An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels

CETP is the target of CETP inhibitors such as anacetrapib and the modulator dalcetrapib. Both molecules have entered Phase III clinical trials, with the ultimate goal of reducing cardiovascular events by raising HDL cholesterol. At the 600-mg dose selected for the dal-OUTCOMES study, dalcetrapib is expected to inhibit CETP activity by approximately 30% and raise HDL-C by approximately 30% with limited effects on LDL cholesterol. Importantly, dalcetrapib does not raise blood pressure or aldosterone levels, two effects previously associated with the CETP inhibitor torcetrapib. Dalcetrapib has been well tolerated at the 600-mg dose. In the dal-PLAQUE atherosclerosis imaging study, dalcetrapib reduced the enlargement of total vessel area over time. In May 2012, following the results of the second interim analysis of dal-OUTCOMES, the Data and Safety Monitoring Board recommended stopping the study owing to a lack of clinically significant benefit, which was followed by Roche's (Basel, Switzerland) decision to terminate the study and the dalcetrapib program (dal-HEART). Contrary to anacetrapib, a potent CETP inhibitor that markedly increases HDL cholesterol and significantly reduces LDL cholesterol, dalcetrapib has allowed us to test the hypothesis that an isolated, moderate elevation in HDL cholesterol prevents cardiovascular events.     

Cholesteryl Ester Transfer Protein Inhibition in Cardiovascular Risk Management: Ongoing Trials will End the Confusion

As delineated in this review, cholesteryl ester transfer protein (CETP) contributes to an atherogenic lipoprotein profile by redistributing cholesteryl esters from high density lipoprotein (HDL) toward apolipoprotein B‐containing lipoproteins, especially when the concentration of acceptor triglyceride‐rich lipoproteins is elevated. However, this lipid transfer protein may have antiatherogenic proprerties as well. Experimental evidence is accumulating which suggests that the atheroprotective reverse cholesterol transport pathway, whereby cholesterol is removed from peripheral macrophages to the liver for metabolism and biliary excretion, is stimulated by CETP in vivo. CETP could also play a role in host defense against infection and inflammatory processes. Moreover, recently published observational studies show that higher CETP levels may confer cardiovascular protection, whereas reported associations of cardiovascular disease (CVD) with CETP gene variations are equivocal. The concept that HDL cholesterol raising through inhibition of CETP may ameliorate CVD risk has been challenged by the failure of the CETP inhibitor, torcetrapib. Adverse clinical outcome associated with the use of this CETP inhibitor has been attributed to off‐target effects, which relate to stimulation of aldosterone. Other CETP inhibitors, such as dalcetrapib and anacetrapib, are unlikely to increase blood pressure. Dalcetrapib is less potent than anacetrapib, which doubles HDL cholesterol. Both inhibitors considerably lower LDL cholesterol.Serious concerns remain about the validity of the concept that HDL cholesterol raising by means of CETP inhibition is a viable strategy. Results of ongoing clinical trials with these drugs will have to be awaited before making up the balance between possible benefits and harms related to pharmacological CETP inhibition.     

New Horizons for Cholesterol Ester Transfer Protein Inhibitors

High-density lipoprotein (HDL) cholesterol levels bear an inverse relationship to cardiovascular risk. To date, however, no intervention specifically targeting HDL has been demonstrated to reduce cardiovascular risk. Cholesterol ester transfer protein (CETP) mediates transfer of cholesterol ester from HDL to apolipoprotein B–containing particles. Most, but not all observational cohort studies indicate that genetic polymorphisms of CETP associated with reduced activity and higher HDL cholesterol levels are also associated with reduced cardiovascular risk. Some, but not all studies indicate that CETP inhibition in rabbits retards atherosclerosis, whereas transgenic CETP expression in mice promotes atherosclerosis. Torcetrapib, the first CETP inhibitor to reach phase III clinical development, was abandoned due to excess mortality associated with increases in aldosterone and blood pressure. Two other CETP inhibitors have entered phase III clinical development. Anacetrapib is a potent inhibitor of CETP that produces very large increases in HDL cholesterol and large reductions in low-density lipoprotein (LDL) cholesterol, beyond those achieved with statins. Dalcetrapib is a less potent CETP inhibitor that produces smaller increases in HDL cholesterol with minimal effect on LDL cholesterol. Both agents appear to allow efflux of cholesterol from macrophages to HDL in vitro, and neither agent affects blood pressure or aldosterone in vivo. Two large cardiovascular outcomes trials, one with anacetrapib and one with dalcetrapib, should provide a conclusive test of the hypothesis that inhibition of CETP decreases cardiovascular risk.     

