Evidence-based Use of Statins for Primary Prevention of Cardiovascular Disease

doi:10.1016/j.amjmed.2011.11.013

The American Journal of Medicine

Volume 125, Issue 5, May 2012, Pages 440-446

https://doi.org/10.1016/j.amjmed.2011.11.013 Get rights and content

Abstract

Three-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, are widely available, inexpensive, and represent a potent therapy for treating elevated cholesterol. Current national guidelines put forth by the Adult Treatment Panel III recommend statins as part of a comprehensive primary prevention strategy for patients with elevated low-density lipoprotein cholesterol at increased risk for developing coronary heart disease within 10 years. Lack of a clear-cut mortality benefit in primary prevention has caused some to question the use of statins for patients without known coronary heart disease. On review of the literature, we conclude that current data support only a modest mortality benefit for statin primary prevention when assessed in the short term (<5 years). Of note, statin primary prevention results in a significant decrease in cardiovascular morbidity over the short and long term and a trend toward increased reduction in mortality over the long term. When appraised together, these data provide compelling evidence to support the use of statins for primary prevention in patients with risk factors for developing coronary heart disease over the next 10 years.

Section snippets

Reliance on All-Cause Mortality: A Flawed Argument

Key to the argument made by opponents of statin use in primary prevention is the assertion that statin therapy does not decrease near-term (<5 years) all-cause mortality.1, 2, 3 Although short-term mortality data are suboptimal, a fundamental goal of primary prevention also must include reduction of morbidity, including events of significant consequence, such as myocardial infarction, stroke, ischemia-related hospitalizations, and invasive revascularization procedures. Although not always

All-Cause Mortality Data for Statin Therapy

Three meta-analyses of the large statin primary prevention randomized controlled trials have been published since 2009 (Table 1).1, 5, 6 The results reveal a modest 9% to 17% relative risk (RR) reduction in all-cause mortality with statins assessed at less than 5 to 10 years of follow-up, with statistical significance of P ≤ .05 in 2 of the 3 trials. Paradoxically, the nearly identical results have been interpreted as arguments for and against statins in primary prevention. If the only goal of

Summary of Key Points and Recommendations

Given its insidious onset yet progressive nature, coronary heart disease should not be thought of as a dichotomous disease state, but rather as a disease spectrum in which select individuals are susceptible to early and rapidly advancing atherosclerosis based on genetic predisposition and lifestyle. There is unequivocal evidence that atherosclerosis begins in young adulthood, can be mitigated at an early age with reduction in risk factors, and can be slowed or potentially reversed with statins.

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Cited by (41)

