Search

Abstract Type 2 diabetes is a causal risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). While treatment with a statin reduces the risk of having an ASCVD event in all people, including those with type-2 diabetes, statin treatment also increases the likelihood of new onset diabetes when given to those with risk factors for developing diabetes. Treatment with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, reduces the risk of having a coronary event over and above that achieved with a statin. However, unlike statins, anacetrapib decreases the risk of developing diabetes. If the reduced risk of new-onset diabetes is confirmed in another CETP inhibitor outcome trial, there will be a case for considering the use of the combination of a statin plus a CETP inhibitor in high ASCVD-risk people who are also at increased risk of developing diabetes. Highlights • Treatment with a statin increases the likelihood of new onset diabetes. • Treatment with a CETP inhibitor reduces risk of new onset diabetes. [ABSTRACT FROM AUTHOR]

Purpose This article reviews therapies that affect HDLs. Findings Lipid-modifying agents in current use (including statins, fibrates, and niacin) increase the concentration of HDL cholesterol to some extent. However, these agents have additional effects (beyond raising HDL) with the potential to reduce atherosclerotic cardiovascular disease (ASCVD) risk, making it difficult to determine (one way or the other) whether an increase in HDL concentration affects risk. New investigational approaches targeting HDLs include infusions of reconstituted HDLs, reinfusion of selectively delipidated plasma in which the concentration of pre-β HDLs (the preferred acceptor of cell cholesterol) has been increased, and inhibitors of cholesteryl ester transfer protein (CETP). Positive results of the effects of reconstituted HDL infusions on coronary atheroma burden encourage further investigation of these agents. One small study on the effects of reinfusing selectively delipidated plasma has also provided results supporting additional development of this approach. CETP inhibitors are the most effective HDL-raising agents developed yet, with the ability to more than double the concentration of HDL cholesterol. They also reduce LDL cholesterol by up to 50%. Clinical outcome trials with the first 2 of these agents (torcetrapib and dalcetrapib) failed and, in the case of torcetrapib, treatment increased ASCVD events and increased both cardiovascular and noncardiovascular death. However, the subsequent discovery that torcetrapib had serious adverse effects unrelated to CETP inhibition meant that trials with this agent were unable to test the hypothesis that inhibiting CETP (or raising the level of HDL cholesterol) would translate into a reduction in ASCVD risk. The trial with dalcetrapib, a relatively weak inhibitor of CETP, was conducted in people soon after an acute coronary event when HDL functionality is impaired. The CETP inhibitor hypothesis will remain untested until completion of ongoing trials with CETP inhibitors that are more potent than dalcetrapib and that do not have the adverse effects of torcetrapib. Implications Positive trials with reconstituted HDL infusions and reinfusions of selectively delipidated plasma will establish HDLs as important therapeutic targets. However, although a positive result in the trials with CETP inhibitors will establish CETP inhibition as a valid strategy to reduce ASCVD risk, it will not be possible to determine with certainty whether the reduction in risk is the consequence of effects on the HDL fraction or whether it is the result of CETP inhibitor−mediated reductions in LDL cholesterol. [ABSTRACT FROM AUTHOR]

Background High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia. Methods and results NZW rabbits were maintained for 6 weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib. The left femoral artery was ligated after 2 weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4 weeks after femoral artery ligation. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib reduced CETP activity by 63 ± 12% and 81 ± 8.6%, increased plasma apoA-I levels by 1.3 ± 0.1- and 1.4 ± 0.1-fold, and increased plasma HDL-cholesterol levels by 1.4 ± 0.1- and 1.7 ± 0.2-fold, respectively. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib increased the number of collateral arteries by 60 ± 16% and 84 ± 27%, and arteriole wall area in the ischemic hindlimbs by 84 ± 16% and 94 ± 13%, respectively. Capillary density in the ischemic hindlimb adductor muscle increased from 1.1 ± 0.2 (control) to 2.1 ± 0.3 and 2.2 ± 0.4 in the 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib-treated animals, respectively. Incubation of HDLs from des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells at apoA-I concentrations comparable with their plasma levels increased tubule network formation. These effects were abolished by knockdown of scavenger receptor-B1 (SR-B1) and PDZK1, and pharmacological inhibition of PI3K/Akt. Conclusion Increasing HDL levels by inhibiting CETP activity is associated with increased collateral blood vessel formation in NZW rabbits with hindlimb ischemia in an SR-B1- and PI3K/Akt-dependent manner. [ABSTRACT FROM AUTHOR]

Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area ( R 2 =0.258, P =0.045; R 2 =0.760, P <0.001), but not for HDL-C ( R 2 =0.030, P =0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99–1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction ( P =0.066), whereas no correlation was found for HDL-C ( P =0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the CETP suppression by 10-dehydrogingerdione, a compound in Zingiber officinale, and its effect on the progression of atherosclerosis in dyslipidemic rabbits and the underlying oxidative and inflammatory consequences. Methods: Twenty-four New Zealand male rabbits were fed either a normal diet or an atherogenic diet. The rabbits on the atherogenic diet received treatments of atorvastatin or 10-dehydrogingerdione and placebo concurrently (n = 6/group). Blood samples were collected after three and six weeks for biochemical analysis. Results: 10-Dehydrogingerdione-treated rabbits showed a significant improvement in serum lipids especially HDL-C in a time-dependant manner. This effect was correlated to its ability to lower CETP. Lp(a), ox-LDL, hsCRP, homocysteine and MMP9 decreased significantly in both 10-dehydrogingerdione- and atorvastatin-treated rabbits compared with placebo (p < 0.001). Lp(a) achieved normal values by both treatments, while homocysteine did not reach normal values by either treatments. Conversely, MMP9 returned below normal values by 10-dehydrogingerdione (p < 0.001), hsCRP and ox-LDL were slightly below normal values (hsCRP: p < 0.001; ox-LDL: p < 0.001 and p < 0.05 in 10-dehydrogingerdione and atorvastatin groups, respectively). The effect achieved by 10-dehydrogingerdione was similar to that of atorvastatin on hsCRP and Lp(a). However, 10-dehydrogingerdione exerted better effect than atorvastatin on homocysteine, MMP9 (p < 0.001) and ox-LDL (p < 0.05). Conclusions: In a rabbit dyslipidemic model, 10-dehydrogingerdione lowers LDL-C and raises HDL-C by suppressing CETP; an effect that modulates inflammatory and oxidative risk factors of CVD. These findings suggested that the naturally occurring 10-dehydrogingerdione might be a potential CETP inhibitor for the treatment of atherosclerosis and residual risk in CVD. [Copyright &y& Elsevier]

Abstract: Introduction: While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia. Methods and Results: Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1±0.6% to 3.6±0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study. Conclusion: In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only. [Copyright &y& Elsevier]

The WHO has predicted that a worldwide epidemic of Type II diabetes, affecting some 300 million persons, can be envisaged in 2003. The key features of the atherogenic lipid phenotype characteristic of Type II diabetes are low HDL-cholesterol levels, mild to marked hypertriglyceridemia involving VLDL and VLDL remnants, and elevated concentrations of both small dense LDL, and free fatty acids (FFA) in the fasting state; indeed, FFA are implicated in the development of peripheral insulin resistance. Elevated transfer rates of cholesteryl esters (CE) from HDL to atherogenic apoB100 lipoproteins (VLDL, IDL, LDL) mediated by cholesteryl ester transfer protein (CETP) underlie the low HDL-C levels typical of Type II diabetes, identifying CETP as a prime pharmacological target. The future clinical application of CETP inhibitors in Type II diabetic subjects, in association with agents which would act synergistically by reducing concentrations of atherogenic CE acceptor lipoproteins (e.g., statins, fibrates, cholesterol absorption inhibitors), is therefore especially attractive. [Copyright &y& Elsevier]