PCSK9 Inhibitors: A Brief Primer

Merle Myerson, MD, EdD


March 28, 2016

The understanding and knowledge of lipid disorders and options for treatment continue to grow. The first lipid drug, the bile acid sequestrant cholestyramine, was developed in the late 1900s, and the first statin drug, lovastatin, was approved by the US Food and Drug Administration (FDA) in 1987. In 2016, we now have a selection of drugs with different targets, potencies, and mechanisms. Among the latest are proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

What Are PCSK9 Inhibitors?

PCSK9 inhibitors are a new class of lipid-lowering medications that are administered as monthly or bimonthly subcutaneous injections. They are monoclonal antibodies to PCSK9, developed after the observation that naturally occurring loss-of-function polymorphisms resulting in PCSK9 underexpression led to lower low-density lipoprotein cholesterol (LDL-C) levels.

How Do PCSK9 Inhibitors Work?

Low-density lipoprotein receptors (LDL-R) in hepatocytes bind to LDL particles and remove them from the circulation. The LDL-R then return to the cell surface to repeat this process. PCSK9 functions as a binding protein; it is expressed primarily in hepatocytes and after secretion binds to the LDL-R and promotes their degradation. By blocking PCSK9, these drugs result in increased availability of LDL-R to remove LDL-C from the circulation.

LDL-R and PCSK9 expression are dynamic processes that respond to the serum concentrations of LDL-C.[1] Statin drugs can increase PCSK9 synthesis as part of the body's response to lower LDL-C levels.[2]

Which PCSK9 Inhibitors Are Approved for Use in the United States?

Alirocumab (Praluent®) was approved by the FDA on July 24, 2015, and evolocumab (Repatha™) was approved on August 27, 2015. A third drug, bococizumab, is currently in phase 3 trials.

What Are the Indications for PCSK9 Inhibitors?

Current FDA-approved indications are as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The FDA also approved evolocumab for use as an adjunct to other LDL-C–lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

How Effective Are They at Lowering LDL-C?

The PCSK9 Inhibitors have been shown to markedly lower LDL-C in phase 3 trials.

The ODYSSEY COMBO II trial randomly assigned patients at high cardiovascular risk and elevated LDL-C despite maximal doses of statin to alirocumab or ezetimibe (on a background of statin therapy). At week 24, the alirocumab group had 50.6% reduction in LDL-C compared with 20.7% for the ezetimibe group.[3] In the GAUSS-2 trial, patients at high cardiovascular risk who were statin intolerant were randomly assigned to either evolocumab (140 mg every 2 weeks or 420 mg monthly) or ezetimibe. After 12 weeks, LDL-C lowering in the evolocumab groups ranged between 53% and 56% compared with 37%-39% for ezetimibe.[4]

PCSK9 inhibitors have also been investigated in patients with HeFH. The ODYSSEY FH I and FH II trials enrolled patients who had inadequate LDL-C control on maximally tolerated drug therapy. Levels of LDL-C were reduced by 51.4% at week 24 and maintained at week 78.[5] Similarly, evolocumab was shown to reduce LDL-C levels by approximately 60% at 12 weeks in patients with HeFH who had been on stable statin regimens in the RUTHERFORD-2 trial.[6]

PCSK9 Inhibitors can be effective in patients with HoFH who have LDL-R activity. In a study of 33 such patients, evolocumab lowered LDL-C by 30.9% at 12 weeks compared with placebo.[7]

Are PCSK9 Inhibitors Indicated for Patients With Statin Intolerance?

The wording in the FDA indications—"maximally tolerated statin therapy"—is not equivalent to "statin intolerant." This is an important distinction in terms of usage and insurance coverage. The determination of inability to tolerate statin therapy is complex and requires assessing whether symptoms are real or perceived, as well as whether alternative therapies (ie, switching to a different statin, alternative dosing, or use of nonstatin medication) can treat the dyslipidemia.[8]

The FDA avoided including the term "statin intolerant" on the label because of concerns that this "could promote a condition that is not well-understood and encourage some patients to prematurely abandon statins."[9]

Have PCSK9 Inhibitors Been Shown to Lower the Risk for MI or CV Death?

