Editor's Message  |   April 2011
Cardiovascular Benefits of Aggressive Cholesterol-Lowering Therapy
Author Notes
  • Address correspondence to Dr Clearfield, Dean, Touro University College of Osteopathic Medicine–California, 1310 Club Dr, Vallejo, CA 94592-1159.Email: 
Article Information
Cardiovascular Disorders / Preventive Medicine
Editor's Message   |   April 2011
Cardiovascular Benefits of Aggressive Cholesterol-Lowering Therapy
The Journal of the American Osteopathic Association, April 2011, Vol. 111, i-eS2. doi:
The Journal of the American Osteopathic Association, April 2011, Vol. 111, i-eS2. doi:
In the 3 articles in this supplement to JAOA—The Journal of the American Osteopathic Association, Drs Cruickshank,1 Cohen,2 and Smiley3 review the rationales behind the various lipid goals stipulated in the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines and the progress that has been made toward meeting those goals. In the lead article of this supplement, Dr Cruickshank highlights the progress in achieving low-density lipoprotein cholesterol (LDL-C) goals in clinical practice, citing surveys that include the Lipid Treatment Assessment Project (L-TAP) (1996-1997),4 the L-TAP 2 (2006-2007),5 and the American Osteopathic Clinical Assessment Program (AOA-CAP) (2005-2010).6 From 1996 to 2010, there was greater success in achieving lipid-lowering goals set by the National Cholesterol Education Panel, as noted in the NEPTUNE (National Cholesterol Education Program Evaluation ProjecT Utilizing Novel E-Technology) trial,7 the L-TAP 2, and the AOA-CAP. The success rates for achieving LDL-C goals in these 3 studies were 57%, 67%, and 56%, respectively, in high-risk subjects, but only 18%, 30%, and 20%, respectively, in patients at very high risk, for whom the LDL-C goal was less than 70 mg/dL.5-7 Despite a substantial clinical trial database demonstrating the benefits of attaining guideline LDL-C goals, these data suggest that a considerable treatment gap still remains in many patients, especially those at the highest cardiovascular risk. 
In the next article, Dr Cohen details the evidence base from clinical trials demonstrating the rationale for more aggressive lipid lowering through statin therapy.2 Dr Cohen eloquently presents a case that continued lowering of LDL-C has a continuous, graded, and strong relationship to reduced cardiovascular events for patients with and patients without preexisting coronary heart disease (secondary and primary prevention, respectively). Although the article emphasizes higher-risk patients with preexisting CHD (secondary prevention), it also includes an analysis of JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), which resulted in statistically significant reductions in the rate of first major cardiovascular events within a large primary prevention cohort.8 The concept of lifetime cardiovascular risk extends the ideas presented in Dr Cohen's article and suggests that many individuals deemed at moderate or even low risk over a 10-year period may very well have a high lifetime risk for a cardiovascular event.9 This hypothesis proposes that the risk of continued exposure to abnormal lipoproteins, even at moderately elevated levels, may be compounded over time, resulting in progressive atherosclerosis and resultant cardiovascular events. For example, in individuals with lifetime LDL-C levels reduced by approximately 28% (about 40 mg/dL) due to a nonsense mutation of PCSK9 gene, a reduction of up to 88% in the rate of coronary heart disease events has been reported.10 This 88% reduction is quite different from the 30% reduction predicted by a similar decrease in LDL-C levels noted in a meta-analysis of statin trials.11 Individuals with the PCSK9 mutations have lower LDL-C levels throughout their entire lives, which may actually triple their risk reduction compared with those whose LDL-C levels are lowered similarly but are measured for only a 5-year span. 
In patients treated with statins for more than 5 years—which is greater than the usual duration in clinical trials—findings suggest a continuing widening of the gap between patients treated with statins and untreated patients, for both primary and secondary prevention.12,13 Over longer time spans, such as decades, the sustained benefit from the lower LDL-C levels achieved with continuous statin therapy may approach the 88% reductions noted with lifelong PCSK9 mutations. 
