Failure Of Torcetrapib Research Articles

HDL and Cardiovascular Risk

High-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver. Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease. Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction. This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP). Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial

Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. F Hoffmann-La Roche Ltd.

Cardiovascular Disease and Dyslipidemia: Beyond LDL

Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles rather depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to "off-target" effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.

Heart Association Considers Certifying Hospitals Based on Quality and Results

trapib comes following disappointing earlier trials investigating CETP inhibition, notably with torcetrapib; a trial assessing clinical outcomes of torcetrapib therapy was terminated in 2006 after the drug was shown to cause excess deaths and cardiovascular events. The question was whether the torcetrapib’s poor showing was a class effect or isolated to that specific drug. “We did not know after torcetrapib failed whether the entire strategy would actually achieve success,” said Steven E. Nissen, MD, chairman of the Cleveland Clinic Foundation’s Department of Cardiovascular Medicine and an investigator of torcetrapib. “I believe the failure of torcetrapib was due to an off-target toxicity, that it increased aldosterone, and that offered the possibility of another CETP inhibitor to show success without that offtarget effect.” Nissen said anacetrapib looks promising, but even after the news from the AHA, the drug’s benefit remains a promise only. “The effect on lipids is what caught everyone’s attention, but I would caution everyone that lipid changes are a surrogate end point, and we have come to be suspicious of surrogate end points; there is not a guarantee of success.” Harlan M. Krumholz, MD, professor of medicine at Yale University School of Medicine in New Haven, Conn, and a skeptic of surrogate end points as providing meaningful results that translate to improved hard outcomes, said Merck is doing the DEFINE trial the right way. “DEFINE is a great prelude to a definitive trial to determine the effect on outcomes, but it is not more than that, so it leaves us ready for the next piece of information,” Krumholz said. “I applaud Merck for proceeding to an outcomes trial.”

HDL: o yin-yang da doença cardiovascular

Epidemiological studies demonstrate an inverse correlation between plasma HDL-cholesterol (HDL-C) concentration and incidence of cardiovascular disease (CVD). The antiatherogenic role of HDL has been attributed to its anti-inflammatory, antithrombotic and antioxidant properties, besides its participation in the reverse cholesterol transport (RCT), whereby cholesterol from peripheral tissues (including macrophages of the arterial intima) is delivered to the liver for excretion in bile. Due to these actions, HDL-C has evolved as an attractive target for prevention of CVD. However, the failure of torcetrapib, drug that substantially increases HDL-C levels, in preventing CVD and data from studies with animal models and with carriers of monogenic disorders affecting HDL-C levels in humans provide conflicting data about HDL being antiatherogenic. This review addresses the current state of knowledge regarding HDL based on these recent controversies.

Implications of torcetrapib failure for the future of HDL therapy: is HDL-cholesterol the right target?

Owing to many potentially anti-atherogenic functions and the inverse correlation of high-density lipoprotein (HDL)-cholesterol (C) plasma levels with cardiovascular risk, HDLs have evolved as an attractive target for the prevention and therapy of coronary heart disease. Previously, the failure of torcetrapib, the frequent confounding of low HDL-C with other pro-atherogenic conditions, as well as inconsistent data from patients and animal models with genetic HDL dyslipidemias, left in doubt the suitability of HDL-C as a target for anti-atherogenic therapy. However, HDL-C is an integrative but nonfunctional measure of particle size and number. Therefore, biomarkers reflecting the functionality of HDL particles are needed to assess and monitor the cardiovascular risk exerted by disturbances and treatments of HDL metabolism, respectively. Moreover, the discovery of novel therapeutics that improve HDL metabolism, mimic HDL function, or cure the regulatory network underlying dyslipidemias and dysfunctions of HDL should be a major aim of atherosclerosis research.

The end of the road for CETP inhibitors after torcetrapib?

Because high-density lipoprotein cholesterol (HDL-C) levels are inversely related to cardiovascular disease (CVD), raising HDL-C levels would seem intuitively valuable. However, the recent failure of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib to decrease CVD has raised doubts regarding HDL-C raising in general and CETP inhibition in particular for CVD prevention. We briefly discuss the complexity of HDL metabolism, caveats of CETP inhibition, possible mechanisms for torcetrapib's failure, and the potential utility of other CETP inhibitors. Torcetrapib likely failed because of off-target effects, since other CETP inhibitors, such as dalcetrapib (JTT-705/R1658) or anacetrapib (MK-0859), do not increase blood pressure, a specific pressor effect of tocetrapib that appears to be CETP-independent. In small human trials of short duration, anacetrapib and dalcetrapib appear to improve the lipoprotein profile without obvious adverse effects, so far. The relationship between HDL metabolism, pharmacologic CETP inhibition, and atherosclerosis requires further elucidation. There seems to be sufficient evidence that evaluation of CETP inhibitors such as dalcetrapib and anacetrapib should proceed, if cautiously, since it remains uncertain whether the increased CVD risk with torcetrapib was related to agent-specific off-target effects or more generally to CETP inhibition as a mechanism to raise HDL.

Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

Torcetrapib Induces Aldosterone and Cortisol Production by an Intracellular Calcium-Mediated Mechanism Independently of Cholesteryl Ester Transfer Protein Inhibition

ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib's effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.

Leapfrogging Data

Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2 Articles pp 2506 and 2515 For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …

Current and emerging paradigms in the therapeutic management of atherosclerosis

Background: The pathogenesis of atherosclerosis lies in abnormalities in lipoprotein metabolism leading to pathological interactions with vessel walls and the release of inflammatory components, which further aggravate the disease condition. Objective: To elucidate current and emerging trends in drug discovery towards the development of new entities regulating lipoprotein metabolism and inflammatory components to combat the progression of atherosclerosis. Methods: Research/review articles in the public domain and press releases were employed. Results/conclusion: With the recent failure of torcetrapib and succinobucol, drug discovery and development efforts towards the treatment of atherosclerosis have received a big jolt and have been slowed down to certain extent. But this could be a starting point for several new mechanisms that are emerging to discover new drugs to combat the disease.

The failure of torcetrapib: is there a case for independent preclinical and clinical testing? – correspondence

I read with interest Dr Doggrell's opinion [1] that the torcetrapib failure ‘may have come to light earlier if clinical outcomes studies had a higher priority than repeated trials, in different pop...

The failure of torcetrapib: is there a case for independent preclinical and clinical testing? – author's reply

My editorial [1] was an independent review of the published preclinical and clinical data for torcetrapib in order to consider, with hindsight, the possible reasons why the development of torcetrap...

The failure of torcetrapib: what have we learned?

The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse 'off-target' effects. In this issue of British Journal of Pharmacology, Forrest and co-workers have elegantly investigated these effects, demonstrating two salient points -- (1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism. Anacetrapib, by contrast, did not demonstrate any pressor or off-target effects. Despite these findings, it remains to be proven whether the adverse cardiovascular outcomes from torcetrapib were indeed related to the pressor effects and whether CETP inhibition by other agents will result in beneficial clinical outcomes. Yet, the studies of Forrest and co-workers do bring us closer to unravelling the reasons behind the failure of torcetrapib.

The failure of torcetrapib: is there a case for independent preclinical and clinical testing?

Background: Torcetrapib was spectacularly withdrawn in December 2006, when a Phase III clinical trial showed increased cardiovascular adverse events. Objective: To consider possible reasons why the development of torcetrapib proceeded so far before adverse events became apparent. Method: Published preclinical and clinical data for torcetrapib are reviewed. Results/conclusions: It seems likely that independent preclinical testing would have shown that torcetrapib increased blood pressure. Such a finding might have halted the development of torcetrapib prior to clinical trial. Although the early clinical testing of torcetrapib showed favourable effects on the surrogate endpoints, an ability to increase blood pressure started to become apparent. When clinical outcome studies were undertaken with torcetrapib, it was shown not to have any benefit on atherosclerosis and to increase cardiovascular events. These finding might have come to light earlier if clinical outcomes studies had had a higher priority than repeated trials, in different populations, of torcetrapib on surrogate outcomes.

The continuing complexities of high-density lipoprotein metabolism in drug discovery and development

The termination of the Phase III clinical trial of Pfizer's CETP inhibitor torcetrapib, Investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE), due to excess mortality in the treatment group raised many questions for those involved in the discovery and development of drugs targeting high-density lipoprotein and of atherosclerosis in general. Although the reasons for the failure of torcetrapib are still not known, some of the consequences for the wider field are already apparent. Several imaging studies with torcetrapib showed no change in the various measures of lesion size, which gave some confidence in the interpretation of such studies. Although the case for raising high-density lipoprotein is strong and widely accepted, there will be a much closer interrogation of drugs targeting new mechanisms that will result in longer development times. In the meantime, existing drugs which modify high-density lipoprotein are being revisited, particularly niacin. This editorial commentary briefly discusses these and related issues from the perspective of 6 months following the termination of ILLUMINATE.

Torcetrapib's Failure May Not Doom Rest of Class

Torcetrapib's Failure May Not Doom Rest of Class

Torcetrapib Failure May Not Doom Other Drugs in Class

Torcetrapib Failure May Not Doom Other Drugs in Class