The Role of Statins in ASCVD

Abstract

Statins are comprehensive lipid-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. As an effective cholesterol-lowering drug, statins inhibit a key step in the cholesterol biosynthesis pathway and have made outstanding contributions to the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). The mechanism is to competitively inhibit the endogenous cholesterol synthesis rate-limiting enzyme HMG-CoA reductase, block the intracellular hydroxy valerate metabolic pathway, and reduce intracellular cholesterol synthesis. Additionally, these actions also increase the number and activity of low-density lipoprotein (LDL) receptors on the cell membrane surface and promote plasma cholesterol clearance. Therefore, statins can reduce total cholesterol and LDL levels and reduce triglycerides (TG) to a certain extent and increase high-density lipoprotein (HDL). In addition to lipid regulation, statins may also treat ASCVD by improving endothelial function, Inhibiting inflammation, and stabilizing atherosclerotic plaque. This review summarizes the fundamental roles of statins in ASCVD.

1. Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide [1, 2]. With the aging of the population and the increase in cardiovascular risk factors, the morbidity and mortality of CVD continue to increase, and the mortality of ASCVD, mainly ischemic heart disease, and ischemic stroke, has increased significantly [3]. ASCVD refers to clinically diagnosed atherosclerotic diseases, including acute coronary syndrome, stable coronary heart disease, revascularization, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack, and peripheral atherosclerotic diseases. ASCVD is one of the most common clinical diseases [4].

The main risk factors for ASCVD include hypertension, dyslipidemia, and diabetes mellitus [5]. Hypertension is the leading risk factor for ASCVD morbidity and increased mortality, with approximately 50% of cardiovascular morbidity and 20% of cardiovascular mortality attributable to hypertension [6]. It is worth noting that the early prevention and control of hypertension are very important to reduce the long-term risk of ASCVD. The levels of low-density lipoprotein cholesterol (LDL-C) that were most closely associated with ASCVD were significantly elevated in the Chinese population (8.1% ≥4.14 mmol/L, 26.3% ≥3.4 mmol/L), and only 39% had an ideal level of LDL-C (≤2.6 mmol/L) [7]. Diabetes is an independent risk factor for ASCVD [8]. Once ASCVD occurs in diabetic patients, the lesions are complex, and the prognosis is poor. Recently, domestic and foreign guidelines have listed diabetic patients as high-risk groups for ASCVD. Lifestyle interventions (weight loss, diet, and exercise) are the basis for reducing the risk of ASCVD [9], but further pharmacological interventions are needed to achieve optimal lipid control and reduce cardiovascular residual risk. Statins are currently recognized by the medical community as the most powerful drug for lowering cholesterol and significantly reducing the risk of ASCVD.

2. Classification of statins

Statins are fungus-derived molecules that have played an important role in the field of cardiovascular therapy since their discovery in the 1970s [10, 11]. Seven statins are commonly used: atorvastatin, rosuvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and pitavastatin. Due to the different sensitivities of patients to different statins, it is necessary to make drug adjustments in the clinical application according to the range of blood lipid reduction, adverse reactions, liver and kidney function, blood glucose, and blood lipid levels of patients and then carry out statin intervention therapy after designing an appropriate treatment plan. Despite differences in pharmacokinetics and lipophilicity, the biological activities of different statins are similar, making them a fairly homogeneous class of drugs [12]. Among all statins, lovastatin, simvastatin, fluvastatin, and pitavastatin are fat-soluble statins, pravastatin, and rosuvastatin are water-soluble statins, and atorvastatin is a fat-water-soluble statin [13]. The lipid bilayer structure of the animal cell membrane makes it more difficult for water-soluble statins to enter cells, but the transporter on the surface of the liver cell membrane can selectively transport water-soluble statins into cells. Therefore, in the treatment of ASCVD, water-soluble statins can selectively inhibit liver cholesterol synthesis and thus have a low effect on cholesterol synthesis in other parts of the heart, brain, and so on, which not only effectively reduces serum cholesterol levels but also avoids the occurrence of adverse reactions in extrahepatic tissues.

