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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…

Familial hypercholesterolaemia: new genes found

22 May, 13 | by Alistair Lindsay

Familial hypercholesterolaemia is characterised by substantially raised plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and is associated with a risk of coronary heart disease that is five to eight times higher than average. One charity has estimated a saving of £378.7 million from cardiovascular events avoided if all relatives of index cases were identified and treated optimally over 55 years of age. more…

PCSK9 antibody decreases LDL cholesterol in statin-intolerant patients

1 Jan, 13 | by Alistair Lindsay

Approximately 10-20% of patients are unable to tolerate statins or the higher doses needed to achieve LDL cholesterol goals. Perprotein convertase subtilisin/kexin type 9 (PCSK9) mediates the binding and trafficking of LDL receptors, and in phase 1 studies a human monoclonal antibody to to PCSK9 (AMG145)lowered LDL levels. The Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects (GAUSS) trial aimed to assess the efficacy and safety of AMG145 in patients with a documented history of muscle-related adverse effects with statins. 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…

LDL cholesterol lowering in CKD looks SHARP

2 Jul, 11 | by Alistair Lindsay

While the cardiovascular benefits of LDL cholesterol lowering in patients without kidney disease are well established, the effects on people with moderate to severe kidney disease has remained unproven.

The SHARP (Study of Heart and Renal Protection) study was a randomised double-blind trial that included 9270 patients with chronic kidney disease (3023 of whom were on dialysis) and with no known history of cardiovascular disease.  Patients were randomly assigned either to placebo or a combination of simvastatin 20mg od plus ezetimibe 10mg od.  The main outcome measure was defined as a first major cardiovascular event (fatal or non-fatal MI, ischaemic stroke, or any arterial revascularisation procedure). more…

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