Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists' Collaboration meta-analysis for low-density lipoprotein lowering.
ABSTRACT Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.
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ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. Alnylam Pharmaceuticals.The Lancet 10/2013; · 39.06 Impact Factor
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ABSTRACT: Despite population-based improvements in cardiovascular risk factors, such as blood pressure, cholesterol and smoking, cardiovascular disease still remains the number-one cause of mortality in the United States. In 1989, Kaplan coined the term "Deadly Quartet" to represent a combination of risk factors that included upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension [Kaplan in Arch Int Med 7:1514-1520, 1989]. In 2002, the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) essentially added low HDL-C criteria and renamed this the "metabolic syndrome." [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001] However, often forgotten was that a pro-inflammatory state and pro-thrombotic state were also considered components of the syndrome, albeit the panel did not find enough evidence at the time to recommend routine screening for these risk factors [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001]. Now over a decade later, it may be time to reconsider this deadly quartet by reevaluating the roles of obesity and subclinical inflammation as they relate to the metabolic syndrome. To complete this new quartet, the addition of increased exposure to elevated levels of particulate matter in the atmosphere may help elucidate why this cardiovascular pandemic continues, despite our concerted efforts. In this article, we will summarize the evidence, focusing on how statin therapy may further impact this new version of the "deadly quartet".Current Atherosclerosis Reports 01/2014; 16(1):380. · 2.92 Impact Factor
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ABSTRACT: Abstract The most recent guidelines released by the EAS/ESC and the Canadian Cardiovascular Society (CCS) retain low-density lipoprotein cholesterol (LDL-C) as the primary measure of the atherogenic risk of the apolipoprotein B (apoB) lipoproteins and the primary target of LDL-C lowering therapy. Both organizations endorse non-high-density lipoprotein cholesterol (non-HDL-C) and apoB as "alternate/secondary" targets, but neither group offers evidence supporting the continued preference of LDL-C as the primary target over non-HDL-C and apoB. Further, both suggest that non-HDL-C and apoB more or less measure the same thing and, therefore, are essentially interchangeable. But what is the evidence that LDL-C should remain the primary target, and are apoB and non-HDL-C mirror images of one another? Furthermore, are estimation of risk and establishment of treatment targets the only relevant issues, or is diagnosis also an essential objective? These are the questions this article will address. Our principal objectives are: (1) to clarify the differences between LDL-C, non-HDL-C, and apoB and to distinguish what they measure; (2) to summarize the evidence relating to LDL-C, non-HDL-C, and apoB as predictors of cardiovascular risk and as targets for treatment; and (3) to demonstrate that diagnosis of atherogenic dyslipoproteinemias should be a fundamental clinical priority.Critical Reviews in Clinical Laboratory Sciences 11/2013; 50(6):163-71. · 3.78 Impact Factor