Identifying Appropriate Patients for PCSK9 Inhibitors

Cheryl Allen, BS Pharm, MBA; Bryan Bray, PharmD, CPP; Jeffrey Dunn, PharmD, MBA; Jennifer Reiter, PharmD, BCPS, BCACP, BCADM; and Peter L. Salgo, MD, discuss the challenges in identifying appropriate hypercholesterolemia patients to treat with proprotein convertase subtilisin/kexin type 9 inhibitors.

Peter L. Salgo, MD: If you were to create the perfect, or right patient, for these drugs, who’s that right patient?

Cheryl Allen, BS Pharm, MBA: Familial. Genetic.

Peter L. Salgo, MD: Identify a familial hypercholesterolemia patient.

Cheryl Allen, BS Pharm, MBA: If there’s documentation of genetic disease, that should bypass any sort of prior authorization and go straight to therapy.

Jeffrey Dunn, PharmD, MBA: Or significant risk factors with elevated low-density lipoprotein levels (LDL) who are on a statin.

Peter L. Salgo, MD: You’re going to want somebody who’s got familial hypercholesterolemia. The effect of familial hypercholesterolemia is to raise your cholesterol, and we assume that the cholesterol being high is the risk factor (not the gene, per se, unless there’s other alleles in there that are doing strange stuff). If you’re treating this cholesterol and not the gene, why don’t you just treat on the cholesterol?

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: I may be digressing a little bit. We have the perfect patient in practice. That LDL on maximum statin, rosuvastatin 40 mg, can’t get any higher than that. The LDL is still above 180 mg/dL. Assuming adherence, the patient had an 8-year-old nephew with an LDL greater than 300 mg/dL. We didn’t do genetic testing but, clearly, there is familial hypercholesterolemia. The drug was approved—no problem. The patient can’t get it. It costs $300, out-of -pocket, a month. So, we kind of went back a little bit.

Jeffrey Dunn, PharmD, MBA: But see, that’s the no-brainer patient.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: That’s the no-brainer patient.

Jeffrey Dunn, PharmD, MBA: That fits the evidence, but what do we do if we have somebody with no risk factors? They’re on a low-dose statin, or maybe they’re not on a statin, and they have a LDL of 120 mg/dL, or 130 mg/dL. Given the cost of this, what do we do with that?

Bryan Bray, PharmD, CPP: I think with the data with the study that was done in patients with coronary vascular disease, the additional LDL reduction is a positive thing. That kind of cleared that up a little bit.

Peter L. Salgo, MD: Well, let’s examine that patient, because I really want to examine the challenges and identify these appropriate patients. If the LDL is 300 mg/dL, everybody is going to treat. Family history—everybody with that 300 mg/dL—no-brainer. But you brought up the 120 mg/dL LDL patient that’s not on a statin. Is there anybody here who wouldn’t insist on a statin trial first?

Jeffrey Dunn, PharmD, MBA: Or let’s say they’re on a statin but they’re on a moderate statin, or they were on a statin and they discontinued due to, again, perceived side effects. Do you re-challenge with a statin? Do you try to educate? Do you try to go down that path again?

Cheryl Allen, BS Pharm, MBA: It should be multiple statins. Enough statins with nuances from a side effect perspective.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: I completely agree. In the absence of true rhabdomyolysis, I think they should be tried on multiple statins.

Peter L. Salgo, MD: Let’s be precise. Rhabdomyolysis is a very dangerous disease. But we can call muscle cramps and muscle pain “pre-rhabdomyolysis”, if you will, because once you’ve got rhabdomyolysis, you’ve got renal failure and all heck is breaking loose.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: Right.

Peter L. Salgo, MD: Are you actually implying that there’s a category of patients in whom the side effects are worse than other patients?

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: Oh, certainly.

Peter L. Salgo, MD: But they’re all having side effects, and that’s going to affect what you brought up, which is total intolerance, right? Patients are going to go off these drugs if they have any of the side effects.

