Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and morbidity worldwide, despite the introduction of statins about 30 years ago (Benjamin et al. 2018). The pathogenesis of atherosclerosis is initiated by endothelial dysfunction and structural alterations of arterial walls triggered by disturbed laminar stress and elevated circulating apolipoprotein B (apoB)-containing lipoprotein, mainly low-density lipoprotein (LDL) (Kwon et al. 2008; Moore and Tabas 2011). Exposure of sub-endothelial proteoglycans caused by structural alterations of the aorta leads to accumulation of LDL under the endothelial layer through binding with apoB (Kwon et al. 2008). LDL particles in the intima are readily modified by reactive oxygen species, which trigger expression of adhesion molecules and release of chemokines on endothelial cells, leading to recruitment of immune cells in the intima (Weber and Noels 2011). Macrophages retained in the intima engulf modified LDLs such as oxidized LDL (oxLDL) through scavenger receptors, which drive the transformation of macrophages into foam cells (Sakakura et al. 2013). In addition to foam cell formation, macrophages express various costimulatory molecules that activate other immune cells to create inflammatory conditions in lesions (Weber and Noels 2011). In the process of atheroma propagation, accumulation of apoptotic cells, debris, and cholesterol crystals contributes to development of the necrotic core and in turn to plaque destabilization, leading to plaque rupture or erosion (Ylä-Herttuala et al. 2011). Occlusive thrombosis formed by plaque rupture or erosion causes acute cardiovascular events, which underlie mortality due to ASCVD (Sakakura et al. 2013). Rupture-prone plaques consist of large necrotic cores with thin fibrous caps, plaque hemorrhages, neovascularization, and adventitial inflammation (Ylä-Herttuala et al. 2011).

Given the pathophysiology of atherosclerosis (Fig. 1), current therapeutic targets and drugs for ASCVD emphasize normalization of plasma lipids including LDL-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) and attenuation of inflammation in lesions (Weber and Noels 2011; Shapiro and Fazio 2016). In this review, we describe and discuss current and future pharmaceutical therapies for ASCVD in terms of lipid-modifying strategies and anti-inflammation treatments.

Fig. 1
figure 1

Pathogenesis of atherosclerosis. Endothelial dysfunction and structural alteration of the arterial wall are triggered by disturbed laminar stress and elevated circulating apoB-containing lipoprotein, leading to accumulation of LDL within the intima. Modified LDL particles in the intima trigger expression of adhesion molecules and release of chemokines on endothelial cells, leading to recruitment of immune cells in the intima. Macrophages retained in the intima engulf modified LDL through scavenger receptors, driving transformation of macrophages into foam cells. Macrophages also express various costimulatory molecules that activate other immune cells, resulting in inflammatory conditions in the lesions. In the process of atheroma propagation, accumulation of apoptotic cells, debris, cholesterol crystals, and intra-plaque hemorrhage lead to development of the necrotic core, contributing to plaque destabilization and leading to plaque rupture or erosion. ApoB apolipoptrotein B, LDL low-density lipoprotein

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Lipid-modifying therapies

Risk factors for ASCVD include dyslipidemia, hypertension, diabetes, cigarette smoking, and genetic mutations (Bergheanu et al. 2017; Jellinger et al. 2017) (Fig. 2). Among these, hypercholesterolemia is considered a major risk factor for ASCVD (Nelson 2013). Clinical and experimental data have shown that plasma cholesterol, especially LDL-C, is the catalyst for development of ASCVD (Pedersen et al. 1994; Finking and Hanke 1997). Statin mega-trials based on 26 randomized trials of statins indicate that major ASCVD events and mortality are reduced by 22% and 10%, respectively, after reduction of 39 mg/dL in LDL-C level (Cholesterol Treatment Trialists’ et al. 2010). In addition, HDL-C level, hypertriglyceridemia, and lipoprotein(a) (Lp(a)) are considered independent risk factors for ASCVD (Rubin et al. 1991; Elam et al. 2000; Kronenberg and Utermann 2013; Catapano et al. 2017; Jellinger et al. 2017). Although low levels of HDL-C are well correlated with ASCVD, high levels of HDL-C are not related to atheroprotection, indicating that functional HDL level is important (Catapano et al. 2017). Hypertriglyceridemia is a traditional risk factor for ASCVD, but the benefits associated with lower levels of TG in patients with ASCVD are modest (Catapano et al. 2017). Elevated Lp(a), which consists of an LDL-like particle with apolipoprotein A (apoA), has emerged as a risk factor in patients with ASCVD or with strong family history of ASCVD (Kamstrup et al. 2009). In this section, we describe current and future drug therapies and therapeutic targets for regulation of lipid levels in patients with ASCVD (Table 1).

