Statin

Statin is an inhibitor of HMG-CoA reductase, an enzyme that controls the rate-limiting step in the mevalonate pathway of cholesterol synthesis.

From: Methods in Enzymology, 2019

Chapters and Articles

Statins

Lale Tokgözoğlu, ... Joseph J. Saseen, in Clinical Lipidology (Third Edition), 2024

Renal Effects of Statins

Statin treatment is not associated with clinically significant deterioration of renal function. Mild proteinuria, often transient, is rarely seen with high-dose statin treatment but is not associated with impaired renal function.28 Dose reduction may be necessary in patients with severe kidney dysfunction for some statin regimens. Atorvastatin and fluvastatin are less dependent on the kidney for elimination. Chronic kidney disease patients are at high risk for cardiovascular events, and statins reduce ASCVD events by 20% in these patients but are not beneficial in patients on dialysis.32 Although protective effect of statins on the kidney has been suggested by some studies, this has not been confirmed by others.

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Statins

James M. McKenney, ... Joseph S. Saseen, in Clinical Lipidology, 2009

Lipophilicity

Statins also differ in their degree of lipophilicity or lipid solubility. The most lipid soluble are the lactone statins, lovastatin and simvastatin. The logarithm of the partition coefficient (log P) of statins (see Table 22-1) reflects their lipophilicity. The open acid forms of lovastatin and simvastatin, as well as fluvastatin and atorvastatin, have high log P values, identifying their relatively high lipophilicity.87 The more lipid soluble the statin, the more easily it crosses cell membranes and gains access to hepatic and nonhepatic cells by passive diffusion. The hydroxyl substitution in the pravastatin molecule and the methane sulfonamide group in the rosuvastatin molecule renders these statins relatively hydrophilic (see Table 22-1). The practical significance of this property is unknown, since even the hydrophilic statins, pravastatin and rosuvastatin, are transported across hepatic cell membranes by organic anion transporting polypeptides (OATP), most frequently OATP1B1.88 Without the aid of a transport mechanism, these statins would have only limited access to nonhepatic cells, including the blood–brain barrier and the cells of the arterial wall.

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Statins

Frederic T. BillingsIV, Bernhard Riedel, in Essence of Anesthesia Practice (Third Edition), 2011

Overview/Pharmacology

Statins inhibit the reduction of HMG CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Statins primarily inhibit hepatocyte cholesterol synthesis and increase LDL receptor transcription and hepatic LDL cholesterol uptake. Consequently, statins reduce systemic concentrations of LDL cholesterol by 25–55%. Plasma HDL cholesterol levels may rise by 8–10% with atorvastatin and rosuvastatin.

The reduction in intracellular isoprenoid synthesis, which reduces prenylation of small GTPases (e.g., Rac, Rho), and may mediate the beneficial pleiotropic (non-lipid lowering) effects of statins. These effects include atherosclerotic plaque stabilization, inflammation reduction, reversal of endothelial dysfunction (through eNOS upregulation), decreased thrombogenicity, reduced reactive O2 species generation (through NADPH-oxidase assembly inhibition). Improved survival occurs primarily in pts with elevated serum CRP levels. The statin-induced reduction in serum CRP concentration occurs unrelated to lipid levels at baseline or during therapy.

Statins are orally administered once daily and peak plasma concentrations achieved in 1–3 hr.

The hepatic cytochrome P-450 system metabolizes most statins to active and inactive metabolites, and statins are primarily excreted in bile.

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Pocket cardiology

C. William Heise, in Comprehensive Precision Medicine (First Edition), 2024

7.07.2 Statins

Statins are widely used in the United States, with one in four Americans aged 40 and older taking a statin. Atorvastatin and simvastatin are the most prescribed. Statins have a wide therapeutic index. The most common adverse drug reaction is skeletal muscle toxicity, which manifests as statin-associated muscle symptoms (SAMS). SAMS can range from myalgia (pain without evidence of muscle degradation) to myopathy (evidence of muscle degradation with or without myalgia) to rhabdomyolysis (severe muscle damage with the risk of acute kidney injury). Most cases of SAMS are likely due to direct statin myotoxicity, which is concentration-dependent. SAMS are more frequent in clinical practice than in blinded, placebo-controlled trials, and data from the National Health and Nutrition Examination Survey suggest that the “number needed to harm” may be as high as 17. SAMS frequently lead to statin discontinuation, which can result in higher cholesterol levels and increased risk of cardiovascular disease if statins are not reinitiated.

SLCO1B1 is the protein product of the SLCO1B1 gene. It is a member of the solute carrier organic anion transporter family. This protein is also known as OATP1B1 or OATP-C. SLCO1B1 facilitates the hepatic uptake of statins, as well as other exogenous and endogenous compounds such as bilirubin and 17-beta-glucuronosyl estradiol (Niemi et al., 2011).

