Emerging clinical trial data have led to a number of changes in the field of lipids and atherosclerosis over recent years. With the publication of the Adult Treatment Panel III (ATP III) guidelines, the category of high-risk patients, whose low-density lipoprotein cholesterol (LDL-C) target is less than 100 mg/dL, was expanded to include patients with coronary heart disease equivalents, and a recent update to the guidelines recommends the consideration of an optional LDL-C target of less than 70 mg/dL in very-high-risk patients. Clinical trials published since the ATP III guidelines provided enough data to warrant considering a more aggressive approach for some higher-risk patients, and 2 major trials are looking at the potential benefits and risks of higher-dose versus lower-dose statin therapy: one, the Treating to New Targets (TNT) study, will be presented at this American College of Cardiology (March 2005) meeting; the other, the Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) study, will probably be presented in the fall at the AHA meeting.
The Evidence Supporting Lower LDL
The first major piece of recent evidence leading to the lower LDL-C goals was from the Heart Protection Study, in which even those people who started off with a baseline LDL-C of less than 100 mg/dL, the level recommended by the ATP III guidelines, had a significant reduction in LDL-C (by 30%–40%) with simvastatin 40 mg and a significant reduction in adverse events.
The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI-22) subsequently compared pravastatin 40 mg—standard doses of a proven medication—to more intensive therapy with atorvastatin 80 mg, which, at the time, was about as aggressive as one could get with medication. This high dose of atorvastatin proved very effective in lowering LDL-C, to the lowest values achieved in any major trial (62 mg/dL). This reduction in LDL-C was associated with significant clinical benefit.
The smaller Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that a more intensive strategy with high-dose atorvastatin (80 mg) was also more effective than standard-dose pravastatin (40 mg) in slowing the progression of disease. If the LDL-C that has been achieved in all the angiographic trials with statins is plotted against disease progression, one would estimate that LDL-C would need to be reduced to around 70 mg/dL for zero disease progression. We still do not have a large trial with adequate statistical power that has shown actual regression of atherosclerosis with lipid-modifying therapy in human beings.
Different Targets: New Markers, New Levels, New Combinations
An issue frequently raised in Canada and Europe (less often in the United States) is that of whether we should use an apo B target of less than 90 mg/dL. Some studies have suggested that apo B can still be high in patients who have otherwise “optimal” LDL-C values, which raises the question of whether we may need to rethink the whole concept of the concentration of lipids versus the number of atherogenic particles. People with high triglycerides have small, dense LDL particles, increased intermediate-density lipoprotein (IDL) particles, and increased remnants of very-low-density lipoprotein (VLDL). Therefore, the apo B (1 molecule per particle) concentration would be fairly high in these individuals, and independent of the measured absolute level of LDL-C.
In 1988, we were delighted to get a 25% reduction in LDL-C with lovastatin. In the mid-1990s, we had atorvastatin and simvastatin and could achieve 35% to 40% reductions in LDL-C. Now, in 2005, our goal is more on the order of a 50% LDL-C reduction. Options for achieving this goal include high-dose atorvastatin (80 mg), a combination of ezetimibe and simvastatin in a single pill, or rosuvastatin, one of the newer, so-called “super statins.” In addition, to enhance the degree of LDL-C–lowering beyond that attained with statin monotherapy, one can consider adding bile-acid–binding resins, ezetimibe, niacin, or some combination of these. This strategy can also help reduce the likelihood of problems associated with higher-dose statins.
Achieving LDL-C levels of less than 70 mg/dL in clinical practice is not easy, especially in patients with higher baseline levels. With this in mind, we also have to ask ourselves if LDL-C lowering is our only goal, or whether we should look at lowering LDL-C and raising HDL-C.
How can we raise HDL-C? The best way we currently can do this with conventional therapy is with niacin. Niacin was beneficial in the Coronary Drug Project, but came with the down-side of raising glucose. In the Coronary Drug Project, even people with high baseline fasting plasma glucose benefited from therapy. Unfortunately, the Coronary Drug Project investigators could not assess the independent effects of raising HDL-C, because in the 1970s, when the study was done, they didn't measure HDL-C. What about statins used in combination with fibrates? The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study is still in progress, and we await those data.
Cholesteryl ester transfer protein (CETP) is a lipid transfer protein that is secreted by the liver and binds primarily to HDL, greatly facilitating the transfer of cholesteryl esters from HDL to apo-B–containing particles such as VLDL, LDL, and chylomicrons, in exchange for triglyceride. When CETP is inhibited, HDL-C levels rise markedly, by as much as 200%. Results of the Phase II studies of the CETP inhibitor torcetrapib, the one farthest along in clinical development, are to be presented at this ACC meeting. A 60-mg dose of torcetrapib is being used in the current clinical trials, which look at both surrogate endpoints (intima–media thickness [IMT] and intravascular ultrasound [IVUS] results) and clinical events. We should have an answer in the next few years to the question of whether HDL-targeted therapy provides comparable or additive benefit to LDL-lowering with statins.