• Divya Ratan Verma and Eliot A Brinton.
• Division of Cardiology, University of Utah School of Medicine; Utah Foundation for Biomedical Research, Salt Lake City, UT.
• Rev Cardiovasc Med. 2014 Jan 1; 15 (2): 86-101; quiz 101.

AbstractAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability in the United States and other developed nations, and is rising rapidly in the rest of the world. Low-density lipoprotein (LDL) is the major atherogenic particle in most patients at high risk for ASCVD events, and statin-based LDL-lowering treatment is the major focus of treatment for prevention of ASCVD. Despite this, an estimated 57 million US adults (25%) still have moderately elevated levels of LDL-cholesterol (LDL-C) > 160 mg/dL, and many others have an LDL-C above the level considered appropriate for their high-risk status. Although statins are very effective for lowering LDL-C, and other classes of LDL-lowering medications are available, many patients still cannot achieve adequate LDL-lowering with maximal tolerated doses of US Food and Drug Administration-approved treatments. Thus, there is an unmet medical need for statin adjuncts in these patients, as well as for statin alternatives in statin-intolerant patients. A recently discovered human protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), plays an important role in LDL metabolism by promoting degradation of the LDL receptor, and thus reducing clearance of LDL and increasing LDL-C levels. Accordingly, inhibition of PCSK9 activity has become an attractive target for drug development for lowering LDL-C, and human monoclonal antibodies against PCSK9, are now in late-stage clinical development. These antibodies are at least as effective as statins for LDL-C lowering (or more so), and their effects are additive to those of statins. To date, they have been well tolerated and apparently safe in clinical trials. Long-term randomized, controlled trials of their safety, tolerability, and ability to reduce ASCVD are now underway.

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