CURRENTLY, THERE ARE APPROXIMATELY 11 MILLION ADULTS IN THE UNITED STATES who cannot reach their LDL-C goals through the traditional cholesterol-lowering medications currently available.

The new class of medications, called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, may be the key for these patients.

What are PCSK9 inhibitors?
PCSK9 is a protein circulating in the blood that binds to the low-density lipoprotein (LDL) receptor in the liver. Typically, LDL cholesterol (LDL-C) breakdown occurs when the LDL-C binds to the LDL receptor on the hepatocyte. The bound LDL-C is then brought into the liver cells, where it is destroyed.

The LDL receptor can be reused up to 150 times before degradation. But, when PCSK9 is also bound to an LDL receptor, it causes the LDL receptor to break down along with the LDL-C; thus, decreasing the number of LDL receptors available to break down LDL-C, resulting in higher LDL-C levels.

The class of PCSK9 inhibitors work by binding to the PCSK9 protein and preventing it from binding to the LDL receptors. By doing this, it allows LDL receptors to be recycled the maximum amount of times before the body needs to make new receptors; thus, increasing the body’s ability to clear more LDL-C, resulting in lower LDL-C levels.

This class of medications must be injected regularly because the body will make more PCSK9.

Current indications for PCSK9 inhibitors
PCSK9 inhibitors are indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with familial hypercholesterolemia (homozygous or heterozygous) or atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C.

Familial hypercholesterolemia is a genetic condition inherited from the parents. Heterozygous means the patient received the genetic mutation from just 1 parent versus homozygous, where they received it from both parents. Homozygous patients are extremely rare, at approximately 1 in 1 million. These patients typically present to clinic very young, sometimes in their teens, with a heart attack or stroke and LDL-C above 500 mg/dL.

Evolocumab is the only PCSK9 inhibitor with an indication for the homozygous patient, and it is recommended they receive a high-monthly dose of 420 mg every 4 weeks. Heterozygous patients are a little more common, and typically present with a baseline LDL-C greater than 190 mg/dL. These patients tend to have a cardiac event in their 20s or 30s. Most of the patients who need PCSK9 inhibitor therapy will fall into the clinical ASCVD category.

Clinical ASCVD is defined by the 2013 AHA/ACC Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults as coronary artery disease (acute coronary syndrome, history of myocardial infarction, stable or unstable angina, and history of coronary revascularization), stroke or TIA, peripheral arterial disease or history of peripheral arterial revascularization.

These patients, according to the guideline, are candidates for high-intensity statins and for whom we want aggressive LDL-C lowering to try and prevent a future cardiac event. Current indications do not include PCSK9 inhibitors for patients only diagnosed with hyperlipidemia without ASCVD.

Current place in therapy
The ACC has placed PCSK9 inhibitors as third line after statins plus ezetimibe have failed to lower LDL-C enough. Only after that should a PCSK9 inhibitor be considered. Many insurance companies follow this recommendation. They will require the patient try and fail at least 2 high-intensity statin medications (ie, atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg) and, preferably, with ezetimibe 10 mg. Failure can be defined as either intolerant to the medication or inability to achieve goal LDL-C.

Intolerance can be defined as muscle aches or pains or some other form of allergic reaction. The insurance companies will want you to define each patient’s specific intolerance to the statin medication.

If they had myalgias, were there elevated creatinine kinase levels or evidence of rhabdomyolysis? Did the myalgia resolve with discontinuation of statin therapy? Were they challenged again at a lower dose? These are all questions that must be answered and documented to get to insurance approval.

Working closely with nursing staff will help immensely and keep the process very smooth for the patient. Always remember, you will need specific documentation.

Which patients are the best candidates for PCSK9 inhibitors?
Today, the best candidates for PCSK9 inhibitors fall into 1 of the 2 indications above, plus they need to have tried 2 or more statin therapies and/or ezetimibe, fibrates, niacin, and colestipol.

These patients have either not been able to tolerate these medications due to myalagias, nausea, rash, or even sexual dysfunction, or they have failed to achieve their LDL-C goal while on a maximally tolerated statin. If the patient is intolerant to cholesterol-lowering medications, you will need specific documentation, including strength, length of therapy (including dates), and reason for discontinuation.

Maximum benefit of PCSK9 inhibitors can be achieved when used with a statin medication and diet modifications. Statins work via preventing synthesis of cholesterol by inhibiting HMG-CoA reductase, thus reducing cholesterol levels in hepatic cells. This inhibition results in the upregulation of LDL-receptors to bind to LDL-C.

PCSK9 inhibitors then help prevent the breakdown of LDL-receptors; thus, increasing the uptake of LDL-C into the hepatocyte and causing maximum LDL-C lowering. Therefore, those patients who can tolerate even a little bit of statin (ie 2 to 3 doses per week or Red Yeast Rice 600 mg twice per day) will see the maximum benefit when adding a PCSK9 inhibitor to their therapy. These medications are fully humanized monoclonal antibodies and are considered junk protein by the body.

