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Tex Heart Inst J. 2006; 33(2): 180–183.
PMCID: PMC1524680

Lipids

New Guidelines, Intensive Treatment, and Future Directions
Peter H. Jones, MD, FACP

For a long time, our lipid guidelines have focused on low-density lipoprotein (LDL) cholesterol as the primary treatment target. There is a good reason for this: the clinical data continue to show that lowering LDL improves clinical outcomes. Although LDL is almost always the initial target of therapy, it's not the only target. Secondary targets, notably triglycerides and high-density lipoproteins (HDL), need to be considered in higher risk patients. Furthermore, many advocate adequate LDL cholesterol reductions, rather than a specific LDL target.

The National Cholesterol Education Program set forth the Adult Treatment Panel (ATP) III guidelines in 2001 (Table I). Over the subsequent 3 years, there were 5 additional trials, totaling 51,000 patients. While most of the earlier trials were secondary prevention studies, most of these newer trials looked at primary prevention (Fig. 1).

figure 15FF1
Fig. 1 Primary and secondary CHD prevention trials with statins
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TABLE I. National Cholesterol Education Program ATP III Guidelines Update

A very exciting recent analysis from the Cholesterol Treatment Trialist Collaborators involved over 90,000 participants in 14 statin trials (Table II). The analysis showed that lowering LDL 1 mmol/L (or 39 mg/dL) is associated with a 12% reduction in all-cause mortality and an approximately 20% reduction in total cardiovascular risk. There was no difference in the incidence of cancer or non-cardiovascular disease mortality, and the benefit of statins was linearly related to the absolute reductions in LDL, regardless of baseline lipids, risk, age, and gender. For a 1.5-mmol/L reduction (60 mg/dL), there was a 33% reduction in cardiovascular events. For a 2-mmol/L reduction (80 mg/dL), there was a 40% reduction in composite cardiovascular events.

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TABLE II. Efficacy and Safety of Statins: Prospective Meta-Analysis of 90,056 Participants (Cholesterol Treatment Trialist Collaborators)

What is new since the 2004 ATP update? Well, for starters, another 20,000 patients have been evaluated in clinical trials such as CARDS, A to Z, and TNT.

The Collaborative Atorvastatin Diabetes Study (CARDS) was the 1st primary prevention study that compared a statin to placebo in diabetic patients who had no known cardiovascular disease. Over a 4½-year period, there was a 37% reduction in the primary endpoint (a combination of fatal and nonfatal coronary heart disease events), as well as in stroke. This reduction in events began very early, within the 1st couple of years.

The Z phase of the A to Z (Aggrastat to Zocor) trial involved about 4,500 ACS (acute coronary syndrome) patients in whom early intensive statin therapy was compared with delayed statin therapy. Specifically, 1 group received placebo for 4 months and then a lower intensity (20-mg) simvastatin; and the other group received 40-mg Zocor (simvastatin) for 1 month, followed by high-dose (80-mg) simvastatin for 24 months. In the Zocor group, there was a 2.3% absolute reduction in the composite endpoint (major cardiovascular events) at 24 months from 16.7% to 14.4%, but this represented only a nonsignificant 11% reduction. This is in comparison to PROVE-IT (a trial of high-dose atorvastatin versus pravastatin in an ACS population), in which there was a significant 16% reduction in the same composite at the end of 24 months. Cross-trial comparison between these very complex trials is fraught with hazard. For example, the primary event rate in the pravastatin group was 26% in PROVE-IT, and there was an absolute risk reduction of about 3.8% to 22% in the high-dose atorvastatin group. If you ignore the first 4 months of placebo treatment and focus on events after 4 months in A to Z, during active treatment, it appears that more intense therapy is beneficial, with a 22% to 25% reduction in cardiovascular events.

