Anti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements—A Narrative Review

Abstract

Cardiovascular diseases (CVD) are the leading cause of death worldwide. Since the establishment of the “lipid hypothesis”, according to which, cholesterol level is directly correlated to the risk of CVD, many different lipid-lowering agents have been introduced in clinical practice. A majority of these drugs, in addition to their lipid-lowering properties, may also exhibit some anti-inflammatory and immunomodulatory activities. This hypothesis was based on the observation that a decrease in lipid levels occurs along with a decrease in inflammation. Insufficient reduction in the inflammation during treatment with lipid-lowering drugs could be one of the explanations for treatment failure and recurrent CVD events. Thus, the aim of this narrative review was to evaluate the anti-inflammatory properties of currently available lipid-lowering medications including statins, ezetimibe, bile acid sequestrants (BAS), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fibrates, omega-3 fatty acids, and niacin, as well as dietary supplements and novel drugs used in modern times.

1. Introduction

According to the World Health Organization’s (WHO) Global Health Estimates, ischemic heart disease (IHD) was the leading cause of death in 2019, accounting for 16% of all deaths worldwide [1]. Moreover, IHD was the condition with the highest increase in the number of deaths observed in the period from 2000 (2 million deaths) to 2019 (8.9 million deaths) [1]. Atherosclerosis is the main pathological process leading to the development of IHD, as well as many other cardiovascular diseases (CVD) such as carotid, vertebral, and renal artery stenosis; chronic ischemia of the lower limbs; chronic intestinal ischemia; etc. [2]. Atherosclerosis is characterized by the presence of cholesterol deposits in arterial walls; however, it is believed that the key feature of this process is chronic inflammation and that low-density lipoproteins (LDL) play a crucial role in its cascade. However, the association between LDL levels and risk for CVD occurrence is not yet completely understood given that in clinical practice, an increase in lipid levels is not always accompanied by a higher atherosclerotic burden and vice versa [3]. In that light, it has been shown that some other measures such as high-density lipoprotein (HDL) cholesterol and the level of HDL apolipoprotein AI and its ratio to apolipoprotein B (Apo B/A-I ratio) could represent better markers of atherosclerotic burden [3,4]. Despite this, it should be emphasized that data on the levels of different lipid parameters, including LDL, provide only partial information about the association between lipid profile and cardiovascular risk. In addition, lipoproteins may go through a range of modifications that alter their atherogenicity; however, measurement of these modified lipoproteins has not yet been introduced in routine clinical practice [5].

During the atherosclerotic process, cholesterol-rich particles penetrate the wall of arterial blood vessels, which results in subendothelial accumulation and retention of LDL, leading to their oxidization and/or modification [6]. Those oxidized LDL play a pivotal role in the formation of atherosclerotic plaque [7]. Based on the level of their oxidation, oxidized LDLs can be categorized as minimally modified LDL or extensively oxidized LDL [8]. In response to their presence, vascular smooth muscle cells produce mediators involved in the accumulation of monocytes. Oxidized LDL can also take part in this process. Following the recruitment of leukocytes and monocytes in the arterial wall, the next step in the atherosclerotic cascade is the transformation of monocytes into macrophage foam cells [7]. As a result, endothelial dysfunction occurs, resulting in the formation of atherosclerotic plaque, which consists of lipid particles, leukocytes, and calcium [9]. Their presence in the arterial wall is associated with the secretion of different immune mediators. So far, the role of inflammatory biomarkers such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and IL-6 in the atherosclerotic process has been demonstrated [10,11,12,13]. As a result, systemic inflammation occurs, and the most commonly used indicator of its level is high-sensitivity CRP (hsCRP).

Since the establishment of the “lipid hypothesis” [14], according to which cholesterol level is directly correlated to the risk of CVD, many different lipid-lowering agents have been introduced in clinical practice. Interestingly, it has been shown that the majority of these drugs, in addition to their lipid-lowering properties, may also exhibit some anti-inflammatory and immunomodulatory activities. This hypothesis was based on the observation that a decrease in lipid levels occurs along with a decrease in inflammation. However, it is still not elucidated whether these changes in inflammation levels are driven by the lipid-lowering therapy itself or whether they are the result of LDL reduction and a consequent reverse in atherosclerosis. An insufficient reduction in inflammation during treatment with lipid-lowering drugs could be one of the explanations for treatment failure and recurrent CVD events [9]. In line with this, Tuñón et al., in their position paper [15], stated that the impact of the decrease in lipid levels on inflammation status is independent of the use of lipid-lowering therapy. On the other hand, the CANTOS trial tried to propose the proof of concept that modification of the inflammatory pathways themselves, specifically, the IL-6 signaling pathway, could impact the cardiovascular outcomes [13]. Therefore, the development of new treatment modalities with improved anti-inflammatory performances is an area of increasing interest in IHD.

Based on the aforementioned findings, the aim of the present narrative review is to evaluate the anti-inflammatory properties of currently available lipid-lowering medications.