Fig. 2
figure 2

Risk factors for atherosclerotic cardiovascular disease. LDL-C low-density lipoprotein cholesterol, LDL low-density lipoprotein, TC total cholesterol, HDL-C high-density lipoprotein cholesterol, ASCVD atherosclerotic cardiovascular disease, hsCRP high-sensitivity C-reactive protein, Lp-PLA2 lipoprotein-associated phospholipase A2, ApoE4 apolipoprotein E4, TG triglycerides

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Table 1 Summary of lipid-lowering drugs for treating dyslipidemia
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Statins

After discovery of the first cholesterol-lowering drug, mevastatin (ML-236B), which is produced by the fungus Penicillium citrinum, lovastatin (mevinolin, MK803) was derived from the fungus Aspergillus terreus and marketed as a cholesterol-lowering drug (Brown et al. 1976). In 1994, the Scandinavian Simvastatin Survival Study (4S) evaluated the cholesterol-lowering effects of simvastatin (20–40 mg/day) on mortality and morbidity in 4444 patients with coronary heart disease (CHD), concluding that simvastatin reduced LDL-C by 35%, total mortality by 30%, and major coronary events by 34% compared to placebo (Pedersen et al. 1994). Follow-up trials have consistently shown that statins effectively reduce morbidity and mortality in high-risk patients with ASCVD and in generally healthy people. The Cholesterol and Recurrent Events (CARE) study determined that administration of pravastatin (40 mg/day) resulted in an absolute decrease of 3% (10.2% in the pravastatin group; 13.2% in the placebo group) in the study end point of frequency of fatal coronary events or nonfatal myocardial infarctions (Sacks et al. 1996). The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study concluded that pravastatin (40 mg/day) treatment resulted in a relative risk reduction of 24% for mortality from CHD as the primary outcome (Long-Term Intervention with Pravastatin in Ischaemic Disease Study 1998). The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) showed that lovastatin (20–40 mg/day) reduced the risk of first acute major coronary events (116 in the lovastatin group; 183 in the placebo group) in generally healthy men and women with average total cholesterol (TC) and LDL-C and below-average HDL-C levels (Downs et al. 1998). Overall, previous trials determined that statins safely reduce morbidity and mortality due to ASCVD, and that 1% reductions of LDL-C produced 1% reductions of ASCVD events, indicating the importance of managing LDL-C level in patients with ASCVD (Cholesterol Treatment Cholesterol Treatment Trialists’ (CTT) Collaboration et al. 2010). Statins show potential to lower LDL-C, but residual risks remained high in statin-treated ASCVD patients. Therefore, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study investigated the optimal level of LDL-C by comparing results of administration of pravastatin (40 mg/day, standard therapy) and atorvastatin (80 mg/day, intensive therapy) (Cannon et al. 2004). The primary end point, which was rate of combined death from ASCVD, was 26.3% in the pravastatin group and 22.4% in the atorvastatin group, indicating a 16% reduction of relative risk after intensive atorvastatin therapy. Mills et al. suggested that intensive statin therapy reduces the risk of non-fatal events but not of CVD deaths in a meta-analysis of randomized clinical trials (Mills et al. 2011). However, they found that intensive statin therapy reduced mortality in patients with acute coronary syndrome.

Collectively, well conducted clinical trials demonstrate that statin therapy produces remarkable results (Table 2), including consistent benefits associated with reduction in rate of ASCVD without major adverse effects. Nevertheless, two-thirds of statin-treated patients with ASCVD experience reoccurrence of CVD events, and some patients are unsuitable for statin therapy because of therapeutic intolerance to statins or side effects. Therefore, developing new therapeutic targets and drugs remains critical.