Depending on the magnitude of the reduction in plasma LDL-C levels, statins can be divided into three categories: strong-efficiency statins, medium-efficiency statins, and low-efficiency statins. The disturbance of plasma lipoprotein levels, especially the abnormal increase of LDL-C concentration, plays a major role in the development of ASCVD. Therefore, the efficiency of removing excess LDL-C in plasma has become an indicator to evaluate the effectiveness of statins in the treatment of ASCVD. Atorvastatin is a powerful statin with a long effect that can be taken at any time every day. This statin is mainly metabolized by the liver drug enzyme CYP3A4 and has many interactions with other drugs, so attention should be given to the combination of drugs [14]. Rosuvastatin is also a powerful and long-acting statin that can be taken at any time. It is mainly excreted by feces, partially excreted by the kidney, and rarely metabolized by the liver. It has few interactions with other drugs and has high safety when combined with drugs [15]. Pitavastatin is a medium-efficiency statin, which is the lowest dose of statin. Pitavastatin is mainly excreted by feces and has fewer interactions with other drugs, fewer side effects, and minimal influence on blood sugar [16, 17]. Simvastatin is metabolized through the liver drug enzyme CYP3A4. It has more interactions with other drugs, and the action time is short. It should be taken before bed to maximize the lipid-lowering effect [18, 19]. Pravastatin is a medium-efficiency and short-acting statin that is not metabolized by liver drug enzymes. It has less interaction with other drugs, fewer adverse reactions, and less influence on blood sugar [20, 21]. In the treatment of different diseases and different stages of the same disease, the appropriate intensity of statins can not only ensure effective control of the disease but also reduce the toxic side effects of treatment to a minimum.

3. The role of statins in ASCVD

3.1 Lipid regulating effect

Plasma LDL-C levels are closely related to the development of ASCVD. Therefore, pharmacological lipid-lowering therapy has become a reasonable method to prevent and treat ASCVD. Statins are mainly used to lower cholesterol levels in serum, liver, and aorta and to lower very low-density lipoprotein cholesterol (VLDL-C) and LDL-C levels. Different statins’ absorption, excretion, and solubility vary, but they all reduce serum LDL in a nonlinear, dose-dependent manner [22, 23]. The role of statins includes regulating blood lipids and not regulating blood lipids. The main effect of regulating blood lipids is to reduce the levels of LDL-C and TG, but the effect of lowering TG is weak, while the level of high-density lipoprotein cholesterol (HDL-C) is increased. The nonregulating effects of blood lipids include improving vascular endothelial function, inhibiting the proliferation and migration of vascular smooth muscle cells, antioxidation, anti-inflammatory, inhibiting platelet aggregation, and anti-thrombotic effects conducive to preventing the formation of atherosclerosis or stabilizing and reducing atherosclerotic plaques. In hepatocytes, statins competitively inhibit the catalytic action of HMG-CoA reductase, resulting in decreased intracellular cholesterol levels and increased expression of LDL receptors on the cell membrane surface [24]. Therefore, statins reduce plasma LDL-C concentrations by inducing increased uptake of circulating LDL-C in liver cells [25]. In a short-term trial of 76,000 people using statins to lower LDL-C levels, the decrease in LDL-C levels increased year by year, from 11% in the first year to 24% in the second and 33% in the fifth year [26]. Therefore, the longer the statin treatment, the greater the decrease in LDL and the lower the risk of ASCVD.

In addition to high plasma LDL-C concentrations, low levels of HDL-C and high levels of TG are also risk factors for ASCVD, and ASCVD can also be prevented by improving plasma HDL-C and TG levels. Statins also play a role in managing TG and HDL-C levels, and they affect these lipoproteins to varying degrees [27]. Statins can increase the expression of LDL receptors on the membrane surface of liver cells, which not only accelerates the uptake of circulating LDL but also increases the uptake of TG-rich lipoproteins such as VLDL-C and intermediate-density lipoprotein (IDL), thereby reducing plasma TG levels [28]. The lipid-regulating effect of statins also includes an increase in HDL levels [29, 30]. Statins generally raise HDL-C levels by 10–15% [31]. Statins increase the expression of genes involved in HDL metabolism such as apoA-I. Cholesterol ester transfer protein (CETP) is the gene encoding plasma cholesterol ester transfer protein, which mainly mediates the reverse transport process of cholesterol. Statins inhibit CEPT gene expression and plasma activity [32, 33], thereby reducing HDL-C transfer mediated by CETP [34]. Therefore, statins can not only reduce plasma LDL levels but also play a role in lipid regulation by lowering TG levels and increasing HDL levels, which can reduce the risk factors for ASCVD to a large extent.