2. Statins

Statins are the most commonly prescribed lipid-lowering drugs [16]. Currently, seven statins are available on the market: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin [17]. They are usually divided into generations depending on their origin. Representatives of the first generation are isolated from fungal metabolites such as lovastatin, pravastatin, and simvastatin. Synthetic compounds such as atorvastatin, cerivastatin, fluvastatin, pitavastatin, and rosuvastatin represent statins of later generations [16]. Depending on their ability to dissolve in water or lipid-containing media, statins can be divided into hydrophilic (rosuvastatin and pravastatin) or lipophilic (simvastatin, fluvastatin, pitavastatin, lovastatin, atorvastatin) categories [18,19,20,21].

Due to safety concerns regarding the increased risk of rhabdomyolysis, cerivastatin is the only statin withdrawn from the worldwide markets [22].

The lipid-lowering mechanism of action of statins is well known. Statins are reversible and competitive inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme. This enzyme is responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, the rate-limiting step in de novo cholesterol synthesis [23]. A consequence of HMG-CoA reductase enzyme inhibition is decreased mevalonate and cholesterol synthesis, which leads to a compensatory increase in the number of hepatic LDL receptors on the hepatocyte cell surface, uptake of LDL, and its precursors from circulation [16,23,24]. Additionally, statin consumption may inhibit the synthesis of apolipoprotein B-100 (apoB-100) and decrease the synthesis and secretion of triglyceride-rich particles [24,25]. Statins have a modest impact on increasing high-density lipoprotein cholesterol (HDL-C) concentration, while they have no effect on lipoprotein(a) (Lp(a)) concentration and size or density of LDL [25].

Studies have shown that the impact of statins on human health is beyond simple LDL lowering, which is also named “statin pleiotropy” [26,27]. So far, statins exhibited anti-inflammatory effects and benefits in diseases related to inflammation: atherosclerosis [28], chronic heart failure [29], sepsis [30], COVID-19 [31], diabetic nephropathy [32], gastric cancer [33,34], Alzheimer’s diseases [35], bone disorders [36], and autoimmune diseases [37]. Meta-analysis of 15 randomized controlled trials provided evidence that lipophilic statins pose more pleiotropic effects compared to hydrophilic statins due to easier penetration into the cell membranes [38].

Having in mind the association between elevated cholesterol and CVD, it is often difficult to separate the LDL-C-lowering effects of statins from their pleiotropic effects. Nevertheless, through the impact of statins on several factors of inflammation, beneficial statin effects independent of cholesterol reduction may be observed [39]. By considering the mechanism of action of statins, part of their pleotropic effects may be explained as well. Mevalonic acid is synthesized by HMG-CoA reductase and is the precursor of numerous metabolites such as the isoprenoid intermediates farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) [39,40]. When HMG-CoA reductase is blocked, decreased synthesis of isoprenoids and prenylation of small proteins are observed [40]. This evidence may be a possible explanation for the numerous anti-inflammatory effects of statins beyond their lipid-lowering characteristics.

The anti-inflammatory effects of statins can be observed through all the phases of formation, progression, and complications of atherosclerosis [41]. One of the first steps in atherosclerotic lesions is the accumulation of monocytes and macrophages in the arterial walls [42]. Statins can impact the adhesion and migration of inflammatory cells by diminishing the expression of integrin dimer CD11, vascular cell adhesion molecule (VCAM), and leukocyte-function antigen-1 (LFA-1) [42,43,44]. The next step in atherosclerosis is leukocyte migration to subendothelial sites in a process regulated by chemokines [41]. The protective role of statins in this step can be observed through reduced expression of the chemokine monocyte chemoattractant protein-1 (MCP-1), IL-8, which is regulated on activation by normally T-cell expressed and secreted (RANTES) on endothelial cells (ECs) and smooth muscle cells (SMCs) [45,46,47]. Another anti-inflammatory benefit of statins is their ability to reduce the expression of interferon (INF)-γ-induced major histocompatibility complex molecules class II (MHC II) [48].

So far, the correlation between increased levels of the inflammatory marker, CRP, and cardiovascular risk is well described [49]. CRP is an acute-phase reactant, and its production from hepatocytes is stimulated by IL-6, IL-1, and TNF-α [50]. Besides hepatocytes, there is evidence that CRP can be secreted locally by macrophages and artery smooth muscle cells involved in inflammation [51]. Numerous clinical trials have been designed to elucidate details of CRP and statin interaction nature and consequences [52,53,54,55,56]. Several mechanisms of statin-induced reduction in CRP have been proposed. One of the possibilities is the impact of statins on decreasing oxidized LDL (oxLDL) and, therefore, decreased concentration of inflammatory mediators [50]. Recently it has been proposed that the impact of statins on the serum apolipoprotein A-I (apoA-I) levels may be a contributing factor in reducing hsCRP levels [57]. Namely, by increasing apoA-I levels, statins decrease the expression of E-selectin, intracellular adhesion molecule-1 (ICAM-1), and VCAM-1 and consequently decrease inflammation [57]. Another proposed mechanism in combating local inflammation is decreased protein prenylation as a consequence of the ability of statins to decrease oxLDL [39]. As a result of decreased protein prenylation reduction in TNF and IL-6 levels is observed [58]. Interestingly, dual effects of statins were observed regarding the effect on IL-1 levels. On one side there are studies describing the ability of statins to decrease cytokine production such as IL-1 in monocytes in patients with hypercholesterolemia [59,60,61]. The other side of the medal is presented in studies that showed the ability of simvastatin to promote IL-1β activation [62,63]. So far, questions regarding the precise mechanism of statin and IL-1 expression remained open. Besides described mechanisms, even the possibility of direct interactions between statin molecules and CRP are suggested [64].

