REVIEW
Intensive Lowering of Low-Density Lipoprotein Cholesterol Levels for Primary Prevention of Coronary Artery Disease

https://doi.org/10.4065/84.4.345Get rights and content

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States, and a high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CAD. Current guidelines recommend the use of statins to lower LDL-C levels for the primary prevention of CAD based on an individual's risk factor profile and baseline LDL-C level. For moderaterisk individuals, those with 2 or more major risk factors for CAD and a Framingham risk score of 10% to 20%, the recommendation is to use a statin to lower LDL-C levels to less than 130 mg/dL. However, up to 40% of individuals who develop CAD have LDL-C levels lower than this cutoff. In 2004, the National Cholesterol Education Program Adult Treatment Panel III guidelines were updated to include an LDL-C goal of less than 100 mg/dL for individuals at moderately high risk of developing CAD. The guidelines identified several risk factors that when present would favor the use of pharmacological therapy to achieve this more aggressive LDL-C goal. This review evaluates the evidence supporting an LDL-C target of less than 100 mg/dL for moderately high-risk individuals and reviews those risk factors that when present help identify patients who would benefit from achieving this lower LDL-C goal. English-language publications in MEDLINE and references from relevant articles published between January 1, 1980, and November 30, 2008, were reviewed. Main keywords searched were coronary artery disease, hyperlipidemia, statins, cardiac risk factors, inflammatory markers, metabolic syndrome, and coronary artery calcium.

Section snippets

ADVANCING AGE AND SEVERE AND MULTIPLE RISK FACTORS

In older individuals, the LDL-C goal is lower because this population has a much greater burden of coronary atherosclerosis than younger individuals and therefore increased CAD morbidity and mortality. The prevalence of clinical CAD is almost 3-fold higher for individuals older than 60 years compared with younger individuals, and CAD is the leading cause of death among older individuals.1

Many healthy older individuals without clinical CAD have subclinical atherosclerotic disease and are at

FAMILY HISTORY OF PREMATURE CAD

The updated NCEP ATP III guidelines identified a strongly positive family history of premature atherosclerotic cardiovascular disease as a severe risk factor that, when present in moderately high-risk individuals, would favor the use of a lipid-lowering drug to achieve an LDL-C goal of less than 100 mg/dL. An individual with a first-degree male relative who had a CAD event before the age of 55 years or a first-degree female relative who had a CAD event before the age of 65 years is considered

METABOLIC SYNDROME, HIGH TRIGLYCERIDE LEVELS, AND LOW HDL-C LEVELS

The metabolic syndrome represents a constellation of lipid and nonlipid risk factors that together increase the risk of CAD independently of LDL-C levels.22, 23 The NCEP ATP III defines the metabolic syndrome as a diagnosis of 3 or more of the following risk factors: waist circumference greater than 40 inches for men or greater than 35 inches for women, triglyceride levels of 150 mg/dL or higher (to convert to mmol/L, multiply by 0.0113), HDL-C levels of less than 40 mg/dL for men or less than

EMERGING RISK FACTORS

The updated NCEP ATP III guidelines identified 2 emerging risk factors that would favor an LDL-C goal of less than 100 mg/dL for the primary prevention of CAD in moderately high-risk individuals: elevated serum high-sensitivity CRP level greater than 3 mg/L (to convert to nmol/L, multiply by 9.524) and a coronary calcium level in the higher than 75th percentile for a person's age and sex.

Inflammation plays a key role in both the development and progression of atherosclerotic CAD. The most

DISCUSSION

The current evidence supports a strategy of early and aggressive lowering of LDL-C levels for the primary prevention of CAD. Cohen et al43 studied a group of individuals with nonsense mutations in the PCSK9 gene that caused low levels of LDL-C. Although their LDL-C level was only 28% lower than the population without the PCSK9 mutation, their CAD risk was 88% lower. The implications from that study are that a low level of LDL-C throughout life is associated with a very low risk of CAD. Lowering

CONCLUSION

Physicians need to treat moderate-risk patients with lipid-lowering therapy to achieve a lower LDL-C goal of less than 100 mg/dL if the patients have multiple risk factors, an elevated CRP level, or other clinical risk factors identified in the updated NCEP ATP III guidelines. With increased adherence to these guidelines, opportunity exists to substantially reduce the incidence of a first cardiovascular event in higher-risk patients.

