From the LipidSpin Editor: Clinical Lipidology — Heroic Tasks

In Greek mythology Sisyphus was the king of Ephyra (now known as Corinth). He was punished for his self-aggrandizing craftiness and deceitfulness by being forced to roll an immense boulder up a hill, only to watch it come back to hit him, repeating this action for eternity.”1

It is a bit of an exaggeration to compare our task of prescribing proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors as equivalent or even similar to that of Sisyphus, but bear with me as I think this one through.

Clinical lipidology is indeed a privileged specialty. We are experts in the recognition and management of common, uncommon, and rare conditions and decoding the extreme and insidious from the gradual and benign. Our ability to perform our job well enables individuals to outlive their relatives by decades at times and many are extremely grateful even as they occasionally persevere muscle pain, bloating/constipation, flushing, every twoweek bloodletting in the rare patient, and wallet-emptying interventions.

The triumphs in cardiovascular prevention by the last generation are truly remarkable. Between smoking rates dropping from >40 to <20 percent of the U.S. population in that time frame, to the widespread use of statin therapy, it is hard not to think that we have really made a difference in individual lives, our community, and our society (note the selfaggrandizing craftiness and deceitfulness).

The advent of monoclonal antibody therapy against PCSK9 offers an opportunity to build on our successes and we have embraced this novel therapy with open arms and eager anticipation.

Given the robust data and evidence based medicine, there is a clear affirmation of the value of statin drugs in four major risk groups (adults 40–75 years old with clinical atherosclerotic cardiovascular disease [ASCVD], low density lipoproteincholesterol [LDL-C] >190 mg/dL, diabetes, or with calculated risk >/=7.5 percent over 10 years) by the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerosis Cardiovascular Disease in Adults.2 It is tempting, but premature to extrapolate the same benefits of other therapies with similar mechanism of action (up-regulation of the LDL-receptor and clearance of LDL and remnant particles resulting in total, LDL-, and non-high density lipoprotein [HDL]-cholesterol reduction). In fact, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT),3 released after the publication of the 2013 ACC/ AHA Guideline was in line with the LDL-C lowering regression observed by the CTT,4 describing the impact of LDL-C lowering on major ASCVD events in secondary prevention. This observation renewed faith in the LDL-C lowering hypothesis, which holds that therapeutic LDL-C lowering is proportional to ASCVD risk reduction, and the expected benefit is relative to the degree of risk (amount of atherosclerosis present and plaque vulnerability).

This brings me to the Sisyphus-like predicament I recognize in my own practice, and I wonder if others feel the same. I reserved the initial prescriptions to the “slam dunk” cases, so from August until December 2016, all of my PCSK9 inhibitor prescriptions were for my patients with coronary or peripheral artery disease (CAD/PAD) AND familial hypercholesterolemia AND LDL-C>130 mg/dL on high intensity statin and ezetimibe. All of the prescriptions were initially approved and once I got through the list of patients with those features, I liberalized the prescriptions. I prescribed it for patients with clinical ASCVD OR FH, with LDL-C >100 for the former, and >130 mg/DL for the latter, while on as much statin as they could tolerate and ezetimibe. Successful authorization by the insurers for this very expensive therapy has thus become more hit or miss.

Here are some of the lessons I have learned while working to treat them in this new landscape:

•  I found out that clinical ASCVD does not include patients with coronary artery calcium score >300 (or >75th percentile for age/gender despite risk categorization recognized by the 2013 ACC/AHA Guidelines), but it does include carotid obstruction >50 percent or ankle:brachial index <0.9.
•  I found out that “probable” FH is not FH in the eyes of the insurer and that a middle aged person with an LDL-C >250 mg/ dL, who has lost several first degree relatives prematurely to ASCVD does not have FH until a genetic test confirms this.
• • I found out that I can do genetic testing for as little as 100 USD outlay by the patient.
• • I found out that patients with “definite” FH do not require testing to confirm the diagnosis since it is nearly 100 percent in that population.5
• • I found out that precisely diagnosing my patients with familial combined hyperlipidemia (FCHL) means they do not have FH and I can serve them better by changing their diagnosis to FH if I want them to get a PCSK9 inhibitor.
•  •I found out that insurers believe ezetimibe is the recommended next step for someone who requires >50 percent LDL-C reduction, rather than a medicine that lowers LDL-C by 50 to 60 percent (PCSK9 inhibitors).
•  •I found out that our patients will purchase ezetimibe from Canada and that our Congress does not think it is a good idea to legalize this approach.
•  I found out that Medicare patients could get PCSK9 inhibitors for one year on assistance programs, but reauthorization and assistance beyond that is exceedingly difficult.
• • I found out that Medicare is more willing to pay for apheresis (estimated charges at our institution >200k USD/year) than PCSK9 inhibitors.
•  I found out that reams of paperwork completed last year have to be redone this year, AND PCSK9 inhibitors can be denied when patients are taking the medicine because the LDL-C is now below the threshold for approval!

 So, these are some of the arbitrary “rules” to date. None are truly medical-based, but put in place to contain costs for the payors/ shareholders and in the case of Medicare/ Medicaid, the taxpayers. Given the high cost of therapy, it is hard to find great fault with this approach. As clinicians, however, our only constituent is our patient.

Unlike Sisyphus, we will push through to the top of the hill for some of our patients. None of our patients have exactly the same characteristics, and they all deserve a clinician willing to put in the work. I am privileged to have fantastic support for the paperwork needed to prescribe this important therapy, so my personal task is less daunting, but for those of you who have to do this completely on your own, I suggest you put Sisyphus out of your mind and take on the task more like Hercules, conquering your labours with heroism and grace.

At the same time, clinical lipidologists are in a position to advocate for better therapies for our patients and as the PCSK9 inhibitor database grows, we should all expect this task to become less laborious and more applicable to a broader range of patients, and hopefully, less costly. In the meantime, I urge you to continue to embrace the challenge like a lipid hero!