The impact of statins on nuceleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is under investigation. Studies have shown greater effects of lipophilic statins on NLRP3 complexes compared to hydrophilic statins due to their differences in chemistry and pharmacokinetics [39]. NLRP3 inflammasomes are cytosolic proteins, secreted by numerous immune cells and responsible for the activation of caspase-1 which releases IL-1β and IL-18 [65]. Nowadays, cholesterol is marked as an important NLRP3 activator [66]. Depending on the discussed representative of statin, dual impact, both activation or inhibition on NLRP3 has been described [39]. So far, several studies provided insight into molecular mechanisms of statins inflammasome activation including an increase in ATP release, ROS production, and lysosomal rupture [67,68,69]. On the other hand, the downregulation of NLRP3 by atorvastatin, and rosuvastatin is also stated [60,70,71].

Another possible anti-inflammatory mechanism of statins is their impact on the downregulation of nuclear factor-kappa B (NF-kB) and activator protein-1, transcription factors that influence inflammatory cytokines [39,72]. According to one of the hypotheses, the ability of statins to scavenge free oxygen radicals and to stimulate nitric oxide production leads to the stabilization of NF-kB inhibitor protein, IkBα [73,74]. During the years, studies in vitro, in vivo animal models, as well as in humans provided solid evidence regarding atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin anti-inflammatory effects based on inhibition of NF-kB [75,76,77,78,79,80]. As a result of NF-kB inhibition, a shift to an anti-inflammatory response is obvious.

Another anti-inflammatory characteristic of statins that is independent of their lipid-lowering effects is their ability to decrease the expression of toll-like receptors (TLRs) 2 and 4 on immune cells and prevent lipopolysaccharide (LPS)-induced activation of monocytes, mononuclear cells, and endothelial cells [39,81]. As a result, the statins may lead to atherosclerotic plaque stabilization [39]. Depending on the analyzed study, several potential mechanisms on how statin impacts TLR-signaling pathways have been proposed: inhibition of protein prenylation, direct or indirect NF-kB inhibition, inhibition of MyD88/NF-kB pathway, enhancement of anti-inflammatory response elements [82,83,84,85,86]. Besides the previously discussed mechanisms, an additional mechanism of statin on inflammatory pathways is suggested, such as reduction in transforming growth factor (TGF)-β signaling in T cells, suppression of human dendritic cell maturation induced by oxLDL, disruption of T cell activation, and induction of T regulatory cells [87,88]. To unmask full molecular mechanisms and the multifaced anti-inflammatory nature of statins, further studies are needed.

3. Ezetimibe

Ezetimibe is an inhibitor of intestinal and biliary cholesterol absorption [24]. Ezetimibe inhibits cholesterol transport protein Niemann-Pick C1-like protein 1 (NPC1L1) at the level of the brush border of the small intestine [24,89,90]. As a consequence of decreased cholesterol delivery, the liver increases LDL receptor expression and clearance of LDL from the blood [24]. According to the latest European Guidelines on Dyslipidemia, in the case when LDL-C level is not achieved with the maximum tolerated dose of statin, a combination with ezetimibe is recommended [24]. An alleviating circumstance is the availability of ezetimibe generic products [91]. So far, ezetimibe has proved its efficiency in LDL-C reduction as a monotherapy [92] and in combination with statins [93], bile acid sequestrants [94], or bempedoic acid [24].

So far, studies have described the impact of ezetimibe monotherapy in reducing CRP as statistically nonsignificant compared with placebo [95,96]. A more effective reduction in CRP level was observed in a combination of ezetimibe with statins [96,97]. It was suggested that the ezetimibe effect on lowering CRP is not associated with improved anti-inflammatory function, and it may contribute to LDL reduction [98,99]. It was hypothesized that in order to achieve a decreased synthesis of inflammatory markers, such as CRP, a reduction in LDL of over 30% must be reached [97].

The effect of ezetimibe on several other parameters of inflammation was also investigated. It was shown that ezetimibe reduces the size of adipocytes, accumulation of pro-inflammatory cytokines, serum levels of free fatty acids, and the expression of the TNF-α [100,101]. Simvastatin and ezetimibe in combination reduced IL-18 levels and the expression of IL-1b [102]. A study that compared simvastatin, simvastatin/ezetimibe, and rosuvastatin at equivalent doses showed significant and similar reductions in plasma 8-Epi prostaglandin F2α (8-epiPGF2α), oxLDL, and lipoprotein-associated phospholipase A₂ (Lp-PLA₂) activity in patients with primary hypercholesterolemia [59]. Coadministration of simvastatin and ezetimibe resulted in a lower impact on transcription factor NF-kB binding activity compared to simvastatin monotherapy [103]. Considering that NF-kB activation is dependent not only on oxidated LDL cholesterol concentration but also on cytokines, free fatty acids, and molecules included in intracellular defense [103], this result may be additional proof of statin anti-inflammatory action beyond the lipid-lowering effects.