When SLCO1B1 function is decreased due to genetic variability or drug-mediated inhibition, it can lead to a marked increase in cellular exposure to statins, the putative causal factor underlying the link to statin-associated muscle symptoms (SAMS) (Turner and Pirmohamed, 2019). CPIC guidelines, which reflect the American College of Cardiology statin intensity recommendations, should be consulted as these recommendations are complex. In general, however, those persons with predicted SLCO1B1 decreased function should avoid high-intensity, high dose statin regimens and be aware of potential risk of SAMS in moderate-intensity and high dose regimens. Those with SLCO1B1 poor function should avoid high to moderate doses of most statins.

Genetic variations in CYP2C9 have been associated with increased exposure to fluvastatin. However, the pharmacokinetics or pharmacodynamics of other statins are not affected by CYP2C9 genetic variations. For individuals who are intermediate metabolizers, it is recommended that they avoid fluvastatin doses greater than 40 mg. Similarly, for poor metabolizers, it is recommended avoiding fluvastatin doses greater than 20 mg. If higher doses of fluvastatin are required to achieve the desired efficacy, an alternative statin should be considered.

ABCG2 encodes the ATP-binding cassette G2 transporter. This transporter is expressed in various tissues, including the liver, blood-brain barrier, and intestine. It facilitates the export of compounds out of cells into the extracellular space. The recommendations for ABCG2 are specific to rosuvastatin. Individuals with ABCG2 poor function are advised to start with a rosuvastatin dose of ≤20 mg. However, if a higher dose is needed to achieve the desired efficacy, an alternative statin or combination therapy (e.g., statin + other class agent) can be used. Individuals with ABCG2 decreased function may have an increased risk of developing adverse effects, such as SAMS, when taking higher doses of rosuvastatin.

The recommendations given above are primarily applicable to patients who are either receiving a new or a revised (dose or type) statin prescription. However, for patients on a stable statin and dose for at least 4 weeks without any symptoms suggestive of SAMS, it is reasonable to continue that statin and dose long-term, if their SLCO1B1 genotype-statin dose combinations fall within the moderate SAMS risk categories. In contrast, if those patients have been receiving statin therapy for less than 4 weeks, then clinicians may consider changing to a lower SAMS risk statin/dose to prevent the development of SAMS.

For patients who fall into the high SAMS risk categories, and they have been taking that statin therapy for at least 1 year without any negative effects, then it is considered safe to continue that statin therapy long-term. If those patients have been taking statin therapy for less than 1 year, then clinicians may consider changing to a lower SAMS risk statin/dose to reduce the risk for development of SAMS. These recommendations for the minimum duration of statin therapy for continued safe use long-term are primarily based on expert opinion and the onset of SAMS observed for simvastatin in different SLCO1B1 genotypes in a single prospective clinical trial.

The prevalence of statin use is high, and preemptive testing for SLCO1B1, ABCG2, and CYP2C9 may provide several potential benefits. One of these benefits is the reduction in the incidence of SAMS by identifying individuals who are at a significant risk of developing SAMS and recommending a lower statin dose or an alternative statin with a lower SAMS risk. Although there is a lack of prospective data showing that prescribing based on genetic testing results can alter SAMS incidence, emerging data indicate that applying SLCO1B1 testing to clinical practice can result in improvements in patients’ perceptions of statins, appropriate statin prescribing, and neutral data on patient-reported adherence. However, there is mixed data on the reduction of LDL-cholesterol levels as another potential benefit.

These recommendations are based on clinical trials with limited evidence for their impact in broad, population-based implementation. Further research will assist in optimizing statins across all people.

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Gender Differences in Stroke

Rebecca F. Gottesman, Argye E. Hillis, in Principles of Gender-Specific Medicine (Second Edition), 2010

Management of Hyperlipidemia

Statins have a clearly defined role in the secondary prevention of stroke. In a meta-analysis of earlier statin trials, the combined reduction in stroke was 17% for subjects randomized to statin therapy.21 The SPARCL trial showed a similar reduction (hazard radio 0.84 for fatal or nonfatal stroke) among individuals with a prior history of stroke or TIA.22 However, statin trials in particular have been criticized for their limited representation of women. As of 2004, only 25% of study participants in trials testing the role of statins were female.8 Thus, it is less clear what the role of statins is in stroke reduction in women, as compared to men. There is clearly a reduction in composite vascular endpoints in women (OR 0.80, 95% CI 0.71–0.91), in pooled data from randomized trials, but stroke alone was not reduced significantly in women on statins in this meta-analysis nor in other subgroup analyses of randomized or observational studies.23–25 In summary, the existing literature supports the use of statins for stroke prevention in general, and in men specifically, and there is evidence supporting the use of statins for cardiovascular disease prevention in women. There is no clear evidence, however, supporting the role of statins in stroke prevention in women.

