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PCSK9 inhibitors change treatment approach for dyslipidemia
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The FDA recently approved alirocumab and evolocumab for patients on maximally tolerated statin therapy with heterozygous familial hypercholesterolemia or with clinical atherosclerotic CVD such as MI or stroke who require additional lowering of LDL. Evolocumab was also approved for use in homozygous familial hypercholesterolemia.
Alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) are the new members of a class of drugs called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. PCSK9 inhibitors are the latest advance in cholesterol-lowering drugs. They are being hailed as a major breakthrough for patients with high cholesterol.
This commentary explores frequently asked questions about this new class of drugs and how they may change the treatment approach for patients with dyslipidemia.
What are PCSK9 inhibitors and how do they work?
The anti-PCSK9 drugs are either fully human (such as alirocumab and evolocumab) or humanized (such as bococizumab [Pfizer]) monoclonal antibodies that are injected subcutaneously and bind to the PCSK9 molecule in the plasma. PCSK9 is produced in the liver cell, secreted into plasma and binds to the LDL receptor on the liver surface. When the LDL receptor/PCSK9 complex is internalized into the cell, the LDL receptor is directed to lysosomal degradation, rather than being recycled back to the cell surface. Therefore, PCSK9 reduces the amount of LDL receptor expression and, hence, the removal of LDL particles from plasma. When PCSK9 is bound by the monoclonal antibody, it no longer interferes with the LDL receptor intracellular recycling process, thereby increasing the amount of LDL receptors expressed to subsequently remove LDL particles.
Why all the excitement about PCSK9 inhibitors?
The excitement is that an injection of these monoclonal antibodies to PCSK9 every 2 weeks can reduce LDL by 60%, whether given as monotherapy or in addition to statins. [Evolocumab is also available in a larger dose administered once per month.] The adverse event profile is very low (especially, no muscle effects), and the exceptional efficacy allows achievement of LDL targets in high-risk patients, especially those with familial hypercholesterolemia and those with CVD who are tolerating less than optimal doses of statins due to tolerance issues.
Is this therapy the right treatment for all high-risk patients?
The PCSK9 monoclonal antibodies provide additional help in reducing elevated LDL and non-HDL to more optimal levels. Those patients who can achieve optimal lipid targets on appropriate intensity of statins are not the candidates for these drugs at this time; ongoing CVD outcomes trials will address whether there is any incremental benefit in these patients. The patients who are great candidates for these drugs are those with established CVD who have either familial hypercholesterolemia on optimal lipid-lowering drugs, or those who cannot tolerate optimal statin doses due to intolerance, and are not at their LDL goal.
What are the National Lipid Association’s recommendations about LDL goals?
The NLA in the Part 1 Recommendations has clearly stated that both non-HDL and LDL should be at optimal targets to reduce CVD risk. The mainstay of the NLA’s stance is that the amount of atherogenic cholesterol is causative of atherosclerosis and that the lower the total amount of atherogenic cholesterol, the lower the risk for CVD. This viewpoint has been further supported by the results of the IMPROVE-IT study.
Do you believe that PCSK9s will change the way doctors approach LDL as a benchmark for CVD risk reduction?
It is hoped that the clinical adoption of the PCSK9 inhibitors will be based on the concept that achieving atherogenic cholesterol goals in high-risk patients is the cornerstone of CVD prevention. Of course, the completion of the ongoing CVD outcomes trials with these drugs will be crucial to proving this point, along with a low risk of adverse events.
- For more information:
- Peter H. Jones, MD, FNLA, is chief science officer of the NLA and an associate professor in the department of medicine’s section of atherosclerosis and lipid research at Baylor College of Medicine. He can be reached at Baylor College of Medicine, Department of Medicine, Atherosclerosis and Lipid Disorders, 6565 Fannin St., Suite B160A Mailstop A601, Houston, TX 77030; jones@bcm.edu.
Disclosure: Jones reports no relevant financial disclosures.