Evacetrapib

Considerable attention focuses on the ability to develop therapeutic agents that elevate levels of high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) inhibitors have been developed on the basis of their ability to raise HDL-C to a greater extent than lipid-modifying therapies currently used in clinical practice. Initial enthusiasm for CETP inhibition decreased as a result of adverse clinical outcomes observed with the agent torcetrapib. Elucidating off-target toxicities of torcetrapib has provided hope that other CETP inhibitors may still be of potential benefit. Evacetrapib is a novel CETP inhibitor, with favorable effects on plasma lipids and no adverse effects on blood pressure or mineralocorticoid activity in early clinical evaluation. The potential effects on cardiovascular outcomes remain to be determined.     

Anacetrapib: Hope for CETP Inhibitors?

Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high‐density lipoprotein cholesterol (HDL‐C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL‐C raising and low‐density lipoprotein cholesterol (LDL‐C) lowering potential. Phase I and phase II trials with anacetrapib have revealed that anacetrapib is well‐tolerated and does not seem to possess the pressor effects associated with torcetrapib. This article will briefly review the HDL‐C raising through CETP inhibition as an antiatherogenic strategy with a specific focus on anacetrapib.     

High-density Lipoprotein

Epidemiological data clearly show an inverse relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular risk. The HDL-mediated reverse cholesterol transport protects against atherosclerosis and raises the question whether therapeutic strategies to increase HDL levels can cause additional protection from coronary heart disease (CHD). The HDLs are a heterogeneous class of lipoproteins, the metabolism is complex and in certain aspects not well understood. This makes it impossible to predict whether a specific HDL intervention does actually protect against CHD. The currently used medications for raising HDL are fibrates and nicotinic acid; however, these drugs have additional effects on other lipoprotein classes and the benefits have not been finally proven in outcome studies. A promising possibility to raise HDL levels was thought to be the inhibition of cholesterol ester transfer protein (CETP); however, the first two substances tested, torcetrapib and dalcetrapib, failed to show a clinical benefit, and data for anacetrapib are not yet available. It is concluded that there is no proof of concept that therapeutic HDL elevation has a protective effect on cardiovascular events.     

HDL metabolism and CETP inhibition

High density lipoprotein-cholesterol (HDL-C) concentration in the blood is independently and inversely associated with an increased risk of coronary heart disease. Some of the cholesterol-lowering drugs (niacin, fibrates, and statins) incidentally raise HDL-C. These drugs are not effective in causing major changes in HDL-C. Since the discovery of human genetic cholesteryl ester transfer protein (CETP) deficiency in a Japanese population with high levels of HDL-C and apolipoprotein A-I, CETP inhibition has become a novel strategy for raising HDL-C in humans. Mice, a species naturally lacking CETP, were transduced with the human CETP gene, which resulted in dose-related reductions in HDL-C. Rabbits, a species with naturally high levels of CETP, were fed a synthetic CETP inhibitor, JTT-705, leading to both a 90% increase in HDL-C and a 70% reduction in aortic atherosclerotic lesion area. Human intervention trials with a new potent and selective CETP inhibitor, torcetrapib, have taken place. In a phase I multidose trial, HDL-C increased by 91% with torcetrapib 120 mg twice daily. A phase II trial conducted with multiple combinations of torcetrapib and atorvastatin showed that the combination was well tolerated and doses 30 mg and higher of torcetrapib caused 8.3-40.2% changes from baseline HDL-C across the dose range of atorvastatin at 12 weeks. Recently the phase III clinical trial ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) was prematurely terminated because of an increase in mortality in the torcetrapib/atorvastatin treatment arm compared with atorvastatin used alone. In companion studies no improvement in carotid or coronary atherosclerosis could be detected in patients treated with the torcetrapib/atorvastatin combination despite favorable changes in both low density lipoprotein (LDL)- and HDL-cholesterol levels. The future for CETP inhibition with drug therapy is now unclear, and must include a closer look at CETP inhibitor's effects on blood pressure and HDL itself. Accordingly, it was recently shown in 2 double-blind, placebo-controlled, randomized, phase I studies with the CETP inhibitor anacetrapib in healthy individuals and in patients with dyslipidemias that the drug increased HDL and reduced LDL, while having no effect on blood pressure.     