On the other hand, ezetimibe led to the degradation of IkB and, consequently, suppression of NF-kB activation via the mitogen-activated protein kinase (MAPK) pathway. These findings implied that there is a possibility of ezetimibe use in the therapy of inflammatory diseases [101]. The impact of ezetimibe on the Rho-associated coiled-coil-containing protein kinase (ROCK) was also monitored. It was suggested that statins reduced ROCK more significantly compared to statins and ezetimibe in combination [99].

The impact of ezetimibe on the endothelium was also investigated [104,105,106]. Several studies have investigated statin therapy versus statins with ezetimibe and have provided evidence of no difference in endothelial function [98,104,106,107,108,109,110]. It was suggested that in the absence of hypercholesterolemia, ezetimibe has no impact on endothelial function [104,108,109,110]. Furthermore, studies with better results on endothelial function achieved with statins alone were published [98,104,110]. These findings imply once again the possibility of a statin-specific pleiotropic anti-inflammatory effect. On the other hand, one comparative study described the beneficial effect on impaired endothelial function of atorvastatin and ezetimibe compared to atorvastatin alone [111]. It can be observed that ezetimibe may reduce inflammation in combination with statins, but the effect on endothelial function and its mechanisms remains unresolved.

4. Bile Acid Sequestrants (BAS)

BAS are traditional LDL-C-lowering drugs. They bind bile acids in the intestinal tract, increasing their fecal excretion and reducing enterohepatic circulation. As bile acids are the end products of cholesterol metabolism in the liver, the described process leads to increased bile acid synthesis and consequent serum LDL-C lowering and up-regulation of LDL receptors [112]. In addition, BAS glucose-lowering effect is very well established [113]. The three most frequently used medications from this group are cholestyramine, colestipol, and colesevelam. They can be used as monotherapy or in combination with other LDL-C lowering drugs. Recent large meta-analysis of 9 randomized trials and 1324 patients showed a 16.2% stronger reduction in LDL-C in patients treated with a statin and BAS than with statin alone [114]. The other pooled analysis of 3 randomized clinical trials of combined statin and colesevelam therapy demonstrated an additional 9.2% lowering of LDL-C in patients on combined therapy. The same analysis reported a significant hsCRP decrease (median change −23.3%) [115]. Colesevelam as monotherapy also demonstrated a reduction in hsCRP but failed to demonstrate IL-6 and TNF-α reduction [116]. One animal model suggests a possible BAS role in atherosclerosis stabilization in combination with brown fat activation [117].

Treatment with BAS can reduce the bioavailability of some anionic medications and vitamins [118]. However, colesevelam, because of its higher affinity for bile acids, can avoid these side effects [119]. It is not known whether their influence on the absorption of fat-soluble vitamins affects the potential anti-inflammatory properties of these medications. On the other hand, it is well established that high-dose vitamin E supplementation increases all-cause mortality [120], whereas paradoxically, supplementation with low doses in combination with other agents correlates with decreased all-cause mortality, while vitamin E in any dose combined with other agents also correlates with decreased mortality but only in disease-free populations [121]. These findings leave the issue of vitamin E supplementation in BAS treated patients still questionable.

5. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

PCSK9 inhibitors are a heterogeneous group of medications used for the reduction in serum levels of LDL-C [24,122]. Currently, three agents from this group (alirocumab, evolocumab, and inclisiran) have received approval from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (USFDA) for the treatment of primary hypercholesterolemia or mixed dyslipidemia. Alirocumab and evolocumab are monoclonal antibodies for PCSK9 [122], while inclisiran is a synthetic small interfering RNA (siRNA) that, in a specific process, cleaves PCSK9 messenger RNA in the hepatocytes [123]. Both mechanisms lead to the up-regulation of LDL receptors and improved LDL clearance [123,124]. Several other agents that inhibit PCSK9 with similar or different mechanisms of action are under investigation, including anti-PCSK9 vaccines [125] and small oral anti-PCSK9 molecules [126]. Serum LDL-C reduction rates vary among trials investigating PCSK9 inhibitors on top of maximally tolerated statin therapy, but according to a recent large meta-analysis of 48 randomized trials, this rate is consistently between 50 and 65% concerning different agents and different dosage regiments [127]. Each of the three agents also significantly reduces the risk of cardiovascular events based on the FOURIER, the ODYSSEY OUTCOMES, and pooled analysis of the results of ORION-9, -10, and -11 trials [128,129,130].