The Treating to New Targets (TNT) trial compared intensive and less intensive LDL lowering with 80 mg and 10 mg of atorvastatin in a stable coronary heart disease population. The 10-mg dosage of atorvastatin lowered LDL by about 35 mg/dL; 80 mg lowered it by about 55 mg/dL. With the higher-dose atorvastatin over 5 years, there was a significant 22% reduction (2.2% absolute) in major cardiovascular events. Remember, this is not a placebo-controlled trial; this is an active control of lower-dose atorvastatin. In TNT, the lower-dose group wound up with LDLs of about 100 mg/dL; the more intensively treated group wound up with LDLs in the 75- to 77-mg/dL range—the lower end of the “lower is better” scale.

The Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) trial will be presented later at these meetings, and includes 8,888 stable coronary artery disease patients randomized either to 80-mg atorvastatin or to 20-mg simvastatin. IDEAL also will test the “lower is better” approach to LDL for both long-term safety and efficacy, since it is a long-term study.

I am frequently asked how aggressive to be in patients whose LDLs are fairly low to begin with: Is statin therapy safe, and what are the outcomes?

Patients with very low LDLs were examined in the PROVE-IT trial (about 45% of the patient population had LDLs <60 mg/dL on treatment). The lower the achieved LDL with over 2 years of treatment, the better the outcomes. The safety of treatment was similar and maybe even slightly better in the low LDL patients. Later this week, the TNT investigators will present a sub-analysis of the very low LDL cholesterol group with 5 years of treatment (extending the 2 years of treatment studied in PROVE-IT).

While so much of our attention has focused on LDL and statins, I believe that focusing on other dyslipidemias common to metabolic syndrome and to patients with diabetes can also be very important for risk reduction. The soon-to-be-presented Fenofibrate Intervention and Events Lowering in Diabetes (FIELD) trial includes nearly 9,800 diabetic patients randomized to placebo or fenofibrate for 5 years. We hope to see benefit from drugs that focus on the HDL–triglyceride axis as a target for treatment.

As we re-examine the guidelines, a couple of key points emerge. There is no question that the intensity of our lipid treatment should depend on risk. The current guidelines suggest that in highest-risk patients for whom the LDL cholesterol goal is less than 100 mg/dL, you may consider an optional goal of less than 70 mg/dL. There are data to suggest that if the baseline LDL is less than 100 in a high-risk patient, additional treatment may be necessary to lower LDL below 70. Even if LDL cholesterol is optimal, additive treatment with niacin and fibrates should be considered for patients with diabetes or metabolic syndrome, if triglycerides are high, HDL is low, or both.

Who exactly are the patients who merit an LDL treatment goal of less than 70 mg/dL? I call this the “CHD plus” group: coronary heart disease plus diabetes; CHD plus multiple risk factors, including continued heavy smoking; and CHD plus metabolic syndrome. In fact, anybody who presents at the hospital with an acute coronary event should leave the hospital as a high-risk patient. In all of these, I advocate a goal of less than 70. As a side-bar issue, ACS patients should not have their statins discontinued on admission. If patients are not on a statin at the time of admission, start one as soon as feasible and discharge the patient with a statin.

What about primary prevention in high-risk patients? Again, you should carefully consider more intensive LDL lowering (goal of 70 mg/dL) in such highrisk individuals.

Absolute LDL lowering is also important; you should aim for at least a one-third reduction from the baseline LDL, corresponding to at least a 1-mmol/L reduction for most patients. This 1-mmol/L reduction in LDL cholesterol requires that standard doses of statins be prescribed (atorvastatin 10 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20–40 mg, fluvastatin 40–80 mg, and rosuvastatin 5–10 mg). If you're not using these standard doses, you are probably underdosing your patients and will not get a sufficient degree of LDL reduction to provide optimal benefit.

Let me mention a few controversial issues, first among them the so-called pleiotropic effects of statins —the other things they do that might affect cellular function. This action may be due to reduced prenylation of small guanidine triphosphate (GTP) proteins, like RhO, RAS, and RAC. When these proteins are stimulated, they cause cellular activation that affects atherosclerosis in a detrimental way. When you inhibit the farnesylation or geranylation of these proteins, you block their detrimental cellular effects. In vitro, we can demonstrate these pleiotropic effects of statins: nitric oxide synthase is increased, reactive oxygen species are decreased, and metalloproteinases are decreased, along with vascular cell adhesion molecules. There is no clear evidence that any of these potentially favorable effects occurs in vivo, at the plasma levels that statins attain with oral dosing. Among the not-so-desirable pleiotropic effects of statins is their effect on myocytes, which can result in myositis.