The hypertension peril: Lessons from CETP inhibitors

Pharmacologic inhibitors of the cholesteryl ester transfer protein (CETP) are capable of increasing HDL cholesterol by 50% to 100% in humans. Despite intriguing antiatherogenic effects of CETP inhibition in animal models of atherosclerosis, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial investigators observed an excess of cardiovascular and noncardiovascular morbidity and mortality associated with the use of the CETP inhibitor torcetrapib. This review summarizes available clinical and experimental data about potential underlying mechanisms.     

HDL – „Game over“?

The failure of recent clinical trials to improve cardiovascular outcome via pharmacological high density lipoprotein (HDL) cholesterol manipulation and findings that genetically increased concentrations of HDL cholesterol in plasma do not lower the risk of myocardial infarction may question the usefulness of HDL cholesterol as a measure in clinical practice. Cholesteryl ester transfer protein (CETP) inhibition was shown to raise HDL cholesterol levels but the CETP inhibitors torcetrapib and dalcetrapib have shown no clinical benefit. The broad spectrum of lipid-modifying activity of niacin, including HDL cholesterol (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein (a) did not translate into improved clinical outcome in the AIM-HIGH trial and the HPS2-THRIVE trial. New pharmacological data contribute to explanations why evaluating the effects of the combination of extended release (EC) niacin with the prostaglandin D(2) receptor antagonist laropiprant in the HPS2-THRIVE trial showed no improvement in cardiovascular outcome. That HDL cholesterol is a poor metric for targeted intervention and methodological issues of the trials are parts of the current controversy. It has been established that HDL is heterogeneous and contains particles with different lipid compositions and separate anti-atherosclerotic functions. Low HDL due to genetic mutations in apoA-I, the structural protein of HDL, can be causative in syndromes with premature atherosclerosis. It is known that HDL cholesterol has a role as a marker of a high risk for dyslipoproteinemia; however, HDL function may be a preferable measure in the future. Data from ongoing outcome studies with the newer CETP inhibitors anacetrapib and evacetrapib will be crucial for the future of HDL as an important approach to decreasing cardiovascular morbidity and mortality.     

CETP Inhibitors: Will They Live up to Their Promise?

Cholesterol ester transfer protein (CETP) exchanges lipids between circulating plasma lipoproteins and has been considered as an excellent drug target for raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, HDL displays considerably more complexity than low-density lipoprotein (LDL) in terms of structure, proteomics, and several physiologic functions. After the discouraging results from clinical trials of torcetrapib (an early inhibitor of CETP that dramatically raised HDL cholesterol levels), there is renewed hope that dalcetrapib and anacetrapib are sufficiently different structurally and functionally to justify large-scale clinical end point studies. In fact, such trials are already underway in the case of dalcetrapib and are imminent in the case of anacetrapib. These end point trials will show whether CETP inhibition will live up to its promise for atheroprotection.     

CETP Inhibition in CVD Prevention: an Actual Appraisal

By virtue of their effects on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cellular cholesterol efflux, there is considerable interest in the potential use of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) as a novel approach for cardiovascular disease prevention. This is supported by observations from genetic and animal studies suggesting that less CETP activity has favorable cardiovascular effects. Despite the adverse effects of the first CETP inhibitor to move forward in clinical development, torcetrapib, there remains considerable interest in developing alternative CETP inhibitors without the off-target effects of torcetrapib. The clinical development programs leading to a number of promising CETP inhibitors will be reviewed.     

