Response to Letter of Mascitelli L, Ravnskov U, Pezzetta F, and Goldstein M

Some interesting issues are raised in the letter to the editor of Mascitelli et al, and facing these questions is essential in the understanding and advancement of aggressive cardiovascular (CV) disease prevention. Even with the most aggressive lipid-lowering therapy, there is roughly a 60% to 70% failure to reduce coronary heart disease (CHD) events. However, in considering the low-density lipoprotein (LDL) levels throughout the range in the population and the incidence of CV disease, the lipid hypothesis appears well established, starting with the Lipid Research Clinics (LRC) Coronary Primary Prevention Trial, which can be viewed as essentially a pure result of LDL lowering, requiring 7.4 years to see significant benefit. In addition, a pure LDL reduction study, the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial showed statistically significant benefit in reducing CHD mortality as well as overall mortality. There now appears to be a wellestablished log linear relationship between LDL levels from 40 mg/dL to past 190 mg/dL and lowering LDL can be considered the current gold standard of CV disease prevention. Further support of ‘‘lower is better’’ regarding LDL comes from a substudy of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE-IT) trial in which subgroups of LDL <40 mg/dL and LDL 40 to 60 mg/dL had fewer major cardiac events. Coronary heart disease regression benefit from LDL lowering also has been well established in previous and very recent imaging studies. Pleiotropic effects of statins must also be considered and undoubtedly explain the much more rapid CV benefit with statins than with LDL lowering alone. These pleiotropic effects include favorable antithrombotic alterations and suppression of immunologic reactions. Concern regarding cancer and the reduction of LDL is an old concern and one that appears to have been satisfactorily answered in the past as not a problem. Nevertheless, when the data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was presented, questions were again raised, necessitating consideration and response. Multiple previous trials were considered and over approximately 5 years of statin therapy, there was no evidence that lowering LDL by an average of about 40 mg/dL increased the risk of developing a first cancer. In addition, there was no trend toward increased risk for cancer in patients with lower cholesterol levels on more prolonged statin therapy. More specific to the issue of the Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE) trial, the SEAS trial associated ezetimibe with an increase in the new onset of cancer in 101 patients in the activetreatment group versus 65 in the control group. Such an observation had to be answered and to do so, data from 2 large ongoing trials with ezetimibe were considered and these included the Study of Heart and Renal Protection (SHARP) and Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trials. Analysis of these 2 trials plus the SEAS trial led to the conclusion that there is no credible evidence of any adverse effect of ezetimibe on the rates of cancer. In addition, no significant association of cancer and LDL lowering has ever been established. In conclusion, maximum LDL reduction alone reduces CHD events and a lower LDL level appears better. The statins, via their pleiotropic effects, offer additional benefit over and above treatment of LDL, and ezetimibe amplifies these effects by further marked LDL reduction as well as by offering an