Table 2 Summary of landmark statin trials
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Ezetimibe

Ezetimibe is recommended as second line therapy for patients with statin intolerance or who are unable to reach goal LDL-C level with statin therapy alone (Jellinger et al. 2017). Ezetimibe inhibits dietary cholesterol absorption in the intestine by targeting the Niemann-Pick C1-like 1 (NPC1L1) protein at the jejunal enterocyte brush border (Phan et al. 2012; Cannon et al. 2015). In a meta-analysis of randomized controlled trials, ezetimibe monotherapy significantly changed levels of TC (− 13.46%), LDL-C (− 18.58%), HDL-C (+ 3.00%), and TG (− 8.06%) compared to placebo control (Pandor et al. 2009). In combination therapy with statin, ezetimibe induced incremental reduction of LDL-C by 23–24% (Cannon et al. 2015). Although early ezetimibe/statin combination trials showed non-significant differences in aortic stenosis compared to statin alone (Kastelein et al. 2005; Rossebø et al. 2008), recent trials revealed beneficial effects of ezetimibe/statin combination therapy in patients with ASCVD (Baigent et al. 2011; Cannon et al. 2015; Tsujita et al. 2015). A combination therapy of ezetimibe (10 mg/day) and simvastatin (40 mg/day) improved Kaplan–Meier event rates of the primary study end point by 2% compared to simvastatin monotherapy in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (Cannon et al. 2015), and ezetimibe/atorvastatin combination resulted in greater coronary plaque regression than atorvastatin monotherapy in the Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound (PRECISE-IVUS) study (Tsujita et al. 2015). These studies support the use of ezetimibe as second line therapy for statin-intolerant patients with ASCVD.

PCSK9 inhibitor

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease highly expressed in the liver and binds to LDL-R to catalyze its degradation in lysosomes, leading to elevated LDL-C level in serum (Seidah et al. 2014). Abifadel et al. reported that a gain-of-function by missense mutation of the PCSK9 gene in a French family caused autosomal dominant hypercholesterolemia (ADH), which is characterized by increase in LDL-C level (Abifadel et al. 2003). In contrast, loss-of-function mutations due to two nonsense mutations (Y142X and C679X) in the PCSK9 gene decrease serum LDL-C level in African-Americans, and Cohen et al. found that nonsense mutations in PCSK9 reduced the incidence of coronary events (Cohen et al. 2005, 2006). Therefore, clinical development programs are focusing on developing therapeutic antagonists of PCSK9 (Table 3).

Table 3 Summary of PCSK9 inhibition trials
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Two fully human monoclonal antibodies (AMG145 = evolocumab and REGN727 = alirocumab) were validated as inhibitors of PCSK9 in terms of efficacy and safety in patient trials (Robinson et al. 2015; Sabatine et al. 2015). Evolocumab plus standard therapy reduced LDL-C level by 61% and rate of CVD events from 2.18% after standard therapy to 0.95% in patients at high risk for CVD events (Sabatine et al. 2015). Combination therapy of alirocumab and statins at the maximum tolerated dose produced a 62% change from baseline in LDL-C level and reduced the rate of CVD events compared to single therapy in patients at high risk for CVD events (Robinson et al. 2015). The two antibodies have been verified for safety and efficacy for patients at high risk for CVD in several clinical trials (Navarese et al. 2015; Nicholls et al. 2016). Further, combination therapy with PCSK9 inhibitor was examined in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial of evolocumab and in the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trial of alirocumab, in which statins were associated with significantly reduced serum LDL-C level and a composite endpoint of cardiovascular death without major adverse effects in stable or unstable ASCVD patients, respectively (Sabatine et al. 2017; Schwartz et al. 2018).

In the ORION-1 clinical trial, inclisiran, a synthesized small interfering RNA targeting PCSK9 messenger RNA (mRNA), produced promising results in that both single-dose regimens (200, 300, or 500 mg of inclisiran) and two-dose regimens (100, 200, or 300 mg of inclisiran) maintained reductions of PCSK9 (single-dose regimen, from 47.9 to 59.3% and two-dose regimen, 53.2 to 69.1%) and LDL-C level (single-dose regimen, from 27.9 to 41.9% and two-dose regimen, 35.5 to 52.6%) at day 180 (Ray et al. 2017). In comparison with monoclonal antibodies, inclisiran has the potential advantage of decreasing the number of injections and amount of drug required for therapeutic effect.

