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Effects of Statins on Cardiovascular and Cerebrovascular Diseases: History
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Subjects: Allergy
Contributor: Yoichi Morofuji

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established.

  • cerebrovascular diseases
  • cardiovascular diseases
  • pleiotropic effect
  • statin

1. Introduction

Statins potently inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease cholesterol biosynthesis and thereby reduce plasma cholesterol levels. The development of statins as cholesterol-lowering agents began in the mid-1970s when they were discovered as a fungal metabolite, with the first of these being a natural product called mevastatin [1]. Since this discovery, vigorous efforts have been made to develop novel statins, leading to the introduction of a total of eight varieties to date. Over four decades of use have led statins to become one of the most widely prescribed drugs globally, especially for cardiovascular diseases [2][3][4][5][6][7][8]. The association between dyslipidemia and cardiovascular disease has been comprehensively established. On the other hand, statins exhibit pleiotropic properties that are independent of their lipid-lowering effects [9]. Independent of lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects [10][11][12][13][14][15]. The preventive effect of statins on atherothrombotic stroke is well established, but statins can influence other cerebrovascular diseases. Thus, statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies [16]. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not yet been fully elucidated and are still controversial.

2. Statins and Cardiovascular Diseases

An association between dyslipidemia and cardiovascular diseases has been comprehensively established [2][3][4][5][6][7][8]. Evidence on low-density lipoprotein-cholesterol (LDL-C) and cardiovascular disease is more abundant than other dyslipidemias. Many epidemiological studies in Europe and the United States, including the Framingham study, have shown that higher LDL-C levels increase the incidence and mortality of coronary artery disease [17].
Statins are HMG-CoA reductase inhibitors that reduce cholesterol synthesis in the liver. By reducing intracellular cholesterol, statins increase the expression of LDL receptor on the surface of the liver. As a result, LDL uptake from the blood to the liver is increased, and plasma levels of other ApoB-containing lipoproteins, including LDLs, chylomicrons, very low-density lipoproteins (VLDLs), lipoprotein (Lp) (a), and intermediate-density lipoproteins, are decreased. Since the 1990s, large-scale clinical trials, conducted mainly in Europe and the United States, have demonstrated that lipid-lowering therapy with statins reduces cardiovascular events. In 2005, Cholesterol Treatment Trialists’ (CTT) collaborators reported that a one mmol-reduction (38.7 mg/dL) of LDL-C reduced major cardiovascular events (that include non-fatal myocardial infarction (MI), coronary heart disease death, coronary revascularization, and stroke) by 21%, regardless of the baseline LDL-C value [18]. This trial is a meta-analysis of 14 randomized clinical trials (RCTs) comparing statins and placebo groups, showing the efficacy of statins for cardiovascular diseases. The drugs used in this study included simvastatin, lovastatin, pravastatin, fluvastatin, and atorvastatin. In many cases, standard statins were used. Moreover, in 2010, CTT collaborators reported that a meta-analysis of all 26 randomized trials showed similar results to those in 2005. It showed a 22% suppression and 10% reduction in total mortality.
In addition, more intensive statin regimens resulted in a 15% greater reduction in major cardiovascular adverse events than those given in less intensive regimens. In other words, it was suggested that the hypothesis ‘the lower, the better’ is correct to reduce the risk of cardiovascular events for LDL-C [19]. In the 2019 ESC/EAS guidelines for the management of dyslipidemias, recommendations for patients with very high risk atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus (DM) with target organ damage, severe chronic kidney disease (CKD), a calculated systematic coronary risk evaluation of >10% for 10-year risk of fatal cardiovascular disease (CVD), or familial hypercholesterolemia (FH) with ASCVD risk factor, are an LDL-C reduction of >50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). Then, recommendations are also for an LDL-C reduction of >50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) for patients with high risk, an LDL-C goal of <2.6 mmol/L (<100 mg/dL) for moderate risk, and an LDL-C goal of <3.0 mmol/L (<116 mg/dL) for low risk [20].

3. Statins and Cerebrovascular Diseases

The preventive effect of statins on atherothrombotic stroke is well established, but statins can influence other cerebrovascular diseases. Thus, statins have many neurological effects in addition to lowering cholesterol. Herein discusses the effects of statins on cerebrovascular disease from several aspects.