Inhibition of cholesteryl ester transfer protein activity: A new therapeutic approach to raising high-density lipoprotein

High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD), leading to the concept that pharmacologic therapy to raise HDL cholesterol levels may reduce ASCVD risk. There is substantial interest in the concept of inhibition of the cholesteryl ester transfer protein (CETP) as a novel strategy for raising HDL cholesterol levels, as well as reducing levels of atherogenic lipoproteins. This article reviews the physiology of CETP in lipoprotein metabolism and the data in animals and humans that are relevant to the question of whether CETP inhibition may some day be part of the clinical armamentarium for treating dyslipidemia and atherosclerotic vascular disease.     

HDL and CETP Inhibition: Will This DEFINE the Future?

OPINION STATEMENT: The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit.     

Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels.

OBJECTIVES: This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels. BACKGROUND: Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP. METHODS: A total of 162 subjects with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo ( approximately 30 subjects per group). RESULTS: The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p < or = 0.0001 for 30 mg and higher doses) and from 3.0% to -16.5% for low-density lipoprotein cholesterol (LDL-C) (p < 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus -22.2% (p < 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects. CONCLUSIONS: Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated.     

Cholesteryl Ester Transfer Protein (CETP) Inhibitors: Is There Life After Torcetrapib?

Despite tremendous progress made in the management of CHD, a significant number of fatal and nonfatal CHD events still occur, which leads researchers to target other modifiable risk factors for CHD including low HDL-c (high density lipoprotein cholesterol). Although the torcetrapib experience was a major blow to CETP inhibition and indeed to the entire field of HDL-targeted therapeutics, it was not fatal. The off-target effects of torcetrapib appear to be substantial and may have overridden any potential cardiovascular benefit. Despite continued uncertainty regarding the cardiovascular implications of genetic CETP deficiency and pharmacologic CETP inhibition, there remain reasons to believe in the mechanism and the possibility that clean CETP inhibitors will not only improve plasma lipids but also reduce cardiovascular risk.     

Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease

OBJECTIVES: We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD). BACKGROUND: Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD. METHODS: We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V polymorphisms, CETP activity, and HDL cholesterol were determined. RESULTS: Patients carrying the -629A allele had significantly lower CETP activity and higher HDL cholesterol levels. There was a significant association between this polymorphism and the risk of future cardiovascular death. Mortality decreased from 10.8% in CC homozygotes to 4.6% in CA heterozygotes and 4.0% in AA homozygotes (p < 0.0001). This association was independent of potential confounders, particularly HDL cholesterol and CETP activity levels. The clinical benefit of statin therapy was restricted to CC homozygotes, in whom cardiovascular mortality was divided by half (p = 0.01 for treatment x genotype interaction). Similar trends were observed with the CETP/I405V polymorphism, but these effects seemed to be mainly the consequence of linkage disequilibrium with the CETP/C-629A polymorphism. CONCLUSIONS: In patients with CAD, the CETP/-629A allele had a strong protective effect on future mortality from cardiovascular causes, independent of its role on HDL cholesterol and CETP activity levels. Additionally, this common polymorphism appeared to predict which patients with CAD will experience a survival benefit from statin therapy.     

Where are we with high-density lipoprotein raising and inhibition of cholesteryl ester transfer for heart disease risk reduction?