When they are done working, the body’s macrophages just come along and eat them up. They are not excreted from the body through the liver or kidneys. Thus, there is no need to worry about dose-adjusting due to renal or hepatic impairment and, in turn, no drug-drug interactions like we see so often with statin medications. Lastly, patients who have primary hyperlipidemia or mixed dyslipidemia, have not had a cardiac event, and do not have familial hypercholesterolemia, are not good candidates for PCSK9 inhibitors at this time.

Currently, PCSK9 inhibitors do not have an indication for this patient population, so we would not want to recommend these medications to these patients. But, this may change as outcomes data become available for these medications.

How do we get them approved?
The insurance companies have proven to be the most difficult obstacle in getting these medications to the patient. The prior authorization process has been very cumbersome and has many cardiology offices frustrated and discouraged. Here is where specialty pharmacy can make an impact. Many of these offices have never had to deal with specialty medications and are unfamiliar with the process. Having a specialty pharmacy they can rely on to help guide them through the process can be very beneficial.

Since the beginning of 2016, the prior authorization process has gotten better for these medications, as most insurance companies now have criteria in place for which patients they want to cover.

The prior authorization forms are going 1 of 2 ways:
  1. very specific, and if the patient does not fit the criteria exactly, then they will be denied
  2. very vague, and if you do not include the information they are looking for, even though they do not ask for it, they will deny the patient
For the vague prior authorization forms, it is imperative that you include ALL of the following:
  • all of the patient’s cardiac diagnosis (most patients will have multiple)
  • which medications they have been on, including strengths and, if possible, dates they took the medication
  • corresponding LDL-C levels while on the different medications If you receive a denial, do not be discouraged.
Many companies have been very open to the appeal, especially if the patient fits all of the criteria mentioned above. Be sure to read the denial letter from the insurance company, carefully, before drafting an appeal letter to know the exact reason the medication is being denied. A simple letter (1 or 2 pages maximum) explaining your patient’s case against the denial reason will be enough. Sometimes the denial letter is really disguised as a request for more information, therefore, providing the requested information will be enough.

No ezetimibe? No problem
The top denial reason received is due to the patient not having a history of ezetimibe usage. Many companies want patients to have tried and failed ezetimibe before approving PCSK9 medications. Based on the 2013 AHA/ACC guideline, the addition of non-statin therapies may be considered for those patients who are unable to tolerate a high-intensity statin, or who are completely statin intolerant.

But, we know non-statin therapies are not proven to provide any risk reduction of an ASCVD event. For ezetimibe, it will only lower LDL-C approximately 10% to 20% more on top of the statin. If this amount of LDL-C lowering will not get the patient to their goal LDL-C, then there is no need to wait on using a PCSK9 inhibitor to do a trial with ezetimibe. If the prior authorization for the PCSK9 inhibitor only has a yes or no option for ezetimibe usage, then, unfortunately, you will have to mark, no, and explain your case later in an appeal.

An appeal letter has been very successful in getting this denial overturned. Stating the above facts, and therefore preventing the patient from having a PCSK9 inhibitor with a proven LDL-C reduction of 50% to 77%, so they can try ezetimibe, a medication not recommended for a patient with this medical history, is delaying the patient from getting proper therapy, as ezetimibe will not provide enough LDL-C reduction.

Approved, now what?
Depending on the patient’s prescription insurance coverage, they may have to get the medication from their insurance-mandated specialty pharmacy. For commercially insured patients, there are copay cards available through the manufacturer for both products. For Medicare Part D patients with high copays, there are some patient assistance programs available for those patients who qualify. If funds have been exhausted through these programs, both manufacturers have foundation programs available for these patients if they meet the income requirements.

Current PCSK9 Inhibitors available:
  • Praluent (Alirocumab) – Made by Sanofi and Regeneron
    • available as 75-mg/ml or 150-mg/ml syringes or auto inject pens
  • Repatha (Evolocumab) – Made by Amgen
    • available as 140-mg/ml syringe or auto inject pen or a 420-mg/3.5-ml pushtronex system 
More PCSK9 inhibitors on the horizon
Bococizumab, made by Pfizer, is currently in phase 3 trials and expected to come to market later this year.

Unanswered questions for PCSK9 inhibitors
Managed care organizations suggest this new class of drugs could add considerable costs to a relatively cheap statin therapy. As of now, treatment with PCSK9 inhibitors targets high-risk patients who cannot reach appropriate LDL levels with statins alone; however, some studies are looking into monotherapy with PCSK9 inhibitors, as well, to see if they can get the same LDL-C lowering and risk reduction.

The most important question that needs to be answered is how low is too low for LDL-C levels. With patients dropping rapidly from 200 mg/dL LDL-C down to 30 mg/dL LDL-C within a matter of weeks, what are the effects this change has on the body? What is the recommendation when a patient LDL-C drops below 30 mg/dL?

We’ve already seen this in practice, and thoughts on the management of these patients differs between providers. Full cardiovascular outcomes and risk-reduction studies are pending for release early next year. The results of these studies will decide the fate of the PCSK9 drug class in the future, and how the care of high-risk cardiovascular patients are managed going forward.