Omega-3 polyunsaturated fatty acids

Omega-3 polyunsaturated fatty acids (PUFAs) have beneficial effects including lowering TG, enhancing endothelial function, vasodilation, decreasing platelet aggregation ability, and decreasing myocyte excitability (Mozaffarian and Wu 2012). Early clinical trials have shown beneficial effects of omega-3 PUFAs on mortality due to ASCVD (GISSI-Prevenzione Investigators 1999; Yokoyama et al. 2007; Tavazzi et al. 2008), but recent trials and meta-analyses failed to replicate the beneficial effects seen in early trials (Kromhout et al. 2010; Kwak et al. 2012). In a recent systematic review and meta-analysis of 20 studies of 63,630 subjects, Kotwal et al. concluded that omega-3 PUFAs had no overall effects on composite cardiovascular events such as myocardial infarction, stroke, or cardiovascular death [relative risk (RR) 0.96; 95% confidence interval (CI) 0.90–1.03; P = 0.24) or on total mortality (RR 0.95; 95% CI 0.86–1.04; P = 0.28) (Kotwal et al. 2012). However, omega-3 PUFAs exhibited protective effects against vascular death (RR 0.86; 95% CI 0.75–0.99; P = 0.03). In addition, the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDECE-IT) reported that a primary endpoint event occurred in 17.2% of patients treated with icosapent ethyl (total daily dose, 4 g) and purified and stable eicosapentaenoic acid (EPA) compared with 22.0% of the placebo group (Bhatt et al. 2019). The STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia study (STRENGTH), another large prospective randomized controlled outcomes trial planned for 2019, will determine whether Epanova (4 g/day) has beneficial effects against cardiovascular events in statin-treated high risk patients (Nicholls et al. 2018).

Other lipid-lowering agents

- Bempedoic acid (ETC-1002)

Adenosine triphosphate citrate lyase (ACL) is a cytosolic enzyme that is highly expressed in liver and white adipose tissue and is involved in fatty acid and cholesterol biosynthesis through catalyzing acetyl CoA synthesis (Bilen and Ballantyne 2016). ETC-1002, which is a first-in-class, oral, once-daily, small molecule cholesterol synthesis inhibitor, has two major modes of action in inhibition of ACL and activation of AMP-activated protein kinase (AMPK) (Pinkosky et al. 2013). ETC-1002 lowered LDL-C level in patients with hypercholesterolemia by 30% when used as monotherapy, by 48% as part of a combination therapy with ezetimibe (10 mg), and by an additional 22% when used in combination with atorvastatin (10 mg) (Bilen and Ballantyne 2016; Thompson et al. 2016). In addition, ETC-1002 treatment increased the activity of AMPK, a metabolic sensor involved in gluconeogenesis, β-oxidation of fatty acids, mitochondrial density, and inflammatory signaling, resulting in clinical favorable effects on CVD risk factors including hyperglycemia and insulin resistance (Pinkosky et al. 2013; Bilen and Ballantyne 2016). Indeed, ETC-1002 treatment lowered LDL-C level (39%), fasting plasma glucose (− 8.5%), and hsCRP (41%) in patients with hypercholesterolemia and type 2 diabetes mellitus compared to placebo (Gutierrez et al. 2014). Pinkosky et al. demonstrated that ETC-1002 inhibits cholesterol biosynthesis in the liver but not in skeletal muscle because of the tissue distribution of very long-chain acyl-CoA synthetase-1 (ACSVL1), which modulates ETC-1002 (inactive form) to ETC-1002-CoA (active form) (Pinkosky et al. 2016). Thus, ETC-1002 is a potent drug for dramatically reducing the incidence of diabetes mellitus and myotoxicity associated with statin therapy.

Mipomersen

Mipomersen, a synthetic single-strand apoB antisense oligonucleotide (ASO), binds to mRNA coding for apoB-100 and accelerates the degradation of mRNA by the enzyme ribonuclease H (Bell et al. 2011). Mipomersen was developed to treat homozygous familial hypercholesterolemia (HoFH). In clinical trials, mipomersen reduced apoB level (25–34%), LDL-C level (28–36%), and Lp(a) (21–33%) in patients with HoFH, but 18% of patients receiving mipomersen stopped taking the drug due to adverse effects such as skin reactions at the injection site, liver damage, and flu-like symptoms (Raal et al. 2010; McGowan et al. 2012; Stein et al. 2012; Thomas et al. 2013).

Lomitapide

Lomitapide is a small molecule inhibitor of microsomal triglyceride transfer protein (MTP or MTTP), which transfers lipids to apoB in the endoplasmic reticulum to assemble very low-density lipoprotein (VLDL) and chylomicrons (Gregg and Wetterau 1994; Rader and Kastelein 2014). Lomitapide (40 mg/day) reduced level of LDL-C by 50% at 26 weeks and by 38% at week 78 in patients with HoFH, with adverse effects including gastrointestinal symptoms due to increased TG of enterocytes, hepatic fat accumulation, and elevation of transaminases (Cuchel et al. 2013).