What about lipoprotein size? Should we measure it in all our patients and use the results to adjust therapy? Current data strongly support a primary goal of reducing the number of atherogenic particles—LDL, VLDL, and triglyceride-rich lipoproteins—as measured by LDL and non-HDL cholesterol. Improving particle size is a secondary goal. How do we do that? Niacin, fish oils, fibrates, weight reduction, and exercise all provide that additive benefit of increasing LDL particle size, on top of reducing particle number. Specialized testing may help you make some of those decisions. For instance, if you're wondering about combination treatment, you might test for particle size and pattern. If you want to know if high Lp(a) is an issue, you can use special testing; should Lp(a) be elevated, add niacin.

Combination therapy itself can be an issue in specific circumstances. In patients who have genetic problems (very, very high LDLs), combinations of statins, bile acid resins, ezetimibe—or all 3, plus niacin—are options to lower LDL 70% or more. In the setting of very high triglycerides, you can use fibrates and niacin, in combination with omega-3 fatty acids, to reduce the risk of pancreatitis and vascular disease. There are also mixed dyslipidemias, particularly the atherogenic dyslipidemia of insulin resistance and metabolic syndrome. Statins, plus niacin or fibrate, plus or minus omega-3 fatty acid, are all potential combinations worth considering.

A number of future studies will be looking at combination therapy, particularly in patients with diabetes and metabolic syndrome. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial here in the United States has a 2-by-2 factorial design and will randomize 2,900 patients to a statin plus fenofibrate, versus 2,900 patients on a statin alone. They are also going to be randomized to intensive versus standard glycemic control.

The NIH-sponsored AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) study will involve metabolic syndrome patients, rather than overtly diabetic patients, and will compare a statin alone versus a statin plus niacin in 3,300 patients. The goal is to get the LDL less than 80 mg/dL; and, if needed, bile acid resins or ezetimibe can be added.

In the lipid world, HDL represents a whole new frontier, and there are a number of very interesting new drug therapies. There are LXR (liver X receptor) agonists, which stimulate ABC (ATP-binding cassette transporter) A-1—which may increase reverse-cholesterol transport, but also increases triglyceride synthesis and tends to cause hepatic steatosis to an unacceptable degree. You probably won't see LXR agonists any time soon. There are the CETP (cholesteryl ester transfer protein) inhibitors (such as torcetrapib, which is probably not going to be marketed alone, but in combination with a statin). There is recombinant Apo A-I Milano, which involves acute intravenous treatment, perhaps post-ACS (as an induction), to be followed by long-term lipid treatment. There are also much less complex and less expensive Apo A-I mimetics, which are also injectable. Also on the horizon are D-amino acids, which are orally stable, and which act like A-I mimetics.

In conclusion, LDL cholesterol is still the primary target of treatment, with the intensity of treatment stratified on the basis of global risk. In high-risk patients (the “CHD-plus” patients), the treatment goal should probably be to achieve an LDL of less than 70 mg/dL, rather than less than 100. You should consider that metabolic syndrome patients with risk factors plus a high C-reactive protein constitute a group meriting special attention. They should be treated as intensely as somebody with known coronary disease. Lipid-lowering statins are the cornerstone of therapy and should be dosed to lower LDL by at least 35%. Combination drug treatment is the wave of the future for very complex and high-risk patients.

Footnotes

Address for reprints: Peter H. Jones, MD, Associate Professor of Medicine, 6565 Fannin Street, MSA 1601; Suite A657, Houston, TX 77030. E-mail: ude.cmt.mcb@senoj

Presented at the Texas Heart Institute's symposium “Evolving Standards in Cardiovascular Care: What Have We Learned? Where Are We Going?” held at the Adam's Mark Hotel; 12 November 2005; Dallas


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