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HDL and Cardiovascular Risk: Rethinking the Relationship

17 Feb, 15 | by Alistair Lindsay

Although lower HDL levels are associated with increased cardiovascular risk, therapies to raise HDL levels have failed to reduce cardiovascular events.  In this sub-study of the longitudinal Dallas Heart Study, the authors turn their attention from absolute levels of HDL to reverse cholesterol transport in the shape of HDL efflux capacity.  This efflux capacity is a measure of HDL particles’ ability to accept cholesterol from macrophages.  Using a novel fluorescent cellular assay, HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity were measured in 2924 adults with no history of cardiovascular disease.  The primary end-point was a cardiovascular event, which included a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes over a median of 9.4 years of follow-up.   more…

Gene mutation reduces risk of coronary disease  

20 Dec, 14 | by Alistair Lindsay

Niemann-Pick C1-like 1 (NPC1L1) protein is expressed in the small intestine and liver and facilitates the transport of intraluminal dietary cholesterol into enterocytes. This transporter is the target of the drug ezetimibe and inhibition of the transporter is known to significantly reduce plasma levels of LDL cholesterol. In this genetic study, the authors first sequenced NPC1L1 to search for mutations that inactivated the transporter and then determined whether these mutations were correlated with a lower risk of coronary heart disease. First, NPC1L1 was sequenced in 7364 patients with known coronary heart disease and in 14,728 healthy controls. The authors identified 15 distinct NPC1L1 inactivating mutations with the most common mutation being p.Arg406X. more…

PCSK9 shows benefit in cholesterol lowering

25 Nov, 12 | by Alistair Lindsay

Despite the potency of high dose statins, many patients fail to reach targets for LDL cholesterol reduction.  Whilst the addition of a second agent such as niacin or ezetemibe results in an additional 10-20% reduction in cholesterol, there remains an unmet need for more potent therapies.  Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing their degradation and reducing the rate at which LDL cholesterol is removed from the circulation.  The injectable fully human monoclonal antibody SAR236553 binds PCSK9, resulting in increases in LDL receptor recycling and reductions in LDL cholesterol.  In this phase 2, multicenter, double-blind, placebo-controlled trial 92 patients who had LDL cholesterol levels of 2.6 mmol/l or higher despite statin therapy were randomised to 8 weeks treatment with atorvastatin 80 mg plus SAR236553 fortmightly, atorvastatin 10 mg plus SAR236553, or atorvastatin 80 mg plus placebo injections.  more…

Novel cholesterol lowering agent shows promise

19 Sep, 12 | by Alistair Lindsay

Serum PCSK9 plays an active role in controlling the expression of LDL receptors by targeting them for lysosomal destruction.  REGN727/SAR236553 (REGN727) is a novel human monoclonal antibody which inhibits PCSK9 binding to the LDL receptor; a previous phase 1 proof of concept trial suggested the potential for significant reductions in LDL in familial hypercholesterolaemia. more…

Statins show benefit regardless of CRP

6 Feb, 11 | by Alistair Lindsay

Some previous studies – most noticeably the JUPITER trial – have suggested that the vascular benefits of statin therapy may be greater in the presence of inflammation.  C-reactive protein (CRP), a systemic marker of inflammation, has been associated with the risk of ischaemic heart disease, stroke, and vascular mortality, but its ability to act as a biomarker that can be used to guide treatment remains controversial.  This study tested the hypothesis that the effects of statin therapy differ according to baseline concentrations of CRP and LDL cholesterol. more…

Anacetrapib shows promise

8 Jan, 11 | by Alistair Lindsay

Despite the success of statins for both primary and secondary prevention, many patients continue to have a high residual risk of cardiovascular events related to sub-optimal lipid control.  One approach to raising HDL cholesterol is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes the transfer of cholesteryl esters from HDL and other lipoprotein fractions, with inhibition of CETP increasing HDL, and concomitantly lowering LDL.  The first CETP inhibitor to make it to Phase III trial was torcetrapib in the ILLUMINATE study, but this was terminated early after the drug was shown to paradoxically cause an excess of deaths and cardiovascular events.  Analysis of these results suggested that torcetrapib was acting off-target and increasing blood pressure, and that the adverse effects were not related to CETP inhibition per se.  While torcetrapib was hastily jettisoned, development on other CETP inhibitors has continued and in this large study the safety of anacetrapib was assessed. more…

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