Emerging targets

Angiopoietin-like 3 (ANGPTL3)

Loss-of-function mutations in the ANGPTL3 gene are associated with reductions of plasma TG, LDL-C, and HDL-C levels, inspiring the development of therapeutic agents targeting ANGPTL3 in ASCVD (Robciuc et al. 2013). ANGPTL3 acts as a dual inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), resulting in elevation of plasma TG, LDL-C, and HDL-C levels (Fujimoto et al. 2006; Lee et al. 2009). In a clinical trial, ANGPTL3-LRx, an antisense inhibitor of ANGPTL3, resulted in reductions of TG (33.2% to 63.1%), LDL-C (1.3% to 32.9%), and total cholesterol (8.7% to 34.3%) in healthy adults (Graham et al. 2017). Dewey et al. verified that evinacumab, a human monoclonal antibody against ANGPTL3, decreased atheroma and necrotic core size compared to a control antibody in dyslipidemic mice, and that evinacumab reduced fasting TG level by 76% and LDL-C level by 23% in healthy human volunteers, highlighting its possible use as a new therapeutic agent against ASCVD (Dewey et al. 2017).

Lipoprotein(a)

Genetic studies and epidemiologic studies consistently suggest that Lp(a) is an independent risk factor for ASCVD (Danesh et al. 2000; Kamstrup et al. 2009). Lp(a) consists of one molecule of apo(a) linked to one molecule of apoB-100 of the LDL-like particle (Albers et al. 1996). Due to its structural similarity to plasminogen and tissue plasminogen activator (tPA), Lp(a) interferes with the fibrinolytic system and stimulates secretion of plasminogen activator inhibitor 1 (PAI-1), leading to atherothrombosis (Eaton et al. 1987). Lp(a) carries cholesterol and oxidized phospholipids, both of which contribute to progression of atherosclerosis through recruitment of inflammatory cells and proliferation of smooth muscle cells (Tsimikas et al. 2005; Banach 2016).

Although selective therapeutic agents that decrease Lp(a) without affecting other lipoproteins are not available, lipid-lowering drugs including niacin, mipomersen, lomitapide, PCSK9 inhibitors, cholesterol-ester-transfer protein (CETP) inhibitor, and atorvastatin reduce Lp(a) level and also affect other lipids and lipoproteins. In a phase 1/2a trial, IONIS-APO(a)-LRx, a ligand-conjugated antisense oligonucleotide targeting apo(a) designed to be highly and selectively taken up by hepatocytes, resulted in mean reduction in Lp(a) by 66% in the 10 mg group, by 80% in the 20 mg group, and by 92% in the 40 mg group, without adverse effects (Viney et al. 2016). Therefore, IONIS-APO(a)-LRx may be a potent therapy to reduce Lp(a) concentration in patients with high Lp(a)-mediated ASCVD.

Anti-inflammation therapies

Despite the importance of cholesterol in ASCVD, more than 50% of ASCVD patients treated with lipid-lowering drugs still suffer from major ASCVD events and mortality even after achieving goal LDL-C level (Castelli 1996; Libby et al. 2000; Catapano et al. 2017; Jellinger et al. 2017). This convergence of clinical findings indicates the need to develop non-lipid-lowering drugs for treatment of ASCVD (Ridker and Luscher 2014; Ridker 2016). The underlying pathogenesis of atherosclerosis involves imbalanced lipid regulation and inflammatory response, and unleashed inflammation is closely related to initiation, progression, and thrombotic complications of atherosclerosis (Weber and Noels 2011). Indeed, modified LDL such as oxLDL and glycation of LDL evokes endothelial dysfunction and recruitment of immune cells into arterial walls, propagating atheroma (Libby et al. 2011; Park and Oh 2011). Maladaptive immune responses in advanced atherosclerosis deleteriously affect the resolution of inflammation, which leads to expansion of the necrotic core and plaque destabilization (Sakakura et al. 2013). Therefore, inflammation participates in all stages of atherosclerosis from initiation to progression to destabilization, suggesting that resolving inflammation by targeting pivotal pro- or anti-inflammatory molecules or cells may be useful for giving assistance to lipid-lowering therapies (Fig. 3). In this section, we review therapeutic agents and targets thought to resolve inflammation in ASCVD.

