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|STUDY SUMMARY: ODYSSEY LONG TERM|
|Objective||To assess the safety, tolerability and efficacy of treatment with a monoclonal antibody to PCSK9 (alirocumab) in patients at high risk of cardiovascular disease (CVD) on maximally tolerated lipid-lowering therapy (including statin)|
|Study design||Randomised, double-blind, placebo-controlled study. Patients were allocated 2:1 to alirocumab (150 mg subcutaneously every 2 weeks) or placebo for 78 weeks. The mean duration of treatment was 65 weeks (both arms).|
|Study population||2,341 patients at high risk of CVD (including patients with heterozygous familial hypercholesterolaemia) with LDL cholesterol levels ≥1.81 mmol/L (70 mg/dL) on maximally tolerated statin therapy; 1,553 were randomised to treatment with alirocumab and 788 received placebo.|
Alirocumab is the first non-statin treatment that appears to reduce additional CV events on top of statin therapy, and this is very encouraging since previous trials of various lipid-lowering drugs have failed to find this.
|STUDY SUMMARY: Tran-Dinh et al.|
|Objective||To evaluate the potential for risk of haemorrhagic complications after cerebral ischaemia/reperfusion at very low levels of LDL cholesterol, using an experimental model (mice with PCSK9 deficiency).|
|Study design||Experimental animal model|
|Study population||Mice with genetic PCSK9 deficiency (PCSK9 −/−) and wild type mice (PCSK9 +/+). The PCSK9 deficient mice had significantly lower LDL cholesterol levels (mean 0.2 g/L) compared with controls; these levels are in the same range as those observed in patients treated with PCSK9 inhibitors.|
|Methods||Both groups of mice were fed a high-fat/high-cholesterol (21%/0.15%) diet for 1 month and were then subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous haemorrhagic transformation was assessed by quantification of haemoglobin in ischaemic tissue.|
Haemoglobin concentration in ischaemic cerebral tissue did not differ between PCSK9 deficient and wild type mice (31.5 [18.9–60.1] versus 32.8 [14.7–69.9] ng/mg protein, p=0.81). There was also no difference in infarct volume between the two groups.
In addition, using a validated in vitro model of the blood–brain barrier, there was no difference in endothelial barrier integrity at decreasing LDL cholesterol levels under ischaemia/reperfusion conditions.
|Author's conclusion||These observations suggest that PCSK9 inhibition, leading to LDL cholesterol lowering, should not increase haemorrhagic complications after acute ischaemic stroke.|
PCSK9 plays a critical role in regulating cholesterol homeostasis. Although its mechanism of action remains to be fully elucidated, it is thought that binding of PCSK9 to the surface of the cell leads to conformational changes, in turn enhancing intracellular degradation of hepatic LDL receptors, resulting in an increase in plasma LDL cholesterol levels.1 On this basis, therefore, inhibition of PCSK9 has emerged as a novel target for further lowering of LDL cholesterol levels, in patients at high CV risk inadequately treated by statins or intolerant to statins. However, it is also relevant that inhibitors of PCSK9 also have important effects on other lipids, notably lipoprotein(a),2 which is a potential contributor to lipid-related residual CV risk.3 Certainly, the clinical development of monoclonal antibody therapies to PCSK9 has gathered pace, with three of these agents now in large prospective outcomes studies.4-7
Given the pitfalls of recent trials of novel lipid-modifying therapies which attempted to address the issue of residual CV risk, there has been much interest in foretelling the results. Hence this post hoc analysis from ODYSSEY LONG TERM. These findings provide reassuring safety data for treatment up to 78 weeks, as well as a hint in the right direction for potential clinical benefits. However, we need to bear in mind that this study was not powered for analysis of CV outcomes, as well as the limitations inherent in post hoc analyses.
A second question associated with PCSK9 inhibition concerns the safety of very low LDL cholesterol levels, specifically in relation to the risk of haemorrhagic complications after ischaemic stroke.8,9 However, the results from this experimental model by Tran-Dinh et al (2014) suggest that lowering of LDL cholesterol levels with PCSK9 inhibition should not increase the risk of haemorrhagic complications after acute ischemic stroke, albeit with the caveat that this is an animal model which does not account for the cumulative LDL-lowering effects associated with PCSK9 inhibition on top of statin therapy.
Despite these reservations, these studies do suggest promise for this novel therapy to address lipid-related residual CV risk.
1. Petrides F, Shearston K, Chatelais M et al. The promises of PCSK9 inhibition. Curr Opin Lipidol 2013;24:307–12.