Journal Article•
CETP inhibition in cardiovascular risk management: a critical appraisal (vol 37, pg 90, 2007)
TL;DR: In this paper, the effect of cholesteryl ester transfer protein (CETP) on HDL cholesterol was investigated in a large-scale phase III clinical trial, with torcetrapib being only evaluated in combination therapy with atorvastatin.
Abstract: In view of the cardioprotective effect of high‐density lipoproteins (HDL) and the limited effects of statin and fibrate therapy on HDL cholesterol, it is clinically relevant to test whether pharmacological treatment aimed at raising HDL lowers cardiovascular risk. Cholesteryl ester transfer protein (CETP) is a new therapeutic target, because the cholesteryl ester transfer process lowers HDL cholesterol and contributes to an atherogenic lipoprotein profile, particularly when plasma triglycerides are high. Clinical evidence suggests that coronary artery calcification as well as intima media thickness is positively related to plasma cholesteryl ester transfer, and that high plasma CETP concentration is associated with increased cardiovascular risk in hypertriglyceridaemia. However, CETP could also have anti‐atherogenic potential, since it provides a potentially beneficial route for delivery of HDL‐derived cholesteryl esters to the liver. In addition, CETP could also favourably stimulate peripheral cell cholesterol removal and enhance hepatic cholesterol uptake. Recent evidence suggests that a high CETP level may confer lower cardiovascular risk in the context of low triglycerides. At maximal doses, the CETP inhibitors JTT‐705 and torcetrapib elicit a marked rise in HDL cholesterol of up to 34% and 91–106%, respectively. The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large‐scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin. When and how to use CETP inhibitors, e.g. in combination with a statin or a fibrate, is a major challenge. We propose that low HDL cholesterol in the context of high triglycerides, such as found in type 2 diabetes mellitus, could become an important indication area for this new class of drugs.
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TL;DR: Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk.
Abstract: Context The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk. Objective To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. Data Sources Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. Study Selection Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and −629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], −631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms. Data Extraction Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. Results Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113 833 healthy participants, and 46 studies had data on 27 196 coronary cases and 55 338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (−9.7%; 95% confidence interval [CI], −11.7% to −7.8%), lower mean CETP activity (−8.6%; 95% CI, −13.0% to −4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and −629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for −629C>A. Conclusions Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.
471 citations
TL;DR: Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments.
428 citations
TL;DR: In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality, suggesting that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels.
Abstract: Aims Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB -B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes.
Methods and results We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB -B2 showed reduced CETP levels and higher HDL-cholesterol ( P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 ( P = 0.01) for atherosclerotic disease death, 1.53 ( P = 0.03) for ischaemic heart disease death, and 1.30 ( P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints.
Conclusion In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.
102 citations
TL;DR: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalents.
87 citations
TL;DR: It was concluded that AP favorably improved distribution of cholesterol in lipoproteins, most likely, by its inhibition on CETP activity.
Abstract: Previous reports demonstrated that hypocholesterolemic activity of apple was associated with its pectin and fiber. This report was to investigate the effect of apple polyphenols (AP) on blood cholesterol level and gene expression of cholesterol-regulating enzymes in Golden Syrian hamsters maintained on a 0.1% cholesterol diet. It was found that dietary supplementation of 0.3 or 0.6% of AP did not affect plasma total cholesterol (TC), but it increased HDL cholesterol (HDL-C) and decreased non-HDL-C, thus leading to a lower ratio of non-HDL-C to HDL-C. Plasma total triacylglycerol (TG) level was also significantly reduced when hamsters were fed a diet supplemented with 0.6% AP. Western blot analysis did not find any effect of AP on sterol regulatory element-binding protein 2 (SREBP-2), LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), and cholesterol-7alpha-hydroxylase (CYP7A). Most interesting was that supplementation of AP had no effect on protein abundance of plasma cholesteryl ester transport protein (CETP), but it suppressed plasma CETP activity. A series of in vitro assays confirmed that AP inhibited CETP in a dose dependent manner. It was concluded that AP favorably improved distribution of cholesterol in lipoproteins, most likely, by its inhibition on CETP activity.
83 citations
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TL;DR: A consistent inverse relation of high-density lipoprotein cholesterol levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.
Abstract: The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.
3,149 citations
TL;DR: The removal of cholesterol from cells, like its delivery, appears to be specific and well regulated, and RCT can now be understood in molecular terms.
1,509 citations
TL;DR: Small-molecule inhibitors of CETP have now been tested in human subjects and shown to increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB, and test the hypothesis in randomized trials of humans that pharmacological inhibition of CETp retards the development of atherosclerosis.
Abstract: Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from antiatherogenic HDLs to proatherogenic apolipoprotein B (apoB)-containing lipoproteins, including VLDLs, VLDL remnants, IDLs, and LDLs. A deficiency of CETP is associated with increased HDL levels and decreased LDL levels, a profile that is typically antiatherogenic. Studies in rabbits, a species with naturally high levels of CETP, support the therapeutic potential of CETP inhibition as an approach to retarding atherogenesis. Studies in mice, a species that lacks CETP activity, have provided mixed results. Human subjects with heterozygous CETP deficiency and an HDL cholesterol level >60 mg/dL have a reduced risk of coronary heart disease. Evidence that atherosclerosis may be increased in CETP-deficient subjects whose HDL levels are not increased is difficult to interpret and may reflect confounding or bias. Small-molecule inhibitors of CETP have now been tested in human subjects and shown to increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB. Thus, it seems important and timely to test the hypothesis in randomized trials of humans that pharmacological inhibition of CETP retards the development of atherosclerosis.
827 citations
TL;DR: Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia.
Abstract: The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent " VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes. Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia.
796 citations
TL;DR: In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol Levels and also decreased LDL cholesterol Levels, both when administered as monotherapy and when administered in combination with a statin.
Abstract: background Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels. methods We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks. results Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort.
757 citations