PURPOSE OF REVIEW: To review recent research in the area of high-density lipoprotein raising and coronary heart disease risk reduction. RECENT FINDINGS: A decreased high-density lipoprotein-cholesterol is an important coronary heart disease risk factor and raising high-density lipoprotein-cholesterol has been associated with coronary heart disease risk reduction. A relative new strategy for raising high-density lipoprotein-cholesterol, i.e. inhibition of cholesteryl ester transfer protein, is markedly effective. Cholesteryl ester transfer protein inhibitors prevent the transfer of cholesteryl ester from high-density lipoprotein to triglyceride-rich lipoproteins in exchange for triglyceride. One inhibitor, torcetrapib, binds to cholesteryl ester transfer protein on high-density lipoprotein, markedly raises high-density lipoprotein-cholesteryl ester and has no effect on fecal cholesterol excretion, but can raise blood pressure. A large clinical trial in coronary heart disease patients on atorvastatin was recently stopped prematurely because of excess mortality in those receiving torcetrapib vs. placebo and two other trials reported no benefit of torcetrapib on coronary atherosclerosis or carotid artery intimal medial thickness as compared with subjects on atorvastatin alone. SUMMARY: The adverse effects of torcetrapib may be compound-specific and, since the crystal structure of cholesteryl ester transfer protein is now known, it should be possible to develop more optimal cholesteryl ester transfer protein inhibitors that do not form a nonproductive complex with cholesteryl ester transfer protein on the high-density lipoprotein particle, as has been reported for torcetrapib. The alternative for high-density lipoprotein raising is to develop more effective and better tolerated niacin preparations.     

Will torcetrapib be the next big thing in coronary heart disease risk reduction?

Scientists are seeking ways to increase high-density lipoprotein (HDL) cholesterol to lower coronary heart disease (CHD). Emerging from this search is torcetrapib, a partial inhibitor of cholesteryl ester transfer protein. Via this mechanism, cholesteryl ester is prevented from being transferred to apolipoprotein B-containing lipoproteins and is retained in HDL particles, where ostensibly it may be delivered directly to the liver for elimination. Proof that this may reduce atherosclerotic vascular disease is provided by population studies of cholesteryl ester transfer protein (CETP) deficiencies and single nucleotide polymorphisms of CETP, and experiments in animal models treated with torcetrapib. Torcetrapib effectively raises HDL cholesterol when used alone and when added to background therapy with atorvastatin. The drug appears to be well tolerated. Large surrogate and survival outcome trials are underway to document its impact on CHD.     

Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease

High-density lipoproteins (HDL) protect against cardiovascular disease. HDL removes and transports excess cholesterol from peripheral cells to the liver for removal from the body. HDL also protects low-density lipoproteins (LDL) from oxidation and inhibits expression of adhesion molecules in endothelial cells, preventing monocyte movement into the vessel wall. The ABCA1 transporter regulates intracellular cholesterol levels in the liver and in peripheral cells by effluxing excess cholesterol to lipid-poor apoA-I to form nascent HDL, which is converted to mature alpha-HDL by esterification of cholesterol to cholesteryl esters (CE) by lecithin cholesterol acyltransferase. The hepatic ABCA1 transporter and apoA-I are major determinants of levels of plasma alpha-HDL cholesterol as well as poorly lipidated apoA-I, which interact with ABCA1 transporters on peripheral cells in the process of reverse cholesterol transport. Cholesterol in HDL is transported directly back to the liver by HDL or after transfer of CE by the cholesteryl ester transfer protein (CETP) by the apoB lipoproteins. Current approaches to increasing HDL to determine the efficacy of HDL in reducing atherosclerosis involve acute HDL therapy with infusions of apoA-I or apoA-I mimetic peptides and chronic long-term therapy with selective agents to increase HDL, including CETP inhibitors.     

Raising HDL cholesterol for cardiovascular disease prevention: Is this still feasible?

Plasma high-density lipoprotein cholesterol (HDLC) has received considerable attention as a potential therapeutic target to further reduce cardiovascular risk in the statin era. However, doubts about the clinical benefit achievable with treatments enhancing plasma HDLC levels have been raised by the premature termination of a large phase 3 trial with torcetrapib—the most potent and furthest developed HDLC-raising compound—resulting from excess mortality in patients receiving the drug. The causes of torcetrapib failure are unknown and may be related to the drug’s mode of action, off-target toxic effects, or a mixture of both. The failure of torcetrapib does not mean that the concept of targeting HDL in cardiovascular prevention is dead. Other HDLC-raising therapies, which act through disparate molecular mechanisms, are in various stages of preclinical and clinical development. The alternative is the direct administration of synthetic HDL, which has proven activity on atherosclerosis regression in coronary patients.