3.2 Improve endothelial function

Lowering plasma LDL-C levels is the most significant clinical benefit of statin therapy, but more evidence suggests that statins improve vascular function in a variety of ways in addition to lowering plasma LDL-C. In a clinical trial on cerebrovascular risk, LDL-C levels dropped slightly, but there was a significant reduction in cerebrovascular risk [35]. Endothelial dysfunction is the initial step in the development of ASCVD, accompanied by the aggregation of monocytes and macrophages. Statins can reduce the adhesion of monocytes and macrophages to endothelial cells (ECs) [36], which reduces the formation of foam cells and the release of inflammatory factors, ultimately inhibiting vascular inflammation and plaque formation. Pretreatment with atorvastatin has been shown to reduce the adhesion of U937 monocytes to interleukin-1β-activated endothelial cells [37]. Therefore, the inhibitory effect of statins on endothelial cell adhesion is also an important target for the clinical treatment of ASCVD.

Another manifestation of endothelial dysfunction is reduced nitric oxide (NO) biosynthesis [38, 39, 40]. NO is a well-known vasodilator and an important regulator of vascular tone, platelet aggregation, and vascular smooth muscle cell (SMC) proliferation. In ECs, NO is produced by endothelial nitric oxide synthase (eNOS). NO-mediated vasodilation is impaired in patients with ASCVD [41]. Statins have been shown to have beneficial effects on vascular tone. Statin therapy improves endothelial function by increasing NO production and utilization. In a clinical trial, fluvastatin was used to treat patients with hypercholesterolemia, resulting in increased bioavailability of NO and significant improvement in endothelium-dependent vasodilation [42]. Statins can restore NO bioavailability in a variety of ways. Statins can increase eNOS levels in ECs by stabilizing eNOS mRNA and preventing its interaction with inhibitory proteins [43]. Statins increase eNOS activity by enhancing phosphorylated inositol-3 kinase-mediated Akt [44] phosphorylation and heat shock protein 90 [45] tyrosine phosphorylation. Statins prevent the reduction in eNOS by reducing hypoxia and inflammation [46]. Statins can increase the expression of tetrahydrotrexate (BH4) by upregulating the mRNA level of guanosine 5c-triphosphate cyclic hydrolase I and promote eNOS to preferentially generate NO instead of superoxide anion [47]. In addition, statins can protect BH4 by reducing vascular oxidative stress by inhibiting the production of superoxide anions. Therefore, statins can promote NO bioavailability and improve endothelial function by increasing eNOS levels and activity.

3.3 Suppression of inflammation

Inflammation is an important pathophysiological mechanism in the occurrence and development of ASCVD and plays a role in all stages of atherosclerosis [5, 48]. In early endothelial injury, ECs are activated to maintain and enhance local inflammation and the development of atherosclerotic lesions by regulating the expression of cytokines, chemokines, and leukocyte adhesion molecules [49]. Therefore, blocking key proinflammatory mechanisms is beneficial to the treatment of ASCVD. The anti-inflammatory effects of statins have been demonstrated in several clinical trials and studies [50, 51]. Statins inhibit the production and release of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin [52]. Other studies indicate that statins play a direct anti-inflammatory role by interfering with endothelial cell adhesion and cross-endothelial migration of white blood cells to the site of inflammation [53]. In addition, statins can limit the occurrence and development of ASCVD by reducing the production of reactive oxygen species (ROS) and inhibiting the formation of oxidized low-density lipoprotein (ox-LDL) and foam cells.

