PCSK9 Inhibitors and CV Risk

The role of PCSK9 inhibitors as treatment for dyslipidemia now that statin therapies are available.


Deepak L. Bhatt, MD, MPH: Speaking of PCSK9 inhibitors, let’s turn back to Dr Budoff. I was going to say this is a new class of medicine. They’re not that new anymore but are still exciting. Can you talk a little about the PCSK9 inhibitors, how they work, who you might use them for? Dose ezetimibe still have a role with PCSK9 inhibitors around? What are your thoughts about those issues?

Matthew J. Budoff, MD: Yes. As we use our statins first, along with diet and exercise, we do have ancillary therapies that have been proven to add on to the statin background. Dr Navar already mentioned one of the trials, and that really showed us that we can get an additional 15% event reduction by adding PCSK9 inhibitors in patients with stable coronary disease. And the way that they work is complementary to statins. Statins stop the synthesis of cholesterol. PCSK9s enhance the reuptake and degradation of cholesterol.

PCSK9 is a protein developed in the liver. And basically it causes, really kills, if you will, the LDL [low-density lipoprotein] receptors on the liver. So we have a decrease in LDL receptors. The LDL floats in our bloodstream, does not get taken up by the liver, and our LDL levels stay elevated. If you block PCSK9 with these monoclonal antibodies that are very specific and have virtually no other adverse effects and work very directly at blocking PCSK9, we end up lowering that protein. We end up with many more LDL receptors, and the liver can then lower LDL. It’s pretty remarkable and consistent that the PCSK9 inhibitors lower LDL by about 60%, whether the patient is on a statin or not. For whichever PCSK9 we choose, we get an additional 50% to 60% LDL reduction by using these therapies.

So, they work. They lower events. Both trials with PCSK9 inhibitors lowered events by about 15%. They’ve been studied in stable coronary disease. They’ve been studied in patients with acute coronary syndromes. They really show incremental benefit.

Once I’ve decided to use a PCSK9 because their LDL is still too high, whatever I perceive that to be based on our targets, if I think that they’re above their given target and I can’t get there with statin monotherapy, I might try ezetimibe first. The IMPROVE-IT trial did show a small but significant benefit. But if that doesn’t get them there, then I’m fairly quick to try a PCSK9 inhibitor. And if I do that, I usually stop the ezetimibe because they’ll get to their goal almost always with statin plus PCSK9. I don’t need that additional benefit of ezetimibe anymore, and I’m a believer in less is more as far as number of therapies. I’d rather not have them on 3 cholesterol medicines if 2 will do the job.

Ann Marie Navar, MD, PhD: I have a quick correction for the audience here. Thank you, Dr Budoff, for the reminder. I misspoke. The data that I quoted are in those with stable cardiovascular disease. It was the ODYSSEY study that looked at PCSK9 inhibitors and those with more recent events. So just a quick correction on that.

Deepak L. Bhatt, MD, MPH: Oh, but you’re basically right. It’s really the class of medicines that have shown a significant effect. There are differences between the trials in terms of the population study, but they are viewed as a pair for a covered stable atherosclerosis, and ODYSSEY covered those with a recent acute coronary syndrome. And it goes back to a point I think Dr Budoff made about statins. You tend to get earlier benefits. The sicker patients tend to get more benefits, especially on harder events. In the ODYSSEY OUTCOMES trial, we actually showed a reduction in all-cause mortality. At least there was a nominally significant reduction in all-cause mortality.

So the potential of lower LDL being better extends in the right patients at high risk, even to all-cause mortality.

Dr Budoff, do you have any issues at all with injections in your practice? Have any patients said, “I’m not going to take an injection?” Because, of course, the PCSK9 inhibitors are injections.

Matthew J. Budoff, MD: I was very concerned about this when this class was first being studied. These companies came and I was participating in these trials as an investigator. I was very nervous about patients injecting themselves because we didn’t have injectables in cardiology prior to this, other than maybe a little use of Lovenox [enoxaparin] for short periods. We rarely used injectables.

I was surprised how well they are tolerated, honestly. They’re not frequent. They’re used every 2 weeks or every 4 weeks. They are self-injectors. Patients don’t have to draw up a dose, they’re premeasured. They’re a very simple injector system. They just put them on their thigh or the abdomen and hit a button. And 15 seconds later, they’re done. So I really am surprised, and I find them to be very well tolerated. I think the companies have done a nice job of making it simple for our patients to be on an injectable therapy.

Deepak L. Bhatt, MD, MPH: I agree. I haven’t found it to be as much of a barrier as I initially thought it would be.

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