Jeffrey Dunn, PharmD, MBA: That’s a challenge. How do you define statin-intolerance? That is a huge, huge issue.

Bryan Bray, PharmD, CPP: There’s 3 categories. There’s myalgias, myositis, and rhabdomyolysis. And some of those patients will have elevated CKs (creatine kinases) in addition to their symptoms, but then there’s also data that shows that perhaps patients that might have just the myositis end of it or the myalgia part of it could also continue to be getting muscle damage. So, it leaves us in a conundrum that if a patient starts to complain (we do this in private practice all the time), and they run through 5 or 6 statins, in every one of them (they have muscle pain), you can’t treat them and then you’re left with nothing left to treat the patient. Then, we’re putting patients on combinations of lower effective medications to try to get some LDL reduction.

Peter L. Salgo, MD: But I want to come back to the patient who just won’t take it. That is to say it sounds mild to us, as clinicians, and pharmacists, and payers, in the sense of, all right, “You just have a little muscle pain or something else that you just didn’t like about it. You can’t get anything else. We’re insisting you take it because it’s mild.” But to the patient, that’s a lot. They’re going to stop it, right?

Cheryl Allen, BS Pharm, MBA: They will. I think about changing the statin therapy, though. You said 6. I don’t know that you have to go to 6, but definitely 2 or 3. Because what we find at times, just as a pharmacist, is working with patients, you do see different responses to statin therapy.

Jeffrey Dunn, PharmD, MBA: There are hydrophilic statins. There are others that have better side effect profiles. The point that I’m trying to make in bringing that up was that in the studies (the outcome studies that we have with the PCSK9s) are on a statin. If we’re following the medicine, we need to have those patients on a statin. And there are a bunch of options now. There are better tolerated statins. We want them on a statin because it’s the combined benefit of these drugs that are driving the reduction in events. At least that’s the data that we have.

Peter L. Salgo, MD: Well, that’s what the research was done on.

Jeffrey Dunn, PharmD, MBA: Exactly.

Peter L. Salgo, MD: And, of course, I’m going to ask a question for which there’s no good answer. There is no good research on patients without statins on these drugs long-term, right? It just hasn’t been done, which doesn’t mean they’re not effective. It just means the research isn’t there. Are you going to deny people these drugs simply because the investigators didn’t construct the survey that way?

Cheryl Allen, BS Pharm, MBA: Certainly, patients are being denied, today.

Jeffrey Dunn, PharmD, MBA: Because of the cost of the drugs.

Jennifer Reiter, PharmD, BCPS, BCACP, BCADM: I think on the muscle symptoms with statins, we don’t want to discount the importance of the initial assessment of the patient before they’re started, making sure that we’re checking thyroid levels, and vitamin D levels, and those underlying causes for muscle symptoms, to get a good baseline assessment. I think that’s often overlooked in these patients. And so, we start them on a statin when they’re already at high risk for having muscle problems for different reasons. That’s really important to keep that in mind.

Peter L. Salgo, MD: When I hear of an LDL cholesterol level of 20 mg/dL, I get a little worried. That’s not physiologic, right? That is infra-physiologic. Is there, even though (as far as we can tell) there’s no threshold below which there is no observable improvement, a number that scares everybody? How low is too low?

Cheryl Allen, BS Pharm, MBA: I don’t think we know that number.

Bryan Bray, PharmD, CPP: Well, we know that 30 mg/dL is okay in the current study.

Cheryl Allen, BS Pharm, MBA: Well, that’s 2-year study data.

Bryan Bray, PharmD, CPP: Yes, a 2-year study. We know it is okay, at least in the 2-year study. I think it’s still to be debated. With the longer outcome studies, I think we’ll have a little more information on that. Until that comes out, I think people get nervous with it. Certainly, at 20 mg/dL, I would be nervous about that.

Peter L. Salgo, MD: I’d be nervous, I think, unless I had 10-year data. We’re not going to get 10 years for the next 8 years, at least.