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Blood Coagulation and Atherothrombosis

Hiroshi Ashikaga, Kenneth R. Chien, in Molecular Basis of Cardiovascular Disease (Second Edition), 2004

Lipid-Lowering Agents

HMG-CoA reductase inhibitors (statins) have been proven effective in both primary and secondary prevention of coronary artery disease. In addition to their lipid-lowering effects, statins appear to reduce the propensity for atherothrombosis by attenuating the extrinsic pathway of coagulation in patients with atherosclerosis. Statins reduce TF expression and activity through inhibition of Rho/Rho-kinase and activation of Akt in human macrophages and endothelial cells.221,235,236 Statins also inhibit cytokine-stimulated CD40 expression on these cells, further reducing TF upregulation.237

High-resolution MRI has enabled long-term, noninvasive observation of atherosclerotic plaques in human patients. Prolonged statin therapy causes significant regression of established atherosclerotic lesions with markedly decreased lipid content.238,239 Observational studies reported that early initiation of statin therapy in patients with acute myocardial infarction is associated with a significant risk reduction in mortality, and discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.240,241 However, a recent randomized clinical trial showed that early initiation of aggressive statin therapy for patients with acute coronary syndrome did not reduce the risk of major cardiac events compared with the placebo group, despite significant reduction in recurrent ischemic events in the first 16 weeks.242

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Statins and Muscle Damage

Matthew J. Sorrentino, in Nutrition and Skeletal Muscle, 2019

Abstract

Statin-induced muscle toxicity may impact up to 20% of treated patients. Many patients will experience mild muscle aches and weakness without evidence for muscle damage. More severe muscle toxicity includes myositis, rhabdomyositis, and autoimmune-mediated necrolizing myositis. The exact mechanism underlying myonecrosis is not fully understood but may involve pathways that have roles in muscle atrophy. Myalgias can be relieved in some patients by changing the statin medication to a differently metabolized statin or using alternative dosing schedules. Significant muscle damage requires stopping the statin and considering alternative lipid-lowering agents.

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Heart Failure Prevention

Vasiliki V. Georgiopoulou, ... Javed Butler, in Preventive Cardiology: Companion to Braunwald's Heart Disease, 2011

Statins

Statins are of proven benefit in patients with coronary heart disease212,231; however, their usefulness in the setting of left ventricular dysfunction remains under investigation. Preprocedural treatment with a statin before percutaneous coronary intervention is associated with lower levels of periprocedural creatine kinase elevation.207 Ishii and coworkers232 reported that chronic statin therapy before the onset of the acute event is associated with improved perfusion and reduced myocardial necrosis after the intervention. Prospective studies in humans reported an effect of statins on the risk for development of heart failure in high-risk patients, most of whom were free of heart failure at enrollment. Kjekshus and associates233 showed an 11% lower risk of new-onset heart failure in patients with stable coronary heart disease treated with statins. Similar trends were also demonstrated in other studies,234 supporting a role for statins in the prevention of heart failure. Notably, statins appears to prevent further progression of heart failure and to decrease mortality in this population.

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Special Patient Populations: Women and Elderly

Carl J. Lavie, Nanette K. Wenger, in Clinical Lipidology, 2009

Safety of and Adherence to Statins in Elderly

Although statins are generally considered extremely safe and well tolerated in elderly patients, several factors might predispose elderly patients to statin-related adverse events (Tables 38-5 and 38-6).78 It could be argued that many of these factors define the elderly population, making them the most likely group of patients susceptible to the major adverse effects of statin therapy. Given the high likelihood of multiple medication use in the elderly and the increased evidence supporting the benefits of statins in this population, a thorough knowledge of statin pharmacology, drug interactions, and safety considerations is necessary for selecting statins and concomitant medications in older persons.

Recent studies have demonstrated poor adherence rates for statin therapy in the elderly. In fact, in three large cohorts of elderly patients with ACS, with chronic CHD, or without CHD, statin adherence at 2 years was 40%, 35%, and 25% of patients, respectively, in these three groups.62,79 In a study of 34,501 elderly patients prescribed statins, 60% compliance was noted with statins at 6 months compared with only 32% at 10 years.80 In fact, fewer than 50% of patients of all ages prescribed statins are adherent 12 months after initiating treatment. These studies demonstrate that greater efforts are needed to promote better adherence to lipid medications, especially statins, to enhance statin therapy in preventive cardiology in the elderly.

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Atorvastatin in the Treatment of Traumatic Brain Injury

A.N. Sen, ... C.S. Robertson, in New Therapeutics for Traumatic Brain Injury, 2017

Abstract

Statins have been recently investigated as a novel neurotherapeutic medication to prevent secondary injury in patients with traumatic brain injury. Through a number of mechanisms including antiapoptotic effects, increased angiogenesis, antioxidant and antiinflammatory mechanisms, and augmentation of neurogenesis and synaptogenesis; statins have been demonstrated in in vitro and animal preclinical studies to have neuroprotective effects in multiple injury models. A significant paucity exists in clinical studies of the application of statins to traumatic brain injury patients. Inferences can be drawn, however, from the ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage literature in which more extensive investigations of statins have been conducted. Significant further research is needed to determine the efficacy and role of statins in traumatic brain injury.

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