FDA Approves PCSK-9 Inhibitors Alirocumab and Evolocumab Based on LDL Cholesterol Reduction

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The FDA approves PCSK-9 inhibitors alirocumab and evolocumab, amid cardiovascular risk debate.

The Food and Drug Administration (FDA) approved two monoclonal antibodies that inactivate proprotein convertase subtilisin-kexintype 9 (PCSK-9), alirocumab and evolocumab, because of their ability to lower low-density lipoprotein (LDL) cholesterol levels in the bloodstream.

The Endocrinologic and Metabolic Drugs Advisory Committee of the FDA met in June  2015 with concerns about the effects that alirocumab and evolocumab have for patients at risk for cardiovascular disease (CVD).

“Establishing evidence of improved cardiovascular outcomes is key to evaluating medications from any new drug class intended to reduce such risk,” the authors wrote in a perspective published in the New England Journal of Medicine. “As substantially as alirocumab and evolocumab reduce LDL cholesterol, definitive evidence of reduced cardiovascular event rates is essential.”

Alirocumab reduces LDL cholesterol by 39% to 62% compared with placebo, and evolocumab by 47% to 56%. Both are administered by injection.

The FDA was also concerned about possible gastrointestinal, metabolic, and neurocognitive adverse effects, because the patients who would use this drug would have either  primary hypercholesterolemia, mixed dyslipidemia, and  are unable to take statins.

Using the amount of LDL cholesterol reduction as a measure of approval can be beneficial because it demonstrates a statistically significant effect of the medication and  only requires exposing a few patients to the drug for a short amount of time. However, the adverse effects of the drug may not develop until a large number of patients are exposed to the drug for a longer time.

This method of approval would also allow evaluations of the drug on patients with uncommon disorders. Evolocumab, the authors note, was tested on an uncommon disorder called homozygous familial hypercholesterolemia, which significantly reduced LDL cholesterol levels for patients with the condition. It was unanimously recommended for approval by the advisory committee.

“Patients with existing cardiovascular disease and persistently high LDL cholesterol levels despite high-intensity statin therapy also have important unmet medical needs,” the authors concluded.  “For this much larger population, the FDA must weigh the benefits of early approval against the possibility that the drugs will be substituted for maximally tolerated statins, even though there’s much better evidence of statins’ clinical benefit.”

Approving the drugs allows patients unable to take statins another medication option, but approximately 70% of patients who are labeled as statin intolerant are actually overdiagnosed and can withstand smaller doses.

The advisory committee voted 13 to 3 to approve alirocumab and 11 to 4 to approve evolocumab. The members who had advocated the drugs’ approval wanted to provide a potentially beneficial option to patients with high risk of CVD before the cardiovascular risk trials were completed.

Many of the members, including those who approved the drugs, also stated that LDL cholesterol levels were not a reliable alternative for cardiovascular benefit data.  According to the authors, it is essential that more research be conducted to gain definitive evidence that the drugs can reduce cardiovascular event rates.

Disclosure: The authors all participated as voting members of the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting for alirocumab. Dr. Smith and Dr. Hiatt voted for the approval of evolocumab.


  1. Everett BM, Smith RJ, Hiatt WR.  Reducing LDL with PCSK9 Inhibitors—The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015. doi: 10.1056/NEJMp1508120.