Fig. 3
figure 3

Inflammatory pathways with potential uses as therapeutic targets for atherosclerotic cardiovascular disease (Modified from Ridker (2016)). IL-1β interleukin-1beta, IL-6 interleukin-6, PAI-1 plasminogen activator inhibitor type-1, CRP C-reactive protein, hsCRP high-sensitivity C-reactive protein

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CANTOS trial: interleukin (IL)-1β neutralizing monoclonal antibody (canakinumab)

The interleukin-1 (IL-1) family, consisting of IL-1α and IL-1β isoforms, plays important roles in the pathogenesis of atherosclerosis such as increasing adhesion molecule expression on endothelial cells, triggering vascular smooth muscle cell proliferation, and up-regulating IL-6, which induces the elevation of several acute phase reactants including hsCRP, fibrinogen, and PAI-1 on hepatocytes (Bevilacqua et al. 1985; Libby et al. 1988; Ridker et al. 2012; Ridker and Luscher 2014; Ridker 2016; Libby 2017). Dysregulation of IL-1β activation by genetic mutations causes severe inflammation and fever (Mariathasan and Monack 2007), indicating that IL-1β is a key molecule in the inflammation pathway. Therefore, modulation of IL-1β may be effective in patients with ASCVD.

Canakinumab is a fully human monoclonal antibody neutralizing IL-1β that was approved for treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), which is a spectrum of auto-inflammatory syndromes including Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, and neonatal-onset multisystem inflammatory disease (Dinarello et al. 2012). In the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, canakinumab (50, 150, 300 mg, administered subcutaneously every 3 months) was evaluated in patients with prior MI and high level of hsCRP (≥ 2 mg/L) (Ridker et al. 2017a, b; Aday and Ridker 2018). The primary end point was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. After 48 months, canakinumab treatment reduced hsCRP levels by 26% in the 50 mg group, by 37% in the 150 mg group, and by 41% in the 300 mg group compared to placebo, without affecting lipid levels. The incidence rate of the primary end point was 4.50 events per 100 person-years in the placebo group and 4.11, 3.86, and 3.90 events per 100 person-years in the 50, 150, and 300 mg groups, respectively. Therefore, anti-inflammatory therapy targeting IL-1β with canakinumab significantly reduced the rate of recurrent CVD events compared to placebo without affecting lipid levels.

Cardiovascular inflammation reduction trial (CIRT)

Low-dose methotrexate (10–30 mg/week) is broadly used to treat patients with cancer or autoimmune disease (Saag et al. 2008; Singh et al. 2012). When low-dose methotrexate treatment is used as an immune system suppressant in patients with rheumatologic disease, it reduces markers of inflammation, including CRP, IL-6, and tumor necrosis factor α (TNF α), without affecting lipid levels, blood pressure, or platelet function (Rho et al. 2009). In a meta-analysis, patients with rheumatologic disease receiving methotrexate treatment showed 21% lower risk of cardiovascular events compared to those receiving other anti-rheumatic therapies (Micha et al. 2011).

The CIRT is a randomized clinical trial to determine whether direct inhibition of inflammation by low-dose methotrexate (15-20 mg/week) had clinical relevance for anti-atherothrombosis in prior MI patients with type 2 diabetes or metabolic syndrome (Everett et al. 2013). The primary end point of the CIRT is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. The CIRT was stopped after 4786 patients of the planned 7000 patients had been enrolled, and the results are anticipated in 2018.

Interleukin-6 receptor (IL-6R) antagonist

IL-6 is a cytokine derived from immune cells, adipocytes, and smooth muscle cells (Tanaka et al. 2014). Although IL-6 acts as an anti-inflammatory myokine in muscle (Petersen and Pedersen 2005; Brandt and Pedersen 2010), it also stimulates inflammatory and auto-immune processes in several diseases including rheumatoid arthritis, diabetes, and atherosclerosis (Davies and Choy 2014; Tanaka et al. 2014). IL-6 is a major pro-inflammatory cytokine in the pathogenesis of atherosclerosis, stimulating production of CRP and fibrinogen from hepatocytes (Heinrich et al. 1990). Increased plasma IL-6 level is associated with mortality due to ASCVD independent of other risk factors, and genetic polymorphisms in the IL-6 signaling pathway at rs2228145 and rs7529229 are associated with lower levels of hsCRP and of vascular risk (IL6R Genetics Consortium Emerging Risk Factors Collaboration et al. 2012; Interleukin-6 Receptor Mendelian Randomisation Analysis et al. 2012).

