Author + information
- Richard V. Milani, MD, FACC⁎ ( and )
- Carl J. Lavie, MD, FACC
- ↵⁎Reprint requests and correspondence:
Dr. Richard V. Milani, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans, Louisiana 70121.
For over 2 decades, the primary focus of lipid intervention has been the reduction of low-density lipoprotein cholesterol (LDL-C). Although initial therapies using bile acid sequestrants and/or fibrates yielded relatively small reductions in LDL-C, and were often associated with unpleasant side effects, early studies suggested the potential for more impressive clinical event reduction should more potent therapies become available (1). That potential was realized with introduction of the statin class of drugs, whereby large reductions in LDL-C were possible without major side effects. Multiple trials have now established the durability of these agents in reducing cardiovascular events in a broad array of populations and age groups, from high-risk secondary prevention patients to moderate-risk primary prevention populations (2). The last major clinical question regarding LDL-C reduction has been recently addressed with the completion of 4 major “intensity” trials, revealing the optimal target for LDL-C reduction (3–6). Today, statins are the largest therapeutic class of drugs sold in the U.S. (7).
The next frontier of lipid intervention will clearly focus on non-LDL particles, and the greatest potential exists with raising levels of high-density lipoprotein cholesterol (HDL-C). In epidemiologic, lipid intervention, and serial angiographic trials, levels of HDL-C actually correlate more strongly with atherosclerosis and overall coronary heart disease (CHD) risk than does LDL-C. In the Framingham Heart Study, although risk is highest in patients presenting with the combination of high LDL-C and low HDL-C, risk remains substantial even in patients with relatively low LDL-C who also have low HDL-C (8). In a meta-analysis of 4 large American studies, for every 1 mg/dl change in HDL-C, CHD was affected by nearly 3% in men and 4% in women and overall cardiovascular disease (CVD) mortality by 4% in men and 5% in women (9).
Early intervention trials targeting HDL-C parallel the seminal studies of LDL-C reduction, where drug-induced changes in the targeted lipid particle were modest and often accompanied by troublesome drug-related side effects. Nicotinic acid or niacin has by far the best effect on raising levels of HDL-C and has had 2 trials demonstrating mortality reduction (10). Niacin typically increases levels of HDL-C by 25%, but increases of >35% can be observed in patients with low levels of HDL-C combined with hypertriglyceridemia (11). The most troublesome side effect of niacin, however, is cutaneous flushing which has markedly limited its widespread use. Fibrates (gemfibrozil and fenofibrate) effectively increase HDL by 15% to 25% in patients with hypertriglyceridemia, but typically have <10% effect in patients with lower levels of triglycerides (12). Statins can produce modest increases in HDL-C, typically raising levels by approximately 5% (10% to 15% with rosuvastatin) (13,14). It is noteworthy that these HDL-C effects, unlike with fibrates, are generally independent of the triglyceride concentration (12).
Cholesteryl ester transfer protein inhibition
A new class of therapeutic agents targeting cholesteryl ester transfer protein (CETP) has now emerged that can markedly increase levels of HDL-C and offers the potential to reduce atherosclerosis and CHD events (15–17). Cholesteryl ester transfer protein is secreted by the liver and is a major mediator in the metabolic interaction between HDL and apolipoprotein (apo)B-containing lipoproteins, including very-low-density lipoprotein (VLDL) and LDL. The primary function of CETP is to redistribute cholesteryl esters (CEs) and triglycerides between lipoproteins. Whether CETP activity is fundamentally atherogenic, however, is a matter of considerable debate. It has been suggested that elevated levels of CETP are the result of dyslipidemia rather than its cause (15,18). By promoting the transfer of CEs to VLDL and LDL, CETP may account for a considerable portion of cholesterol returned to the liver in humans, thus having antiatherogenic activity. However, in moving CEs from HDL to VLDL and LDL, CETP decreases levels of HDL, thus resulting in a reduction in reverse cholesterol transport (RCT) via the HDL fraction and potentially diminishing other antiatherogenic effects associated with HDL particles. In addition, the increased levels of VLDL and LDL can promote atherosclerosis by facilitating the return of cholesterol to macrophages in the vessel wall and thus lead to increased foam cell formation.
Therefore, CETP plays an important role in several key pathways of lipid metabolism and theoretically may be associated with both proatherogenic and antiatherogenic activities. The results of various animal and human studies involving CETP deficiencies, biologic models to suppress CETP activity, and pharmacologic CETP inhibitors have been reviewed in detail elsewhere (15,16). On balance, however, the currently available data from both animal and human studies suggest that elevated CETP levels are associated with increased risk of atherosclerosis by decreasing HDL-C, increasing levels of LDL-C, and reducing both HDL and LDL particle size. On the other hand, decreased CETP activity appears to be antiatherogenic, particularly if associated with a significant increase in HDL-C levels. Moreover, the recent finding that HDL with apoE from CETP-deficient humans can effectively accept unesterified cholesterol from macrophages suggests that CETP inhibitors are likely to be effective in generating an antiatherogenic HDL profile in humans (19).
At the present time, a vaccine (CETi-1) to induce autoantibodies that bind and inhibit endogenous CETP and 2 CETP inhibitors (JTT-705 and torcetrapib) have been evaluated in clinical trials (15–17). In this issue of the Journal, two studies are reported that assess the efficacy and safety of one of these compounds, torcetrapib, either alone or in combination with the potent statin atorvastatin in patients with at least borderline-low levels of HDL-C (20,21). These studies demonstrate the marked efficacy of raising levels of HDL-C with torcetrapib (ranging from 9% to 55%), more so than noted with the other CETP inhibitor (JTT-705). In addition, this therapy has modest additional effects to lower levels of LDL-C, alone or in combination with statin therapy, as well as to produce beneficial changes on LDL and HDL particle size and levels of non–HDL-C and apolipoproteins. Moreover, whereas LDL-C does not significantly fall with torcetrapib monotherapy in patients with borderline-mild elevations in triglycerides, this triglyceride/LDL interaction is prevented by coadministration of torcetrapib with atorvastatin, a combination that is well tolerated. In general, the adverse effect profile of this therapy appears to be quite minimal, although 6 of 277 patients (2%) had significant increases in blood pressure. However, causality remains questionable, because there were no significant changes in arterial pressure in the entire group of patients receiving torcetrapib compared with those receiving placebo.
Although these marked lipid changes with CETP inhibition, in particular, torcetrapib, appear to be extremely promising, caution is needed until completion of ongoing clinical event trials. Considering the concerns regarding some potential proatherogenic mechanisms as well as potentially increasing levels of blood pressure in some patients, torcetrapib must be proven to have safety in medium-term and long-term trials, as well as to produce reductions in atherosclerosis and clinical events.
Despite these concerns, the future of HDL therapy appears very promising. During the last 20 years in preventive cardiology, the emphasis has been on statin therapy and reducing levels of LDL-C. If torcetrapib fulfills its anticipated promise, the next era will be one of CETP inhibition and increasing levels of HDL-C and will usher in a new multidimensional approach to the primary and secondary prevention of atherosclerosis and major CVD events.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- ↵Leading 20 Therapeutic Classes by U.S. Sales, 2005. Press Room, IMS Health Incorporated. Available at: http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_73915261_77140565,00.html. Accessed June, 2006.
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