Although PCSK9 inhibitors are relatively new medications, a substantial amount is already known about their possible pleiotropic effects, primarily anti-inflammatory effects. The association between inflammation, LDL-C levels, and atherosclerosis has been very well established. Moreover, there is evidence suggesting that PCSK9 levels are associated with the severity of coronary artery disease and positively correlate with the levels of inflammatory biomarkers including white blood cell, hsCRP, and fibrinogen [131]. Although traditional LDL-C-lowering drugs, especially statins, have shown a significant reduction in hsCRP, a similar relationship has not been demonstrated in randomized trials that investigated PCSK9 inhibitors [132,133,134]. Accurate mechanisms of anti-inflammatory effects of PCSK9 inhibition in atherosclerosis are still poorly elucidated. Most evidence is from experimental models and a small clinical trial with familial hypercholesterolemia patients, and they suggest impaired monocyte adherence and migration in the atherosclerotic plaque by reducing expression of the ICAM-1 in ECs and C-C chemokine receptor 2 (CCR2) in monocytes [135,136]. The last also showed down-regulation of pro-inflammatory TNF and up-regulation of anti-inflammatory IL-10 [136]. Furthermore, PCSK9 siRNA induces inhibition of PCSK9, and inflammatory mediators involved in the pathogenesis of atherosclerosis IL-1α, IL-6, and TNF-α in oxLDL-stimulated THP-1-derived macrophages via suppression of NF-κB nuclear translocation [137].

There are several studies based on different imaging methods aiming to support that PCSK9 inhibitors reduce arterial wall inflammation and atherosclerosis burden by modifying atherosclerotic plaque characteristics [138,139,140,141,142,143,144,145]. Initially, the ATHEROREMO-IVUS study using intravascular ultrasound virtual histology imaging for coronary atherosclerotic plaque characterization showed that PCSK9 levels were associated with the size of plaque necrotic core, even independently of serum LDL-C levels and concomitant statin therapy [138]. Afterward, many studies using different intravascular imaging techniques such as intravascular ultrasound, near-infrared spectroscopy, and optical coherence tomography almost unequivocally demonstrated that PCSK9 inhibitors positively affect all analyzed histological characteristics of atherosclerotic plaque including atheroma volume, lipid core burden index, fibrous cap thickness, lipid arc, macrophage accumulation, etc. [139,140,141,142]; only the ODYSSEY J-IVUS trial failed to confirm that treatment with alirocumab for 36 weeks after acute coronary syndrome reduces atheroma volume [143]. One small study that used nuclear magnetic resonance for evaluating carotid atherosclerotic plaque composition showed that treatment with alirocumab led to plaque stabilization [144]. Another small study investigating 18F-fluoro-2-deoxy-d-glucose (FDG) uptake in three large arteries (right and left carotid artery and aorta) demonstrated that long-term treatment with PCSK9 inhibitors reduces arterial FDG uptake independently of serum LDL-C levels [145].

There is rising evidence regarding the role of PCSK9 in other types of inflammation, including autoimmune diseases such as systemic lupus erythematosus (SLE), in which elevated serum levels of PCSK9 are associated with higher disease activity [146,147]; psoriasis, which is related to increased serum PCSK9 levels and higher PCSK9 expression in psoriatic lesions than in disease-free skin [148,149]; and HIV infection [150,151]. Data regarding sepsis and septic shock are conflicting. While some authors suggest that elevated PCSK9 levels in septic patients inhibit hepatocyte bacterial endotoxin clearance and promote multiple organ failure [152], the others point to higher mortality in patients with septic shock and lower PCSK9 levels [153], which is also supported by the results of a PCSK9 loss-of-function genotype study [154]. Initial clinical investigations with PCSK9 inhibitors in some of these conditions are promising. Recent studies also indicate elevated PCSK9 levels in many types of cancers, including gastric, colorectal, hepatocellular, breast, and thyroid cancers, and the potential role of PCSK9 in cancer biology [155,156]. Some beneficial effects of anti-PCSK9 immunization are suggested in experimental models of colorectal and breast cancer [157,158]. Moreover, data confirm that PCSK9 inhibition using alirocumab or evolocumab potentiates immune checkpoint inhibition therapy, specifically anti-PD1 antibody treatment, in mouse models of cancers [159]. Nonetheless, clinical data are lacking, and well-designed investigations in different cancer populations are required.

6. Novel LDL-C Lowering Drugs

The EMA and the USFDA approved three more LDL-C lowering drugs: bempedoic acid, as an alternative for the treatment of primary hypercholesterolemia or mixed dyslipidemia; lomitapide; and evinacumab for the treatment of homozygous familial hypercholesterolemia (HoFH). There is strong evidence supporting the LDL-C lowering efficacy of these medications; however, the data regarding their role in inflammation are still insufficient, and further investigations are warranted.