Acknowledgments

Editorial support was provided by Chris Cadman of Envision Pharma, a medical writer funded by Pfizer.

REFERENCES (43)

  • J Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

    N Engl J Med

    (1995)
  • Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins [published corrections appear in Lancet. 2005;366(9494):1358 and 2008;371(9630):2084]

    Lancet

    (2005 Oct 8)
  • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

    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

    (2001)
  • TA Pearson et al.

    AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases

    Circulation

    (2002)
  • SM Grundy et al.

    Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

    Circulation

    (2004)
  • LH Kuller et al.

    Subclinical disease as an independent risk factor for cardiovascular disease

    Circulation

    (1995)
  • P Greenland et al.

    Major risk factors as antecedents of fatal and nonfatal coronary heart disease events

    JAMA

    (2003)
  • RS Vasan et al.

    Relative importance of borderline and elevated levels of coronary heart disease risk factors

    Ann Intern Med

    (2005)
  • DM Lloyd-Jones et al.

    Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring

    JAMA

    (2004)
  • JM Murabito et al.

    Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults

    JAMA

    (2005)
  • AM Valdes et al.

    Association of traditional risk factors with coronary calcification in persons with a family history of premature coronary heart disease: the study of the inherited risk of coronary atherosclerosis

    J Investig Med

    (2001)
  • Cited by (42)

    • Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence

      2023, International Immunopharmacology
      Citation Excerpt :

      Clinically, a CRP value greater than 10 mg/l indicates an acute inflammation but in a Mayo Clinic study, it has been reviewed that CRP as a nonspecific inflammatory marker could be a main emerging risk factor for wellness assessment. In this regard, it has been identified a CRP level of less than 1mg/l is a low risk, a CRP level of 1-3 mg/l is a moderate risk, and a CRP level of greater than 3 mg/l is a high risk [23]. Nehring et al. (2022) also represented another interpretation for different levels of CRP as follows: less than 3 mg/l: normal (level seen in most healthy adults); 3 to 10 mg/l, normal or minor elevation; 10 to 100 mg/l, moderate elevation; more than 100 mg/l: marked elevation; and more than 500 mg/l, severe elevation [24].

    • Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes

      2017, European Journal of Medicinal Chemistry
      Citation Excerpt :

      Cholesterol levels in the body are governed by various factors such as absorption of dietary cholesterol, in situ cholesterol synthesis and biliary cholesterol excretion [5]. Several therapeutic agents have been developed for lowering of lipid levels [9,10a] which are in current use. These include two novel PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors approved in 2015 [10b].

    • Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease

      2015, Life Sciences
      Citation Excerpt :

      It is generally accepted that atherosclerosis, which underlies most ischemic vascular disease, is a multifactorial disease with a number of risk factors, including dyslipidemia, hypertension, diabetes and smoking [39]. All these factors provide potential targets for reducing the risk of the disease, however, cholesterol and lipid levels are considered to be the major targets for reducing the risk of the ischemic heart disease (IHD) [18]. Statins are a chemically and pharmacologically diverse group of drugs that share the ability to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that controls the rate-limiting step of cholesterol synthesis, but this inhibition is followed by other subsequences associated with the mevalonate pathway [1,45].

    View all citing articles on Scopus
    1

    Dr Karalis has received research and grant support from Pfizer and Abbott Pharmaceuticals and is on the speaker's bureau for Pfizer, Abbott, Sanofi-Aventis, and Merck-Schering-Plough Pharmaceuticals.

    View full text