3.1. Cerebral Infarction

Statins are strongly associated with cerebrovascular diseases, especially cerebral infarction. Many large clinical trials have been conducted, showing the positive effect of statins on stroke. Representative studies include the Cholesterol Recurrent Events (CARE) Study [21], the Long-Term Intervention with Pravastatin Ischemic Disease (LIPID) Study [22], and the Heart Protection Study (HPS) [23], all showing a reduction in the incidence of stroke or cerebral infarction. In addition, the Stroke Prevention by Aggressive Reduction of Cholesterol (SPARCL) study [24] showed the efficacy of statins in patients with stroke or transient ischemic attack. These results have been attributed to the importance of the cholesterol-lowering effect, which is the primary effect of statins [23][25]. However, recent studies have shown that cholesterol reduction in stroke is not the major factor, highlighting the importance of pleiotropic effects [26][27][28]. Statins influence intracellular signaling, improve vascular endothelial function, inhibit thrombus formation, and exert anti-inflammatory and antiangiogenic effects. Statin treatment is essential for patients with carotid artery stenosis, as the pleiotropic effect stabilizes the carotid atherosclerotic plaque [29]. This finding has been confirmed by the results of the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study, which showed that low-dose statin reduces the occurrence of stroke due to larger artery atherosclerosis [30]. Although statins have been well studied for the primary and long-term secondary prevention of stroke, their use in the acute phase is controversial. Large retrospective studies have shown that early resumption of statins contributes to improved survival in patients using statins prior to stroke onset [31].

3.2. Intracerebral Hemorrhage

The effect of statins on intracerebral hemorrhage (ICH) has been controversial, as previous epidemiological studies have shown that hypocholesterolemia may cause increasing ICH. Also, the SPARCL study showed an increased occurrence of a cerebral hemorrhage. This is related to the facts that cholesterol is important for maintaining the structure of blood vessels and that statins suppress platelet aggregation. However, recent studies have shown that statins do not increase the risk of hemorrhage, further suggesting their beneficial effects in ICH. A large meta-analysis of 42 trials revealed no apparent association between statins and risk of ICH and showed a reduction in stroke and cerebral infarction [32]. Although several studies have been conducted on statin use and cerebral microbleeds (CMBs) formation, which are related to ICH, there is no clear association [33][34]. In addition, a large prospective cohort study suggested that statins might reduce the risk of ICH [35]. The multifaceted effects of statins may reduce brain damage in patients after ICH and improve their prognosis. Several animal studies have shown that statins have many neuroprotective effects, including protection of the blood–brain barrier (BBB), inhibition of inflammatory cytokines, anti-apoptotic effect, and reduction of brain edema after ICH [36][37][38][39][40]. Although the evidence for statin use in ICH remains unclear, the risks of their use have been low, and there is no need to avoid their use intensively.

3.3. Cerebral Aneurysm and Subarachnoid Hemorrhage

The use of statins in patients with acute subarachnoid hemorrhage has been studied extensively because of their potential effectiveness in treating cerebral vasospasm and delayed ischemic neurological deficit (DIND). However, there is still no consensus on statin use, and their clinical usefulness remains controversial. Several animal studies suggested that statins improve early brain damage and reduce cerebral vasospasm after subarachnoid hemorrhage through their anti-inflammatory, anti-apoptotic, and aquaporin 4 (AQP4) expression-inhibitory effects [41][42][43]. Several clinical trials showed that statins reduce cerebral vasoconstriction and delayed ischemic neurological deficit (DIND) [44][45][46][47], and some meta-analyses also showed this finding [48][49][50]. In contrast, there are some studies that have not shown the clear efficacy of statins [51][52]. The pleiotropic effect of statins may potentially prevent brain damage after subarachnoid hemorrhage; thus, future large-cohort studies are desirable. In addition, recent research has focused on the rupture-preventive statin effects on unruptured cerebral aneurysms. Although several retrospective studies showed that statins reduce aneurysm rupture through their anti-inflammation and endothelial protective effects [53][54], the first prospective randomized controlled trial did not show a clear significant difference [55], thus requiring additional studies.

4. Conclusions

Statins suppress the production of intermediate metabolites of isoprenoid biosynthesis, such as geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), by inhibiting the cholesterol biosynthesis pathway, consequently suppressing the activation of small G-proteins. Small G-proteins play important roles in many systems that regulate cellular functions, and these regulatory effects are partially attributed to the pleiotropic effects of statins. The preventive effect of statins on cardiovascular diseases and atherothrombotic stroke is well established, and is mainly due to cholesterol lowering. However, statins may have other effects that are unrelated to cholesterol-lowering, on cerebrovascular diseases. Statins have been suggested to inhibit the development of cardiovascular diseases through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. Several studies have shown that statins have many neuroprotective effects, including protection of the BBB, inhibition of inflammatory cytokines, an anti-apoptotic effect, and reduction of brain edema. Basic research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies [16]. If they are effective against tumors, the statins can be more reasonable and are better tolerated than traditional chemotherapeutic agents. Statins can then be investigated for their use in the prevention or treatment of cancer alone or in combination with other drugs. It is indispensable to verify the antitumor effect of statins in prospective controlled RCTs to clarify their true effect, as frequently pointed out by the authors of many basic, observational, and clinical studies. Although many animal models and non-randomized data on the pleiotropic effects of statins seems promising and the therapeutic efficacy of statins on cardiovascular and cerebrovascular diseases is being established, proper long term clinical trials and results are necessary to evaluate their therapeutic efficacy on cancer. It is also crucially important from the perspective of drug repositioning [56].

This entry is adapted from the peer-reviewed paper 10.3390/ph15020151

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