Pooled analysis of 4 CLEAR randomized trials of Bempedoic acid in patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia or with both on statin therapy or in statin-intolerant patients showed 17.8% LDL-C reduction in patients on a statin and 24.5% if they were statin-intolerant. Furthermore, the same analyses demonstrated a significant reduction in hsCRP (18.1% in patients on a statin and 27.4% in statin-intolerant patients), indicating a strong anti-inflammatory effect [160]. This effect is mainly related to the direct activation of AMP-activated protein kinase (AMPK). Initial animal model studies suggest a potential favorable impact of this drug on the pathogenesis of atherosclerosis [161,162]. Recently published results of the CLEAR outcome trial reported a beneficial effect of Bempedoic acid on the reduction in major adverse cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization [163].

Treatment with lomitapide has led to significant LDL-C reduction (38% at week 78) in HoFH patients, according to a pivotal trial [164]. Long-term follow-up of these patients confirmed maintained lowering of LDL-C and, also, a progressive decrease in median hsCRP levels [165]. Observational studies of HoFH patients treated with lomitapide reported similar results indicating a steady reduction in LDL-C [166,167]. There are minimal data suggesting a protective lomitapide effect in ASCVD. One case series of six HoFH patients on long-term lomitapide therapy showed carotid intima-media thickness stabilization or regression [168]. In addition, recent studies emphasize the potential anti-cancer effects of lomitapide [169,170].

Records from the ELIPSE HoFH trial of evinacumab with combined lipid-lowering treatment shows a 49% LDL-C reduction compared to combined lipid-lowering treatment alone. A significant reduction was achieved in all analyzed secondary outcomes, including apolipoprotein B (apoB), TG, Lp(a), and apolipoprotein C-III (apoC-III) [171]. Similar trends have been obtained in a small real-world clinical practice trial [172]. On the other hand, there are no data confirming the role of evinacumab in inflammation so far, and data regarding atherosclerosis are rare but promising. Treatment with evinacumab reduced atherosclerotic lesion area and necrotic content in APOE*3Leiden.CETP mice [173]. In two patients treated with evinacumab, major atherosclerotic plaque regression was proven by using coronary computed tomography angiography (CCTA) [174]. Furthermore, there is strong evidence suggesting a relationship between ASCVD and high angiopoietin-like protein 3 (ANGPL3) levels [173,175,176].

7. Fibrates

Fibrates are fibric acid derivate agents, a type of amphipathic carboxylic acid that is currently widely used in patients with dyslipidemia. The USFDA approved the indications of fibrates for usage as an adjunct to dietary modifications in patients with primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Recently, fenofibrate has emerged as a potential adjunct therapy for patients with primary biliary cholangitis who experience an inadequate response to standard therapy [177]. This is confirmed by a meta-analysis of 20 studies with 4783 participants [178], but it is still unapproved by the USFDA. A recent study showed that pemafibrate, which is fundamentally different in structure from other currently available fibrates, may lower incidence of nonalcoholic fatty liver disease [179]. Moreover, pemafibrate treatment in these patients is effective to control hepatic inflammation in the short term [180]. The latest European Society of Cardiology (ESC) guidelines recommended statin treatment as the first drug of choice for reducing CVD risk in high-risk adults with hypertriglyceridemia, while fibrates may be considered for usage in combination with statins in high-risk patients and in primary prevention in individuals who are at the target levels of LDL-C with elevated TG levels [24,181]. Although it is well known that fibrates have beneficial effects on lipid profile, they do not reduce CVD risk, which was recently confirmed in the PROMINENT clinical trial, which included more than ten thousand patients with high risk for CVD. Even though pemafibrate reduced TG, VLDL, and cholesterol remnant levels by 25–30%, incidence of cardiovascular events was not reduced [179].

Fibrates act by binding to the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-α. PPARα activation mediates changes in lipoprotein metabolism by inducing PPARα-dependent gene transcription, particularly by upregulating lipoprotein lipase, a key enzyme for TG-rich lipoprotein catabolism. Moreover, activation of PPARα reduces insulin resistance and dyslipidemia [182]. PPARα has a modulating effect on inflammation activity. Although it has been suggested that PPARα agonists may improve cardiac performance through anti-inflammatory effects [183], this assumption requires further evaluation. PPARα decreases the production of proinflammatory mediators (TNF-α, IL-1, IL-6, and IL-8) and modulates the expression of adhesive and chemotactic molecules. Furthermore, activation of PPARα can induce the production of anti-inflammatory agents, such as IL-10 [184]. Although under certain conditions, PPARα has pro-inflammatory effects, it is well-accepted that PPARα is involved primarily in anti-inflammatory signaling [183]. These effects of target receptor activation, as confirmed by in vitro and in vivo studies of both acute and chronic inflammatory processes [183], may elucidate the potential therapeutic use of fibrates in inflammatory disease. Furthermore, some fibrates (clofibrate, fenofibrate, gemfibrozil, and ciprofibrate) [185], as well as fibrate metabolites (clofibric and fenofibric acids), activate PPARγ, a participant in inflammatory reactions which inhibits the activation of immune cells and the expression of inflammatory factors [186,187]. It is proven that fenofibrate directly upregulates heme oxygenase-1, which contributes to the anti-inflammatory effects in human vascular cells [188]. Fenofibrate and clofibrate activate the gene coding for vanin-1, a protein with anti-inflammatory potential [189].