Tocilizumab is a humanized monoclonal antibody against IL-6R that is used as an immunosuppressive drug for treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis (Fleischmann et al. 2013; Yokota et al. 2016). Despite promising observations, patients with rheumatoid arthritis who received tocilizumab exhibited significant increases of TC, LDL-C, and TG levels compared to a placebo group by week 12 (12.6% vs. 1.7%, 28.1% vs. 2.2%, 10.6% vs-1.9%, respectively), indicating major limitations in the development of IL-6 receptor antagonist treatments for ASCVD (Kawashiri et al. 2011; Strang et al. 2013).

Varespladib and darapladib

The phosholipase A2 superfamily, including secretory phospholipase A2 (sPLA2) and lipoprotein-associated phospholipase A2 (Lp-PLA2), hydrolyzes phospholipid molecules and produces potential atherogenic lipid fractions (Rosenson and Stafforini 2012). Thus, sPLA2 and Lp-PLA2 were considered potential risk factors for ASCVD in animal and observational human studies (Lp et al. 2010; Rosenson 2010; Rosenson and Hurt-Camejo 2012). However, clinical trials to evaluate the efficacy of varespladib (a non-specific sPLA2 inhibitor) and darapladib (a targeted Lp-PLA2 inhibitor) concluded that neither inhibitor had beneficial effects regarding risk of major coronary events (Mohler et al. 2008; Serruys et al. 2008; Rosenson et al. 2010). In addition, Holmes et al. reported that a genetic variant, the PLA2G2A rs 11573156 allele, was associated with reduction of sPLA2 level but not with major vascular events according to Mendelian randomization meta-analysis (Holmes et al. 2013), suggesting that sPLA2 is not a promising therapeutic target for preventing ASCVD.

Limitations and future directions

Currently, the efficacy and safety of canakinumab neutralizing IL-1β has been verified only for treatment of ASCVD. Low-dose methotrexate treatment for ASCVD is also promising in terms of efficacy and safety as a therapy for ASCVD. However, many agonistic or antagonistic candidates in inflammation pathways have failed to develop into useful drugs for treating ASCVD due to the complexity of the specific inflammatory process. To surmount this hurdle, genome-wide association studies (GWAS) would be helpful to develop new therapeutic targets and drugs for ASCVD. Genetic variants in inflammation genes and coronary artery disease including C-X-C motif ligand 12 (CXCL12), SH2B adaptor protein 3 (SH2B3), AB0, Human Leukocyte Antigen (HLA), IL-5, Platelet endothelial cell adhesion molecule 1 (PECAM1), Protein C Receptor (PROCR), and antisense non-coding RNA in the INK4 locus (ANRIL) are potential targets for development of ASCVD therapeutic agents (Fava and Montagnana 2018). Based on the pathogenesis of atherosclerosis, studying targets regulating systemic and/or local lipid metabolism might be helpful to gain insights useful for development of drugs against ASCVD. A small number of adipokines, including adiponectin and retnla, exhibit anti-obesity and anti-inflammatory properties, leading to reduction of atherosclerosis in experimental studies (Okamoto et al. 2002, 2008; Lee et al. 2014). Recently, we proposed that oxidative stress activates macroautophagy/autophagy and contributes to atherogenesis via lipophagic flux, which maintains lowered intracellular cholesterol mass in macrophages (Jeong et al. 2018). This leads to the possibility of using oxidative stress as a novel therapeutic target to regulate macrophage cholesterol homeostasis against ASCVD.

Conclusion

The morbidity and mortality caused by ASCVD have been reduced by lowering LDL-C level through statin therapy, which is a great cornerstone for treatment and prevention of ASCVD. Combination therapies with statins and other lipid-lowering drugs including ezetimibe and PCSK9 inhibitors have yielded additive benefits for treatment of ASCVD. In addition, anti-inflammatory therapies, including canakinumab and low-dose methotrexate, hold promise due to their efficacy and safety for treatment of ASCVD. Although the rate of ASCVD events is significantly reduced by administration of current lipid-lowering drugs and anti-inflammatory agents, morbidity and mortality remain high in ASCVD patients. Constant efforts for development of new therapeutic targets based on GWAS and molecular lipid metabolism would pave the way to a new era of precision medicine for treatment of patients with ASCVD.