To date there have been no definitive studies on hard cardiovascular outcomes. There are several large outcomes trials for alirocumab, evolocumab, and bococizumab underway. The furthest along is the FOURIER trial, which has enrolled more than 27,500 patients; results are expected in late 2017. The ODYSSEY Outcomes study will evaluate alirocumab in more than 18,000 post–acute coronary syndrome patients and is expected to be completed in early 2018. These studies, as well as postmarketing information on safety and efficacy, will be crucial to determining the value of PCSK9 inhibitors.

Are There Any Safety Concerns or Side Effects?

In preapproval studies there have been few worrisome side effects or safety concerns. Injection-site reactions were reported, although the drugs have been tolerable, with safety and efficacy similar between the two approved drugs.

In the ODYSSEY COMBO II trial, there was no excess of treatment-emergent adverse events with alirocumab.[3] Muscle-related adverse events occurred in 12% of the evolocumab-treated patients compared with 23% of the ezetimibe-treated patients in the GAUSS-2 study, with no difference in emergent adverse events or laboratory abnormalities between the study and placebo groups.[4]

In the ODYSSEY FH I and FH II studies, injection-site reactions occurred in 12.4% and 11.4% compared with 11.0 and 7.4% in the placebo groups, respectively.[5] Nasopharyngitis and muscle-related adverse events were reported more frequently in the evolocumab groups (9% and 5%, respectively) than in the placebo groups (5% and 1%) in the RUTHERFORD-2 trial of patients with HeFH.[6]

Concerns have been raised about the potential for cognitive side effects with extensive lipid lowering.[10] Self-reported neurocognitive effects were higher in the ODYSSEY Long-Term study after 78 weeks of treatment with alirocumab (1.2% vs 0.5% for placebo).[11] In the ODYSSEY COMBO II study, neurocognitive events were reported in 0.8% of patients treated with alirocumab and 1.2% of the ezetimibe group. Neurocognitive events were reported in less than 0.2% of patients in both the evolocumab and placebo arms of the phase 2 and 3 trials.

The FDA requested that neurocognitive adverse effects be monitored and cognitive function be assessed in a subset of participants in ongoing long-term studies of PCSK9 inhibitors. These long-term safety data will also inform clinicians in regard to injection-site reactions and possible development of antidrug antibodies.[2]

How Much Do They Cost?

These drugs cost more than $13,000 annually. Although they were not developed to treat the wide range of patients with elevated LDL-C, concern remains about the cost to be borne by patients, insurance, and the public, given that the morbidity and mortality benefits have not been determined. Unlike the very costly but generally one-time-use hepatitis C treatment, PCSK9 inhibitors must be taken for a lifetime.

What New Data Will Be Released at the 2016 American College of Cardiology Scientific Sessions?

The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-3) trial is among the late-breaking trials to be presented. The level of LDL-C lowering at 24 weeks for evolocumab (420 mg monthly) vs ezetimibe (10 mg daily) will be reported for hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance.[12]

Some related abstracts are already available online:


PCSK9 inhibitors are a new class of very potent LDL-C–lowering drugs that can offer treatment to a group of patients who have genetic hyperlipidemia or are at very high risk for cardiovascular disease and are not able to reduce their LDL-C level with existing therapies. Ongoing clinical trials and postmarketing data will provide more information on how these drugs should be used in the treatment of dyslipidemia and the prevention of cardiovascular disease.

Table. Indications, Administration and Dosing, Cost, and Monitoring

Drug Indication Administration and Dosage Annual Cost Monitoring
Alirocumab (Praluent®) Adjunct to:
-Maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic CVD who require additional lowering of LDL-C
Subcutaneous injection

Starting dose: 75 mg once every 2 weeks

If response inadequate, increase to 150 mg once every 2 weeks
$13,440 Measure levels of LDL-C within 4-8 weeks of initiating therapy
Evolocumab (Repatha™) Adjunct to:
-Maximally tolerated statin therapy for treatment of adults with HeFH or clinical atherosclerotic CVD who require additional lowering of LDL-C
-Other LDL-lowering therapies in patients with HoFH who require additional lowering of LDL-C
Subcutaneous injection

HeFH: 140 mg every 2 weeks or420 mg once monthly

HoFH: 420 mg once monthly
$13,015 Measure levels of LDL-C within 4-8 weeks of initiating therapy

CVD = cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol
Sources: The Medical Letter on Drugs and Therapeutics; package inserts


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.