Fibrates have been evaluated in the context of many inflammatory states and diseases. In the randomized controlled trial that enrolled diabetic patients with mixed dyslipidemia, fenofibrate reduced levels of CRP by about 21–28% [190]. The anti-inflammatory effect of fenofibrate in metabolic syndrome is confirmed both in vitro and in an animal model [185,191]. What is more, fenofibrate improves colitis in IL-10-deficient animals, suggesting a possible therapeutic potential in inflammatory bowel disease [192]. Fenofibrate has potential applications both in therapy and for the prevention of bronchial remodeling in asthma [193,194], but that demands further research. The anti-inflammatory effects of fenofibrate have been proposed as a potential explanation of proven protection against diabetic retinopathy [195].

Pemafibrate, a novel selective PPARα modulator that was released in 2018, has superior binding efficiency to PPARα and a favorable safety profile over fenofibrate [196]. Due to these facts and evidence of beneficial effects on inflammation, pemfibrate deserves further evaluation in clinical settings.

Within the last few years, the majority of new synthetic fibrate derivatives have shown many biological effects such as hypolipidemic, hypoglycemic, anti-inflammatory, analgesic, antioxidant, and antiplatelet activities, which are mediated by, or independent of, PPAR activation. In light of their anti-inflammatory potential, amide-based fibrates have been evaluated in many preclinical studies; however, according to our knowledge, their effects have not been examined in clinical settings [197].

Although fibrates, as synthetic PPAR agonists, have effects on inflammation, which are well described and proven in preclinical studies, the benefits of these effects in humans need more clinical evidence. Given that fibrates are considered to be “one more lost paradise in lipid treatment” [198] and without evidence for CVD benefits [179], their anti-inflammatory effects represent an area of special interest, which deserves further elucidation.

8. Omega-3 Fatty Acids

The beneficial effects of omega-3 fatty acids in lipid metabolism regulation are well documented [199,200]. These polyunsaturated fatty acids are associated with decreased plasma TG levels, probably through inhibiting VLDL production [201]. They include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), with the latter two being considered very-long-chain omega-3 fatty acids [202]. Although they can be found in plants, the most significant source of omega-3 fatty acids is fatty fish. Omega-3 and omega-6 polyunsaturated fatty acids represent constituents of the cell membrane. The predominance of omega-3 fatty acids is associated with less inflammatory conditions, while the predominance of omega-6 fatty acids leads to the promotion of inflammatory activity [203]. In line with this, in a systematic review conducted by Natto et al. [204], a relationship between omega-3 fatty acids and a decrease in the level of the following pro-inflammatory mediators was observed: apoB, apoA-I, total cholesterol (TC), and HDL-C. The same study also showed favorable effects of omega-3 fatty acids on TNF-α [204]. Besides their anti-inflammatory effects, omega-3 fatty acids are associated with antidysrhythmic, antiatherogenic, and antithrombotic activity, as well as with a decrease in systolic and diastolic blood pressure levels and overall improvement of endothelial activity [205].

Icosapent ethyl (IPE) is a highly purified ethyl ester of EPA [206]. The MARINE and the ANCHOR trials of IPE reported significant TG reduction in individuals with hypertriglyceridemia previously untreated or on statin therapy (33.1% and 21.5%, respectively) and led to the registration of this drug [207,208]. The same trials demonstrated significant differences in apoB levels between IPA and placebo groups after 12 weeks of treatment (9.1% in the MARINE trial and 8.8% in the ANCHOR trial) [207,208]. Several years later, the REDUCE-IT trial investigating cardiovascular effects of IPE in patients with hypertriglyceridemia and established CVD or diabetes and other risk factors, who were already on statin therapy, showed 25% relative and 4.8% absolute reduction in primary composite end point, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, a key secondary end point, and other tested end points, except death from any cause [209,210]. Similar trends were obtained in many prespecified subgroups, such as patients with a prior myocardial infarction, a prior percutaneous coronary intervention, or a previous coronary artery bypass graft (CABG) or with chronic kidney disease [211,212,213,214]. Furthermore, the REDUCE-IT biomarker sub-study showed a significant difference in serum levels of all tested inflammatory biomarkers (IL-1β, IL-6, hsCRP, oxLDL, homocysteine, Lp(a), lipoprotein-associated phospholipase A₂ (Lp-PLA₂)) at each time point [215]. The subsequent EVAPORATE trial, which enrolled 80 subjects with hypertriglyceridemia and multidetector-computed tomography (MDCS), confirmed that ASCVD demonstrated a clear benefit of IPE on atherosclerotic lesion stabilization proven by a reduction in low-attenuation plaque (LAP) volume and fibrous and fibro-fatty plaque volumes after 18 months of treatment [216]. This trial illuminated potential mechanisms behind the impressive results of the REDUCE-IT trial.

A recent study researching the effects of IPE on a rat model of ulcerative colitis has shown promising results in the reduction in different biohumoral, histologic, and immunohistochemical parameters of inflammation, oxidative stress, and apoptosis in colon tissue [217].