Atherosclerosis: Conventional intake of cardiovascular drugs versus delivery using nanotechnology – A new chance for causative therapy?
2021, Journal of Controlled Release
Citation Excerpt :
In this manner it became possible to reduce cholesterol levels, especially LDL in high risk patients. Like it was already mentioned in the beginning of this article, LDL blood levels are one key risk factor for atherosclerosis, because higher amounts of circulating LDL increase the risk of LDL accumulation in areas of dysfunctional endothelium [119,120]. Statins have been successfully used since their market launch in the 1980s and 1990s [121].
Atherosclerosis is the leading cause of death in developed countries. The pathogenetic mechanism relies on a macrophage-based immune reaction to low density lipoprotein (LDL) deposition in blood vessels with dysfunctional endothelia. Thus, atherosclerosis is defined as a chronic inflammatory disease. A plethora of cardiovascular drugs have been developed and are on the market, but the major shortcoming of standard medications is that they do not address the root cause of the disease. Statins and thiazolidinediones that have recently been recognized to exert specific anti-atherosclerotic effects represent a potential breakthrough on the horizon. But their whole potential cannot be realized due to insufficient availability at the pathological site and severe off-target effects. The focus of this review will be to elaborate how both groups of drugs could immensely profit from nanoparticulate carriers. This delivery principle would allow for their accumulation in target macrophages and endothelial cells of the atherosclerotic plaque, increasing bioavailability where it is needed most. Based on the analyzed literature we conclude design criteria for the delivery of statins and thiazolidinediones with nanoparticles for anti-atherosclerotic therapy. Nanoparticles need to be below a diameter of 100 nm to accumulate in the atherosclerotic plaque and should be fabricated using biodegradable materials. Further, the thiazolidinediones or statins must be encapsulated into the particle core, because especially for thiazolidindiones the uptake into cells is prerequisite for their mechanism of action. For optimal uptake into targeted macrophages and endothelial cells, the ideal particle should present ligands on its surface which bind specifically to scavenger receptors. The impact of statins on the lectin-type oxidized LDL receptor 1 (LOX1) seems particularly promising because of its outstanding role in the inflammatory process. Using this pioneering concept, it will be possible to promote the impact of statins and thiazolidinediones on macrophages and endothelial cells and significantly enhance their anti-atherosclerotic therapeutic potential.
Preparation and characterization of nano statins using oyster mushroom (Pleurotus sajor-caju): a new strategy to reduce toxicity and enhance efficacy for the treatment of cardiovascular disease
2020, European Journal of Integrative Medicine
Citation Excerpt :
Multiple clinical studies have shown that a class of medications termed statins lower cardiovascular morbidity and mortality. Statins, a class of lipid lowering drugs, acts as a competitive inhibitor of the enzyme, 3-hydroxy-3methyl-glutaryl enzyme in the process of converting HMG CoA to mevalonate in cholesterol biosynthesis are commercially available for the treatment of CVDs [3–5]. Though statins are beneficial for the cardiovascular health, long-term adherence to statin therapy may not be the best possible choice recommended due to their risk of dose related side effects [6] poor solubility in water and low bioavailability in human body [7].
Most of the cardiovascular diseases come under the umbrella of atherosclerosis. Statins, a class of drug, well known to treat cardiovascular diseases, exhibit poor solubility and low bioavailability which limits their applications. In this study, oyster mushroom (Pleurotus sajor-caju), was used to prepare nanoparticles of statins to explore whether it could achieve better solubility, bioavailability and efficacy at a lower dose compared with nanoparticles from Lovastatin, a commercial drug.
Nanoparticles of statins were prepared from both the commercial as well as herbal source using the wet milling technique. Prepared nanoparticles from both the sources were characterized using characterization techniques such as DLS, UV–vis spectroscopy, SEM, FTIR and HPLC which were compared with their bulk form for their efficacy. Antioxidant activity of statins was also evaluated by DPPH scavenging assay.
These results demonstrated a new method of preparation of statin nanoparticles. The SEM analysis of herbal as well as commercial nano formulations showed the size ranged between 60–90 nm and their HPLC analysis confirmed the presence and elution of lovastatin at approximately 9 min. Results of the antioxidant assay showed that nanoparticles synthesized from commercial drug, lovastatin, and from mushroom showed 76.57 % and 73.83 % of inhibition, respectively which was much higher than their bulk counterpart which showed only 16.77 % inhibition.
The study has provided a method to combat the toxicity effects associated with bulk statins by synthesising nanoparticles of statins with greater efficacy, higher bioavailability, more solubility and greater radical scavenging capacity at a lower dose.
CRISPR-Cas9-mediated disruption of the HMG-CoA reductase genes of Mucor circinelloides and subcellular localization of the encoded enzymes
2019, Fungal Genetics and Biology
Citation Excerpt :
Although the compensatory effect of the other genes was also observed, these results indicate that hmgR2 has a primary role in the ergosterol biosynthesis. Statins are competitive inhibitors of HMG-CoA reductase and widely used cholesterol lowering agents (Minder et al., 2012). It is known that they may have antifungal effect (Macreadie et al., 2006; Galgóczy et al., 2009) and it has recently been found that they can decrease the virulence of Rhizopus oryzae, the most frequent causative agent of mucormycoses (Bellanger et al., 2016).
Terpenoid compounds, such as sterols, carotenoids or the prenyl groups of various proteins are synthesized via the mevalonate pathway. A rate-limiting step of this pathway is the conversion of 3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid catalyzed by the HMG-CoA reductase. Activity of this enzyme may affect several biological processes, from the synthesis of terpenoid metabolites to the adaptation to various environmental conditions. In this study, the three HMG-CoA reductase genes (i.e. hmgR1, hmgR2 and hmgR3) of the β-carotene producing filamentous fungus, Mucor circinelloides were disrupted individually and simultaneously by a recently developed in vitro plasmid-free CRISPR-Cas9 method. Examination of the mutants revealed that the function of hmgR2 and hmgR3 are partially overlapping and involved in the general terpenoid biosynthesis. Moreover, hmgR2 seemed to have a special role in the ergosterol biosynthesis. Disruption of all three genes affected the germination ability of the spores and the sensitivity to hydrogen peroxide. Disruption of the hmgR1 gene had no effect on the ergosterol production and the sensitivity to statins but caused a reduced growth at lower temperatures. By confocal fluorescence microscopy using strains expressing GFP-tagged HmgR proteins, all three HMG-CoA reductases were localized in the endoplasmic reticulum.
