harmful conditions as acute coronary syndrome directly. However, high-sensitivity C-reactive protein seems to be a major marker and is being closely investigated as a predictor of the risk of detrimental CV events.

Recent research has demonstrated that in groups of subjects with elevated risk of AS, high-sensitivity C-reactive protein could be used to predict cardiovascular disease, CV mortality, and overall mortality [241,242]. High-sensitivity C-reactive protein proved to be better as a predictor of such events than residual C risk (as evaluated by LDL-C). This emphasizes the possible perspectives of utilizing C-reactive protein for prediction in evaluation of the risk of adverse CV events in coronary artery disease. Although it is noteworthy that whereas assessable blood markers, e.g., C-reactive protein, give useful information, their usefulness is still restricted since they are not providing information on the atheromatous plaques’ location and degree [243,244].

Inflammatory biomarkers, such as hs-CRP and IL-6, have gained traction as predictive factors for cardiovascular events, providing critical insights into an individual’s risk profile. Elevated levels of these markers are associated with a higher likelihood of adverse cardiovascular outcomes, making them valuable tools in both primary and secondary prevention strategies. For instance, routine measurement of hs-CRP can be employed in clinical practice to stratify risk among patients, particularly for those with elevated cholesterol levels but no apparent traditional risk factors [245,246]. Monitoring hs-CRP levels can help guide treatment decisions, as a significant reduction in hs-CRP following interventions—such as statin therapy or anti-inflammatory treatments like canakinumab—may indicate a favorable response and reduced cardiovascular risk. Clinicians can utilize point-of-care testing and laboratory assessments to routinely measure these biomarkers, integrating them into risk assessment algorithms [247,248]. Moreover, clinical guidelines suggest using hs-CRP measurements to aid in the decision-making process for statin therapy, especially in individuals with intermediate cardiovascular risk. Maintaining awareness of inflammatory markers and their dynamics can enhance patient care by enabling more personalized and proactive management of cardiovascular disease, ultimately striving for better outcomes through targeted interventions [249].

hs-CRP is recognized as a significant biomarker for predicting cardiovascular events, but its predictive accuracy can be influenced by several factors, including obesity, diabetes, infections, and metabolic syndrome. These conditions can lead to elevated levels of hs-CRP due to their association with chronic inflammation, which complicates the interpretation of hs-CRP as an isolated risk marker [250,251]. For example, the presence of obesity and metabolic syndrome can result in persistently elevated hs-CRP levels, thereby masking an individual’s true cardiovascular risk. Similarly, acute infections can cause marked spikes in hs-CRP, making it challenging to assess long-term cardiovascular risk reliably.

To improve the prediction of cardiovascular events using hs-CRP, several strategies can be employed. First, it is essential to interpret hs-CRP levels in the context of the patient’s overall health status, particularly during periods of chronic inflammation or acute illness [252,253]. Measuring hs-CRP when the patient is in a stable condition can yield more reliable readings. Additionally, integrating hs-CRP with other biomarkers or clinical risk factors could enhance its predictive power. For instance, using hs-CRP alongside traditional lipid profiles, like LDL-C, and other inflammatory markers could provide a more comprehensive assessment of cardiovascular risk [254,255].

Furthermore, considering the individual characteristics such as ethnicity, age, sex, and comorbidities when establishing hs-CRP thresholds is vital. Given the variation in hs-CRP levels among different populations and health conditions, a one-size-fits-all approach may not be appropriate. Personalized risk assessment strategies that account for these factors can lead to more accurate predictions. Lastly, utilizing hs-CRP measurements over time rather than relying on a single measurement can capture the dynamic nature of inflammation and provide better risk stratification [256,257].

In conclusion, while obesity, diabetes, infections, and metabolic syndrome can indeed interfere with the accuracy of hs-CRP as a cardiovascular risk predictor, a holistic and personalized approach to its interpretation, along with the use of complementary biomarkers, can substantially enhance its utility in predicting cardiovascular events. This strategy can help clinicians make more informed decisions and ultimately improve patient outcomes in cardiovascular health [258].

Research indicates that these biomarkers, individually and in combination, can enhance the prediction of cardiovascular events, particularly among patients categorized as “intermediate risk.” For example, studies have demonstrated a robust association between elevated levels of IL-6 and TNF-α with increased atherosclerotic risk, suggesting that these pro-inflammatory cytokines can provide insights into the inflammatory processes underlying cardiovascular disease [260,261].

Combining multiple inflammatory biomarkers may yield a more accurate risk assessment, as different markers reflect various aspects of the inflammatory response involved in atherogenesis. This multifactorial approach can improve risk stratification and potentially help identify individuals who may benefit most from preventive interventions.

For instance, a combined evaluation of hs-CRP, IL-6, fibrinogen, and other inflammatory markers could offer a more precise picture of cardiovascular risk and support more tailored treatment approaches [262,263].