9. Lipid-Lowering Upplements

Currently, many different supplements are used for lipid-lowering purposes. Moreover, many combinations and dosage regiments are available. Anyway, their effectiveness and safety are usually not properly tested and vary significantly. In this study, we discuss results from several small, randomized trials investigating the anti-inflammatory effects of dietary LDL-C-lowering supplements. Red yeast rice monacolin K is probably the most frequently used agent from this group with the strongest evidence for its effectiveness. A recent large meta-analysis of 5868 participants using red yeast rice demonstrated significant LDL-C reduction [218]. Additionally, monacolin K showed a reduction in hsCRP levels in the population with untreated moderate hypercholesterolemia. The same trial demonstrated a decrease in levels of matrix metalloproteinases (MMPs) 2 and 9, which are considered markers of atherosclerotic plaque stability [219]. Moreover, monacolin K in nutraceutical combination with phytosterols, hydroxytyrosol, and vitamin E confirmed reduction in LDL-C and hsCRP levels in subjects with previously untreated hypercholesterolemia and low or moderate cardiovascular risk [220], while monacolin K-free combination did not demonstrate analogous results [221]. Ferulic acid supplementation reduced LDL-C, oxidized LDL-C, hsCRP, and TNF-α, as well as other lipids, oxidative stress, and inflammatory biomarkers in hyperlipidemic subjects [222]. Likewise, eight weeks of supplementation with barberry (Berberis integrrima) significantly lowered LDL-C, CRP, and IL-6 levels in individuals with cardiovascular risk factors [223]. These effects are potentially accomplished via the up-regulation of cell surface LDL receptor expression through the PCSK9 inhibition pathway [224]. New concepts of symbiotic supplementation showed some promising results in improving lipid profiles and decreasing inflammatory biomarkers in hemodialysis patients [225]. On the other hand, a recently published study of lipid-lowering and anti-inflammatory effects of different dietary supplements including fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice failed to demonstrate a significant reduction in LDL-C and hsCRP levels compared to placebo and low-dose Rosuvastatin in subjects with high 10-year risk for ASCVD after 28 days of treatment [226].

10. Conclusions

For a long time, cholesterol has been treated as the central point of ASCVD, and therapeutic modalities have been directed to its lowering. Nevertheless, evidence emerges that there is a significant interplay between lipid metabolism and immunity. The precise underlying mechanisms are yet to be discovered. Elucidating steps in this cascade is of particular interest considering the role of systemic inflammation in the formation of lipid plaques and atherosclerosis. On the other side, it has been demonstrated that, besides their impact on lipid levels, lipid-lowering drugs also express immunomodulatory activities by decreasing lipid levels and through lipid-metabolism-independent pathways (

Table 1. Impact of lipid-lowering drugs on selected inflammatory biomarkers.

Medication	Inflammatory Biomarkers
	CRP or hsCRP	IL-1	IL-6	TNF	IL-10
Statins	↓	↑↓	↓	↓	/
Ezetimibe	↔	/	/	/	/
BAS	↓	/	↔	↔	/
PCSK9i	↔	↓	↓	↓	↑
Bempedoic acid	↓	/	/	/	/
Lomitapide	↓	/	/	/	/
Evinacumab	/	/	/	/	/
Fibrates	↓	↓	↓	↓	↑
Omega-3 fatty acids	/	/	/	↓	/
Icosapent ethyl	↓	↓	↓	/	/

↑—increased concentration; ↓—decreased concentration;/—no date available; ↔—no changes in the concentration; CRP—C—reactive protein; hsCRP—high-sensitivity C—reactive protein; IL-1—interleukin 1; IL-6—interleukin 6; TNF—tumor necrosis factor; IL-10—interleukin 10; BAS—bile acid sequestrants; PCSK9i—proprotein convertase subtilisin/kexin type 9 inhibitors.

). It is still unknown how low lipid levels should be in order to achieve a satisfying decrease in the risk of CVD events and if it is also beneficial to include some anti-inflammatory drugs in the treatment. In this review, it was shown that statins demonstrate anti-inflammatory effects through multiple different mechanisms; however, it is still a matter of debate as to what extent these effects are driven by the drug itself. Positive anti-inflammatory effects of ezetimibe have been documented in animal models, as well as when it was administered in combination with statins. For PCSK9 inhibitors, there are some data suggesting possible alterations in inflammatory marker levels; however, further studies should provide deeper insight. Among omega-3 fatty acids, IPE offers promising results. On the other hand, the role of some lipid-lowering drugs such as BAS, fibrates, novel lipid-lowering drugs, and supplements in decreasing inflammation is questionable and requires further evaluation. Thus, improving knowledge on these interactions could help in tailoring treatments with lipid-lowering drugs and a consequent decrease in inflammation and the risk of new or recurrent CVD events. These observations offer possibilities for further interventions in the field of biomarkers of inflammation and the subsequent introduction of new lipid-lowering treatment modalities. Considering that CVD are attributed to the highest disease burden at the global level, even a small change in treatment effectiveness could have a large impact at the population level. Therefore, further studies in this area are warranted.