The Advent of PCSK9 Inhibitors in Real Life

Patients of all ages and with all kinds of problems seek help in our busy family medicine clinic (10 providers, 33,000 visits a year), which is part of a four-clinic network of the Oregon Health & Science University (OHSU) Family Medicine Department. I work independently (although we do collaborate) from the OHSU Preventive Cardiology Division as the only lipidologist within our department, taking referrals from my colleagues.

When the U.S. Food and Drug Administration (FDA) approval dates were approaching for PCSK9 inhibitors, I contacted field medical teams of Sanofi/ Regeneron (alirocumab) and Amgen (evolocumab). I wanted both scientific information and access to pamphlets, coupons, and other resources. OHSU does not allow the dispensing of samples to patients in office. However, both companies offered assistance programs allowing patients to get started on free samples sent to their homes within one to two weeks from an office visit. They also offered help with reimbursement/insurance specialists, who were crucial to getting the patients approved by insurance.

I was preparing several of my high-risk patients for the advent of new drugs. Many of them were eagerly following the news, while others were hesitant, afraid of the “new statins.” The day after the FDA approved alirocumab, the first patient willing to embrace the new treatment was already in my office. In total, I started 13 patients on PCSK9 inhibitors. Unfortunately, three of them were denied by their insurance and thus discontinued therapy.

I always offered both PCSK9 inhibitors to my patients without recommending one over the other. So far, insurers did not have a preference, but this is likely going to change in the immediate future. My first six patients were started on alirocumab because it was the first drug available in July 2015. All were started on the lowest dose, 75 mg, every two weeks.¹ Because of their excellent response, their dose was not increased. Once evolocumab entered the market, most patients chose it over alirocumab because of the advertised 30-day storage at room temperature without need for refrigeration (vs. 24 hours for alirocumab). Most of my patients have an active lifestyle, and therefore it was a clear advantage. All patients on evolocumab used the biweekly dosing of 140 mg. Not a single patient wanted the monthly administration of three consecutive injections.² After initiation of either alirocumab or evolocumab, low- density lipoprotein cholesterol (LDL-C) and low-density lipoprotein particle (LDL-P) decreased 50 to 70 percent. I have observed no major effects on high-density lipoprotein cholesterol (HDL-C) or triglyceride levels, except in one case, when the latter increased.

Dummy autoinjectors were used to demonstrate drug administration during the initial office visit. I worked together with my patients to fill out the paperwork, including the prescription for the specialty pharmacy. Forms were changing initially almost every week. Patients could also fill out requests for free samples and financial assistance provided by the companies.

One patient came for an office visit to perform the first self-administration in my presence. Another patient was initially afraid to inject himself but, after four visits, he was comfortable enough to continue them at home. None of the other patients had any issue initiating injections at home. Patients occasionally reported minor pain/ irritation at injection sites. One patient reported cold symptoms with each injection. Even the most skeptical patients did not report any other side effects. One potential candidate for this therapy had refused the use of injectable drugs.

The FDA approval for the PCSK9 inhibitors is to use them as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL- cholesterol.”^1,2 In addition, evolocumab is indicated to treat homozygous familial hypercholesterolemia (FH).²

My patients started PCSK9 inhibitors for a range of indications. Two of them were prescribed PCSK9 inhibitors for secondary prevention. One patient had heterozygous familial hypercholesterolemia (HeFH) with coronary artery bypass grafting (CABG) at age 36 and subsequent angina while on rosuvastatin 40mg and ezetimibe 10 mg. After starting a PCSK9 inhibitor her LDL-C is now at 84 mg/dL. Another patient had recurrent coronary events after CABG followed by stenting, despite taking atorvastatin 80 mg plus ezetimibe 10 mg. His LDL-C hovered above 70 mg/dL. Now, it has been successfully lowered to 35 mg/dL.

The remaining 11 patients were prescribed PCSK9 inhibitors for primary prevention in the context of HeFH (eight) or mixed dyslipidemia (three), the latter being an off-label indication. All of them have at least some degree of statin intolerance, but only five patients reported statin-associated myalgias. One patient complained of constipation with statins, ezetimibe, and basically any drug that was not injectable. Another patient reported rashes with statins, niacin, and ezetimibe. The rest reported “clouded minds” or some degree of cognitive impairment. All of them have tolerated PCSK9 inhibitors without problems.

 Real-life prescribing of PCSK9 inhibitors means a tough fight with insurance companies. Initially, many insurers rejected the drugs because they did not fit algorithms based on the 2013 American Heart Association/American College of Cardiology (AHA/ACC) guidelines.³ Some insurers even argued that they were “experimental drugs.” With time, insurers created a more uniform application process demanding details of previously attempted therapy with statins and other agents. Application forms often request the prescription to be written by or in consultation with cardiologists, endocrinologists, or “lipid specialists.”

Such designation did not appear initially on some forms. Insurance companies were often unaware of our existence. The ability of clinical lipidologists to prescribe PCSK9 inhibitors has been now added to the forms I have seen so far, being a welcomed recognition of our specialty.

For some patients, the path to get insurance approval was easy; for others, it was not. Some became angry and frustrated. They saw excellent lipid profiles after using free samples, which turned again into bad numbers, when insurance refused the approval. Some insurers approved PCSK9 inhibitors only if the patient fulfilled Dutch Lipid Clinic Criteria for definite HeFH with a score greater than eight, refusing to accept the National Lipid Association (NLA) and AHA criteria.⁴ One of my patients had a score of eight with an untreated LDL-C of 204 mg/dL. His insurance refused him PCSK9 inhibitors despite him having an Agatson score of 390 demonstrating asymptomatic atherosclerotic cardiovascular disease (ASCVD). Moreover, his genetic testing was negative, which in the insurers view, closed the case. This patient reacted to statins with time- and dose-dependent cognitive impairment; therefore he cannot use them as they impair his work. In contrast, a different insurer provides the same drug to a patient with truly psychogenic statin intolerance with mixed dyslipidemia and a baseline LDL-C of 150 mg/dL. These two examples demonstrate striking differences in access to PCSK9 inhibitors depending on the insurance company. To get PCSK9 inhibitors approved, insurers often request fulfillment of the NLA criteria for statin intolerance.⁵ Frequently, insurers also request proof of failing ezetimibe therapy before approving PCSK9 inhibitors.

It is frustrating that insurance clerks without lipid knowledge make decisions jeopardizing patient care. They do not understand arguments about elevated Lp(a) or elevated LDL-P/apoB/non-HDL-C, following pre-set insurance algorithms. Fortunately, recently published guidance from the ACC about non-statin therapy is of help in the discussion.⁶ The return of LDL-C goals in the document clarifies what constitutes the need for “additional lowering of LDL-C.” The completion of cardiovascular outcome studies will surely provide even more arguments for a wider use of PCSK9 inhibitors. Hopefully, once bocozicumab (Pfizer) receives FDA approval, increased competition will drive their price further down.

This has been a challenging introduction of this new class of drugs. It has come with a fight. It truly challenges my resolve given the time consuming, faulty, and sometimes random criteria for approval.

Dr. Wójcik has no disclosures to report.

References are listed on page 45 of the PDF.