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- W2079314166 abstract "Cholesterol management is the centerpiece of cardiovascular risk reduction. The most commonly used tool for cholesterol control is a daily statin, and the recent American Heart Association/American College of Cardiology guidelines have sanctified this approach by endorsing widespread use of statins in large groups of patients, including those with cardiovascular disease, hypercholesterolemia, diabetes mellitus, and elevated cardiovascular disease risk.1 Challenges to the notion of a daily medication for cholesterol control have been introduced with the discovery of proprotein convertase subtilisin/kexin 9 (PCSK9),2 a secreted serine protease that binds the low-density lipoprotein (LDL) receptor (LDLR) and targets it for lysosomal destruction. Thus, a hyperactive (gain-of-function mutant) PCSK9 causes hypercholesterolemia, whereas a dysfunctional (loss-of-function mutant) PCSK9 causes lifelong low LDL-cholesterol (LDL-C) levels and protection against cardiovascular disease.3 The basic mechanism of PCSK9 action4 and its crystal structure5 made it clear early on that it would be difficult to develop a small molecule inhibitor for this protein. However, because PCSK9 is a secreted protein, it can be targeted with inhibitory antibodies, a modality that would change the paradigm of cholesterol treatment from oral to injectable and from daily to once or twice monthly dosing. A large number of clinical studies with the 2 leading antibodies have shown great efficacy and no safety signals, with LDL-C reductions in the range of 55% to 70% (even without concomitant use of statin) and no reports of myalgia (even in subjects with history of statin intolerance caused by myalgia), transaminase elevations, or alterations in glucose metabolism.6 In addition to neutralizing circulating PCSK9 via antibodies6 or adnectins,7 current drug development strategies also include genetic modalities, such as antisense RNA8 or RNA interference,9 to block PCSK9 synthesis. Given the likelihood that PCSK9 inhibitors will gain regulatory approval in the …" @default.
- W2079314166 created "2016-06-24" @default.
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- W2079314166 date "2014-08-15" @default.
- W2079314166 modified "2023-09-26" @default.
- W2079314166 title "Peeking Into a Cool Future" @default.
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- W2079314166 doi "https://doi.org/10.1161/circresaha.114.304575" @default.
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