Lipid Management Guidelines from the Departments of Veteran Affairs and Defense: A Critique
2016, American Journal of Medicine
Citation Excerpt :
Indeed, a number of reports, including the meta-analysis cited by the VA/DoD, have shown that high-intensity statins, with or without additional nonstatin LDL-C–lowering therapy, can significantly reduce nonfatal myocardial infarction and stroke in high-risk patients, compared with moderate-intensity statins.9-13 In addition, prioritizing mortality as the main outcome used to inform the VA/DoD dyslipidemia guideline recommendations may not be entirely appropriate because follow-up in many of the included trials, particularly in primary prevention, was likely not sufficiently long enough to demonstrate a mortality benefit for LDL-C reduction and because the morbidity from nonfatal myocardial infarction and stroke can be devastating.11,14 To take one example, the mortality benefit derived from statins was not evident in the initial report from the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm after 3 years of follow-up, but was evident when outcomes were reassessed after 11 years.15,16
In December 2014, the US Department of Veterans Affairs and Department of Defense (VA/DoD) published an independent clinical practice guideline for the management of dyslipidemia and cardiovascular disease risk, adding to the myriad of recently published guidelines on this topic. The VA/DoD guidelines differ from major US guidelines published by the American College of Cardiology/American Heart Association in 2013 in the following ways: recommending moderate-intensity statins for the majority of patients with statin indications regardless of atherosclerotic cardiovascular disease risk; advocating for limited on-treatment lipid monitoring; and deemphasizing ancillary data, such as coronary artery calcium testing, to improve atherosclerotic cardiovascular disease risk estimation. In the context of manifold treatment recommendations from numerous guideline committees, the VA/DoD recommendations may generate further confusion and mixed messages among healthcare providers about the optimal treatment of dyslipidemia. In this review, we critically appraise the VA/DoD recommendations with a focus on the evidence base for each area where the VA/DoD guidelines differ from the American College of Cardiology/American Heart Association guidelines. We also call for harmonization of lipid treatment guidelines to ensure high-quality and consistent care for patients with, and at risk for, atherosclerotic cardiovascular disease.
Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer
2016, EBioMedicine
Citation Excerpt :
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) is the rate-limiting enzyme for cholesterol synthesis in the conversion of HMG-CoA to mevalonate. Statins are HMGR inhibitors decreasing serum cholesterol to reduce the incidence of cardiovascular and cerebrovascular disorders (Minder et al., 2012). In addition to cholesterol synthesis, activation of HMGR facilitated protein prenylation, such as farnesylation of Ras oncoproteins for cell growth and carcinogenesis (Thurnher et al., 2012).
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc^Min/+ CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC.
Primary prevention with statins in cardiovascular diseases: A Saudi Arabian perspective
2015, Journal of the Saudi Heart Association
Cardiovascular disease (CVD) constitutes one of the major causes of deaths and disabilities, globally claiming 17.3 million lives a year. Incidence of CVD is expected to rise to 25 million by 2030, and Saudi Arabia, already witnessing a rapid rise in CVDs, is no exception. Statins are the drugs of choice in established CVDs. In the recent past, evidence was increasingly suggesting benefits in primary prevention. But over the last decade Saudi Arabia has a witnessed significant rise in CVD-related deaths. Smoking, high-fat, low-fiber dietary intake, lack of exercise, sedentary life, high blood cholesterol and glucose levels were reported as frequent CVD-risk factors among Saudis, who may therefore be considered for primary prevention with statin. The prevalence of dyslipidemia, in particular, indicates that treatment should be directed at reducing the disorder with lipid-modifying agents and therapeutic lifestyle changes.
The recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines has reported lowering the low-density lipoprotein cholesterol (LDL-C) target levels, prescribed by the 2011 European Society of Cardiology (ESC)/the European Atherosclerosis Society (EAS). The new ACC/AHA guidelines have overemphasized the use of statin while ignoring lipid targets, and have recommended primary prevention with moderate-intensity statin to individuals with diabetes aged 40–75 years and with LDL-C 70–189 mg/dL. Treatment with statin was based on estimated 10-year atherosclerotic-CVD (ASCVD) risk in individuals aged 40–75 years with LDL-C 70 to 189 mg/dL and without clinical ASCVD or diabetes. Adoption of the recent ACC/AHA guidelines will lead to inclusion of a large population for primary prevention with statins, and would cause over treatment to some who actually would not need statin therapy but instead should have been recommended lifestyle modifications. Furthermore, adoption of this guideline may potentially increase the incidences of statin intolerance and side-effects. On the other hand, the most widely used lipid management guideline, the 2011 ESC/EAC guidelines, targets lipid levels at different stages of disease activity before recommending statins. Hence, the 2011 ESC/EAC still offers a holistic and pragmatic approach to treating lipid abnormalities in CVD. Therefore, it is the 2011 ESC/EAC guidelines, and not the recent ACC/AHA guidelines, that should be adopted to draw guidance on primary prevention of CVD in Saudi Arabia.

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ReviewEvidence-based Use of Statins for Primary Prevention of Cardiovascular Disease

Abstract

Section snippets

Reliance on All-Cause Mortality: A Flawed Argument

All-Cause Mortality Data for Statin Therapy

Summary of Key Points and Recommendations

J Am Coll Cardiol

J Am Coll Cardiol

Am J Med

Lancet

Am J Cardiol

Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants

Arch Intern Med

Clinical inertia as a clinical safeguard

JAMA

Diagnostic tests: another frontier for less is more: or why talking to your patient is a safe and effective method of reassurance

Arch Intern Med

Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association

Circulation

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials

BMJ

Statins for the primary prevention of cardiovascular disease

Cochrane Database Syst Rev

Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials

Arch Intern Med

Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)

JAMA

By Jove! What is a clinician to make of JUPITER?

Arch Intern Med

Circ Cardiovasc Qual Outcomes

Long-term follow-up of the West of Scotland Coronary Prevention Study

N Engl J Med

The Anglo-Scandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure

Eur Heart J

Review
Evidence-based Use of Statins for Primary Prevention of Cardiovascular Disease