Dr Myerson is Director of Preventive Cardiology, St. Luke's-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY.
The case against low-density lipoprotein cholesterol (LDL-C) keeps growing. In the 1970s, data from the Framingham Heart Study suggested that serum cholesterol was associated with risk for coronary heart disease (CHD). Intervention trials then showed that lowering cholesterol, in particular LDL-C, was beneficial. Many lipid-lowering drugs were used in these early trials. As statins were being developed, more trials focused on this class.
It wasn't until evidence showed reduced mortality that lipid-lowering therapy received an even bigger boost. The Scandinavian Simvastatin Survival Study looked at 4444 patients with angina or history of myocardial infarction and elevated LDL-C.1 Long-term treatment with simvastatin (Zocor) improved survival compared with placebo.
The benefit of lipid lowering in primary prevention was more difficult to demonstrate. The West of Scotland Coronary Prevention Study, conducted in the early 1990s, provided the first evidence that lipid lowering could prevent death in people without CHD.2 This study looked at men with moderate hypercholesterolemia and no known coronary disease. Treatment with pravastatin (Pravachol) was associated with fewer coronary events and deaths compared with placebo.
How Low to Go?
With a benefit to lowering LDL-C well established, the next question became?How low should LDL-C be? The 2004 National Cholesterol Education Program (NCEP) Adult Treatment Panel III stated that for high-risk patients, <100 mg/dL is recommended, but with a "therapeutic option" for a target of <70 mg/dL.
Four trials since then have attempted to answer how low should we go. In the A to Z (Aggrastat to Zocor), PROVE-IT TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy?Thrombolysis in Myocardial Infarction 22), Treating to New Targets (TNT), and IDEAL (Incremental Decrease in End Points Through Aggressive Lipid-Lowering) trials, intensive statin therapy to lower LDL-C levels to <100 mg/dL, with many <70 mg/dL, was shown safe and effective. These results have led physicians to opt for the target of <70 mg/dL in high-risk patients (ie, those with known cardiovascular disease or diabetes).
John C. LaRosa, MD, FACP, chair of the TNT trial steering committee, and president of the State University of New York Health Science Center, Brooklyn, believes that "in patients with coronary artery disease, going to or below 70 is probably a good idea. While we don't know the answer to ?How low?' we have presented additional data from the TNT trial showing that levels in the 50s are not dangerous." He also thinks we may not have additional trials testing lower limits, as what we have now is "as good as it is going to get."
New Goals Bring New Problems
Physicians soon found that previous regimens and monotherapy were not getting patients to LDL-C goal. In addition, the 2004 guidelines established new targets for high-density lipoprotein cholesterol (HDL-C) and triglycerides. Higher doses and combination therapy, often with 3 agents, were required to bring patients to goal. And although side effects had not been a major concern with lipid-lowering agents, physicians were now hearing complaints of muscle soreness and seeing elevations in creatine kinase (CK) and liver function tests.
The withdrawal of cerivastatin (Baycol, Lipobay) because of serious side effects, in particular, increased incidence of rhabdomyolysis, raised concerns. The National Lipid Association appointed a Safety Assessment Task Force, consisting of experts in musculoskeletal disorders, hepatology, nephrology, and neurology, that conducted a systematic review of existing safety data.3
The task force could not determine the precise cause for elevations in liver transaminase levels, but thought the most relevant question was whether statins caused serious liver dysfunction or failure. The answer was not clear, in part because of the rarity of these events.
Muscle symptoms or signs (CK elevation) are the most common adverse effects associated with statin therapy, but serious events were rare. In 21 trials providing 180,000 person-years of follow-up in patients treated with a statin or placebo, muscle symptoms and CK elevations >10 times the upper limit of normal occurred only in 5 patients per 100,000 person-years and 1.6 patients per 100,000 person-years. The exact mechanism for muscle injury is not known but believed to be related to the statin concentration in the blood, which is influenced by pharmacokinetics, dose, and patient risk factors for myopathy. The task force felt that it was not necessary to routinely monitor CK levels in patients receiving statin therapy.
Although the task force statement is very thorough and helpful, much of the data reviewed may reflect statin use before the new targets were established. We are now using statins at higher doses and combination therapy more often and in more patients. It remains to be seen whether the prevalence of side effects, both mild and severe, will increase over the next decade.
New Goals, More Drugs
Statins remain the mainstay of therapy for most lipid disorders, as they lower LDL-C and triglycerides and raise HDL-C. They also have other benefits, including plaque stabilization, and antiinflammatory and antithrombogenic characteristics. Fibric acids have been shown to specifically lower triglycerides and increase HDL-C. Bile acid sequestrants lower LDL-C and raise HDL-C. Nicotinic acids lower LDL-C and triglycerides and raise HDL-C.
Several new products have been developed, which are generally used in conjunction with existing classes.
Intestinal Absorption Inhibitors:
Ezetimibe (Zetia) selectively inhibits cholesterol absorption and works in the brush border membrane of intestinal epithelial cells. It has minimal systemic exposure, no clinically significant pharmacokinetic drug interactions, and does not require safety monitoring when used alone. Therapy with ezetimibe produces a modest lowering of LDL-C and triglycerides, as well as a raising of HDL-C levels. Because of its modest effect, it is marketed at 10 mg as an add-on to statin therapy in patients who are not at goal. A combination formulation?ezetimibe/simvastatin (Vytorin)?is available.
Omega-3 Fatty Acids:
Omega-3 polyunsaturated fatty acids (mainly eicosapentaenoic and docosahexaenoic acids) are essential human nutrients found in fatty fish, such as salmon. They have been shown to lower plasma triglycerides and may have other benefits in persons with known CHD. They are generally well tolerated and have no major side effects. Prescription preparations are available in 1-g capsules, and the daily dosage is 1 to 4 g. Omega-3 fatty acids may be used alone or in conjunction with other agents.
Extended-Release Nicotinic Acid
: Niacin is a B vitamin. Its exact lipid-lowering mechanism is not completely understood, but it reduces hepatic synthesis of very low LDL (substrate for LDL) and triglycerides. Niacin also blocks hepatic uptake of apolipoprotein A-I, a major component of HDL, thereby increasing HDL-C levels. A major drawback has been flushing, which is reduced with the extended-release (ER) preparations.
An investigational drug (MK-0524; Merck) is in phase 3 testing that combines ER niacin with a DP-1 receptor antagonist and significantly reduces flushing. ER niacin is now also available in a combination pill with lovastatin (Advicor).
Cholesterol Ester Transfer Protein Inhibition: Torcetrapib, the first in what appeared to be a promising new drug class, was abruptly withdrawn by Pfizer during the phase 3 clinical trials. The drug targeted the cholesterol ester transfer protein, which is secreted by the liver, and its inhibition elevates HDL-C. Initial studies showed blood pressure elevations in some patients taking the drug, but interim results from a large trial showed increased deaths and heart problems in patients randomized to torcetrapib.
We truly are in a new era in the management of dyslipidemia. New goals have meant more pills, new pills, and new combinations. We are also diagnosing people at a younger age, thus patients will be treated for many years. No study has looked at what 40 or 50 years of lipid-lowering therapy will do?and how safe it ultimately will be.
1. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). . 1994; 344:1383-1389.
N Engl J Med
2. Shepherd J, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. . 1995; 333:1301-1307.
3. McKenney J, et al. Report of the Nation-al Lipid Association's Statin Safety Task Force. Am J Cardiol. 2006; 97(suppl 1):1C-97C.