Adverse Effects of PCSK9 Inhibitors in CVD



Deepak Bhatt, MD, MPH: Brett, you have used PCSK9 inhibitors in a lot of patients, and the data from the clinical trials really don’t show much in the way of adverse effects other than minor site reactions. How about in your practice? Have you seen any real-world use, any adverse effects, beyond what was described in the trials?

Brett Nowlan, MD, FACC, RPVI: No, honestly. As an overall comment, that is 1 of the strongest things to be said about the drugs in that there’s really excellent tolerance. They have a very clean adverse-effect and safety profile in general. I like to explain this to patients. If you look at the commonly listed adverse effects—things like nasopharyngitis, injection site reactions, UTI [urinary tract infection], and diarrhea—what’s important is not that laundry list but how that laundry list compares with the laundry list on placebo. Of course that’s true for all clinical trials.

When you look at that comparison, the only thing that seems to be statistically significantly different is local injection site reactions. Certainly in my experience in my practice, these are usually quite minor. They’re not a hindrance to use. If someone is having problems with those injection site reactions, I’ll often tell them to make sure the drug is out of the refrigerator and at room temperature before using. If they’re having a problem with 1 site, perhaps you can change sites to the anterior thigh or back of the arm. If it’s a recurrent problem, which is really quite uncommon, perhaps they can take a nonsteroidal anti-inflammatory by mouth 30 minutes before the injection.

One interesting thing, if there is a recurrent problem with injection site reactions, there are some data to indicate that it’s actually the incipient—the polysorbate that comes with these drugs to prevent precipitation—that may be the problem. In evolocumab it is polysorbate 80. Thankfully those don’t actually cross-react. Certainly, if you have ongoing problems with injection site reactions, it’s very reasonable to switch agents because you won’t to tend to get crossover problem. But these reactions are typically infrequent. They’re minor, and they’re typically not recurrent. I really haven’t found them a hindrance to use.

Deepak Bhatt, MD, MPH: That’s a real pearl. Jamie, did you know that about different polysorbate concentrations?

James A. Underberg, MD: I did not. But I will tell you that given the fact that there are 2 of these medicines commercially available, something I commonly do is simply changed to the other 1. They’re slightly different or slightly different preparations, and there is no reason you shouldn’t give it a try. I will tell you that over the course of the several hundred patients who I have on these medications, I have had patients complain of things that I cannot myself ascribe to the medication. But if people believe, like other medications, that it is causing a problem, you’re going to have to stop it and try something else.

In our space, when we hear about those complaints, we also dutifully have to report them because that’s the appropriate thing to do. It finds its way into the database, and it becomes available as a known adverse effect. I think that’s good as well as bad because if you think about how these drugs work, they’re not metabolized through the kidney or the liver. They’re cleared through reticular endothelial system. You really shouldn’t have any of these issues with it. My experience has been excellent tolerability, especially in patients who come to me having failed multiple other medicines. By the time they come to a referral lipidologist, they’ve tried most of the reasonable stuff.

Having a PCSK9 inhibitor available has been extremely helpful, especially for my patients with severe inherited lipid disorders and the folks with ASCVD [atherosclerotic cardiovascular disease] who are really at high risk, we know that.

Deepak Bhatt, MD, MPH: Any thoughts, Jamie, about their cost effectiveness?

James A. Underberg, MD: It’s interesting. As the price has come down, they have achieved greater cost effectiveness. The issue with PCSK9 inhibitors, from my perspective, and the cost-effectiveness space is oftentimes not related to the cost of the medication but what it takes to get the drug into the hands of the patient. Often that’s a co-pay issue. As the cost has come down, co-pay issues, especially with Medicare patients, have improved. But there are still problems sometimes with it.

We know that the patients who are prescribed PCSK9 inhibitors, who either don’t get them approved or have the prescriptions abandoned at the pharmacies—much like statin-intolerant patients—have significantly higher rates of recurrent ASCVD, MI [myocardial infarction], stroke, and combined cardiovascular end points. Getting drugs into the hands of a patient, as something that they can tolerate and be adherent to, is really important when it comes to ASCVD risk reduction—super important.

Robert Busch, MD: One of the most fun things of a phone call you can make to a patient after they’re on this is, about a month in, to ask them if they have any grandchildren. This is because, guess what, their LDL [low-density lipoprotein] is lower than their grandchild’s LDL. I enjoy making that phone call, particularly if it’s 1 digit. I’m not striving for 1 digit, but when it’s there it’s unbelievable.

James A. Underberg, MD: Yeah, absolutely.

Deepak Bhatt, MD, MPH: The results can be quite impressive. You’re quite right. That was a great discussion about reducing cardiovascular risk, in particular focusing on LDL, cholesterol, and triglycerides.

Transcript Edited for Clarity

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