In the final article of this supplement, Dr Smiley reviews the lifestyle and the pharmacotherapeutic options available to maximize reductions in cardiovascular risk. Maximized interventions that aggressively lower LDL-C levels to less than 70 mg/dL may stabilize plaque and reduce plaque vulnerability (ie, plaque fractures that result in an acute event such as myocardial infarction, unstable angina, and death from thrombus formation) enough to potentially negate adverse effects from other risk factors such as elevated blood pressure and cigarette smoking. There is also potential to negate adverse effects from low levels of high-density lipoprotein cholesterol and elevated triglyceride levels, but it is theoretical and will require further studies such as the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes).14 
In a recent editorial, William Roberts, MD, editor of the American Journal of Cardiology, succinctly summarized this complex issue into a simple phrase: “It's the cholesterol, stupid!”15 This opinion was recently supported by the Cholesterol Treatment Trialists' Collaboration,11 a meta-analysis of 170,000 participants in 26 randomized trials, which demonstrated a 12% reduction in cardiovascular events per 1 mmol/L (39 mg/dL) decrease in LDL-C during the first year of statin therapy, followed by a consistent 25% reduction per year during each subsequent year. Extrapolating these data to primary prevention trials, achieving LDL-C reductions of 1 to 3 mmol/L for a decade or more with statins could very well lower 10-year cardiovascular event rates to less than 2%, and possibly less than 1%. 
The articles in this supplement, which were developed in part from a symposium conducted during the American Osteopathic Association's 115th Annual Osteopathic Medical Conference and Exposition on October 25, 2010, show that a model for achieving these more aggressive LDL-C reductions is clearly within our grasp and should result in astounding benefits for our patients. 
 Financial Disclosures: Dr Clearfield discloses that he is a consultant for AstraZeneca LP.
 This supplement is supported by an independent educational grant from Merck & Co, Inc.
Cruickshank JM. Achieving cholesterol targets: how well are we doing? J Am Osteopath Assoc. 2011;111(4 suppl 3):eS3-eS6.
Cohen JD. Rationale for aggressive lipid lowering in high-risk patients. J Am Osteopath Assoc. 2011;111(4 suppl 3):eS7-eS12.
Smiley WH III. Getting patients to goal: closing the gap. J Am Osteopath Assoc. 2011;111(4 suppl 3):eS13-eS17.
Pearson TA, Laurora I, Chy H, et al. The Lipid Treatment Assessment Project (L-TAP): a multi-center survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160(4):459-467.
Waters D, Brotons C, Chiang CW, et al. Lipid Treatment Assessment Project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation. 2009;120(1):28-34.
American Osteopathic Association. AOA Clinical Assessment Program. Accessed April 8, 2011.
Davidson M, Maki, Pearson T, et al. Results of the National Cholesterol Education Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) survey and implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol. 2005;96(4):556-563.
Ridker P, Danielson E, Fonseca F, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.
Lloyd-Jones DM, Dyer AR, Wang R, Daviglus ML, Greenland P. Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death. (Chicago Heart Association Detection Project in Industry). Am J Cardiol. 2007;99(4):535-540.
Cohen JC, Boerwinkle E, Mosely TH, Hobbs HH. Sequence variations in PCSK9, low LDL and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.
Baigent C, Blackwell L, Emberson J, et al. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL-cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376(9753):1670-1681.
Pedersen, TR, Cater NB, Faergeman O, et al. Comparison of atorvastatin 80 mg/day versus simvastatin 20 to 40 mg/day on frequency of cardiovascular events late (five years) after acute myocardial infarction (from the Incremental in End Points through Aggressive Lipid Lowering [IDEAL] trial). Am J Cardiol. 2010;106(3):354-359.
Ford I, Murray H, Packard C, et al. Long term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;357(15):1477-1486.
The AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol Rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J. 2011;161(3):471-477.e2.
Roberts WC. It's the cholesterol, stupid! Am J Cardiol. 2010;106(9):1364-1366.