C-reactive protein (CRP) is a nonspecific inflammatory marker that is stimulated by inflammatory cytokines in the liver. In the early stage of ASCVD, macrophages accumulate at the damaged endothelium, release a large amount of TNF-α and IL-6, and induce the liver to synthesize a large amount of CRP [54]. CRP can cause vascular endothelial cell (VEC) damage and prevent the repair and proliferation of VECs. Numerous studies have shown that statins reduce inflammation by lowering the levels of CRP [55, 56]. Although CRP and LDL can coexist in atherosclerotic plaques [57], there is no correlation between the CRP-lowering effect and the lipid-lowering effect of statins. In a clinical study of statins, atorvastatin reduced hepatogenic acute phase reactant CRP and serum amyloid A in patients with hypercholesterolemia [58]. In addition, statins regulate the expression of several proinflammatory and atherosclerotic cytokines and the formation of ROS by regulating the GTP-binding protein pathway [59].

3.4 Stabilization of atherosclerotic plaques

The occurrence of ASCVD is a slow process that is characterized by lesions of affected arteries starting from the intima and the subsequent presence of a variety of lesions, including local plaque caused by the accumulation of lipid and complex sugars, fibrous tissue hyperplasia and calcareous deposits, as well as a progressive degeneration of the arterial middle layer. Secondary lesions include intraplaque bleeding, plaque rupture, and local thrombosis [60, 61]. Therefore, inhibiting the development of atherosclerotic plaque and stabilizing the plaques that have formed are particularly important in the treatment of ASCVD. Some early clinical studies have shown that statin therapy can slow plaque progression [62, 63], which makes the effect of statins even richer. By reducing the release of proinflammatory cytokines, statins play an anti-inflammatory role while reducing the recruitment of monocytes, thus inhibiting plaque progression. In addition, statins inhibit the production of ROS and ox-LDL and reduce the number of foam cells formed by macrophage phagocytosis of ox-LDL, which also helps to slow plaque progression.

Atherosclerotic plaques can be divided into noncalcified plaques and densely calcified plaques. The larger the proportion of densely calcified plaque, the better the stability of the plaque. Proinflammatory M1 and anti-inflammatory M2 macrophages play a role in forming these two types of plaques. Studies have shown that statins can promote the transformation of the macrophage phenotype from M1 to M2 near plaques, which promotes the improvement of plaque stability [64]. The thickness of the fibrous cap is also an indicator of plaque stability, and a thin fibrous cap represents vulnerable plaque. Statins can improve plaque stability by increasing the thickness of the fibrous cap [65]. Therefore, statins can improve plaque stability by promoting the phenotypic transformation of macrophages and increasing the thickness of the fibrous cap, thus reducing the risk of subsequent cardiovascular obstruction caused by plaque rupture.

4. Conclusion and perspectives

Statins play multiple roles in the prevention and treatment of ASCVD. Statins improve plasma cholesterol levels by regulating the number of LDL receptors on the membrane surface of liver cells and the expression of genes related to HDL metabolism. Statins can repair endothelial function by inhibiting mononuclear and macrophage adhesion to ECs and improving the bioavailability of NO. Statins inhibit inflammation by inhibiting the production of pro-inflammatory factors, ROS and CRP. Finally, statins limit plaque progression by inhibiting inflammation, promoting macrophage phenotypic transformation, and fibrous cap thickening.

In recent years, with the gradual deepening of research on the pharmacological action and mechanism of statins, the high efficiency of statins has attracted more attention. However, possible disadvantages have gradually emerged with the widespread use of statins. In addition to the financial burden of long-term use of high-dose statins, there are also very serious safety concerns, such as statin-associated muscle symptoms, new-onset type 2 diabetes, cognitive, renal, and hepatic dysfunctions, interstitial lung disease, and other reactions. These adverse reactions will greatly limit their clinical application. Therefore, doctors should evaluate the advantages and disadvantages of treatment and use methods such as reduction and intermittent use of statins, conversion between statins, replacement of nonstatin lipid-lowering drugs, the combination of statins and lipid-lowering drugs, and combination of protective drugs to reduce the adverse consequences of statin therapy. It is also hoped that a more complete treatment strategy will emerge in the future so that the risk of statin therapy can be minimized or there may even be no risk.

Acknowledgments

This project was supported by Grant 32171174 from the National Natural Science Foundation of China; Grant 2018Y9100 from the Joint Funds for the Innovation of Science and Technology, Fujian Province, China; and by Grant 440100220000000011797 from the Health Technology Promotion Project, Guangdong Province, China.

Conflict of interest

The author declares no conflict of interest.