A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia
ABSTRACT Background Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. Methods We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. Results Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. Conclusions At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879 .).
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ABSTRACT: This paper is an effort to review all the most important studies and guidelines in the topics of lipid, blood pressure and kidney published in 2014. Irrespective of advances, the options for improving simultaneous hypercholesterolemia and hypertension management (as well as its complication - chronic kidney disease) remain a problem. Recommending hypolidemic, hypotensive and kidney disease drugs to obtain therapy targets in cardiovascular, diabetic, elderly and kidney disease (=high risk) patients might strengthen risk factor control, improve compliance and the therapy efficacy, and in the consequence reduce the risk of cardiovascular events and mortality rate. That is why the authors have decided to summary and discuss the recent scientific achievements in the field of lipid, blood pressure and kidney. Copyright © 2015. Published by Elsevier Ltd.Pharmacological Research 03/2015; 95. DOI:10.1016/j.phrs.2015.03.009 · 3.98 Impact Factor
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ABSTRACT: To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012-May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe (difference 29.8 ± 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. clinicaltrials.gov Identifier: NCT01644188. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: firstname.lastname@example.org.European Heart Journal 02/2015; DOI:10.1093/eurheartj/ehv028 · 14.72 Impact Factor
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ABSTRACT: The discovery and elucidation of the role of the low-density lipoprotein receptor (LDL-R) in familial hypercholesterolemia (FH) ushered in the statin group of drugs. These drugs, in addition to lowering low-density lipoprotein cholesterol (LDL-C), result in a significant reduction in cardiovascular events (CVE) and mortality. Recently, a gain-of-function mutation in another protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), was reported to result in a FH phenotype by promoting degradation of the LDL-R. More importantly, loss-of-function mutations in the same gene resulted in low LDL-C and a reduction in CVE, making this an enticing target for drug development. Numerous strategies have been developed to target PCSK9, the most successful being monoclonal antibodies (mAbs) that bind PCSK9. These mAbs have been shown to reduce LDL-C around 50% as either monotherapy with diet or in combination with statin therapy. In this short perspective, we discuss the biochemistry and biology of PCSK9 in relation to lipid metabolism and the promising studies in humans demonstrating a substantial reduction in LDL-C with relative good short-term safety of PCSK9 mAbs.