Dawn of a New Era? A Cardiologist Takes Stock of PCSK9 Inhibitors

Friday could be a big day for cardiologists.

The long-awaited US Food and Drug Administration decision on at least one cholesterol-lowering PCSK9 inhibitor is due to be announced. The FDA is scheduled to say whether it agrees with its own advisory committees that it should approve alirocumab (Praluent/Sanofi-Regeneron).

The agency could also reveal its decision on a competitor drug called evolocumab (Repatha/Amgen), though that announcement is officially scheduled for Aug. 27. The Amgen product was approved July 21 in Europe.

MD Magazine asked New York City cardiologist David Vorchheimer, MD, of the Montefiore Einstein Center for Heart and Vascular Care what PCSK9 approvals could mean for physicians and patients. Vorchheimer has offices on Manhattan’s Upper Eastside, and at the Bronx-based Montefiore system’s main campus.

PCSK9 inhibitor drugs are being touted as the best thing since statins and the FDA’s advisory panels have recommended they be approved. How would you rate your level of anticipation when it comes to PCSK9 inhibitors being available?

It depends on the patient. For a large majority of patients, LDL cholesterol can very effectively be lowered with statins. For most patients PCSK9 inhibitors will not be first-line agents. But for the person who is not tolerating a statin, or who is not at goal with LDL lowering, for me, a cardiologist, this is very exciting. There is not a huge need for these drugs when it comes to the general population, but there is for a significant chunk of patients. For myself, as a cardiologist, It’s a case of enthusiasm tempered with the need to wait for more safety and efficacy data.

Some are predicting that up to 50% of people with high LDL cholesterol might use these drugs ultimately. If the FDA approves them, will PCSK9 inhibitors become blockbusters?

As with all new therapies it will take time to get safety and outcome data. If that data shows they are safe and effective, their use will expand.

Looking at your own practice, of 100 patients who need help lowering LDL cholesterol, how many would be likely candidates for PCSK9 inhibitors?

It would be three groups—patients who can’t tolerate statins, patients who are not getting to LDL goal with statins, and patients with homozygous familial hypercholesterolemia. I’d say about 10% to 15% of patients if you lump them all together. I’d start with the patients who are truly statin-intolerant then if you get good results, expand it to the next group.

How worrisome are potential neurological effects?

There’s not a lot of concern. The preliminary studies do show they have some cognitive side effects—as do statins. But the vast majority of dementia is related to vascular disease, not to Alzheimer’s, but to vascular disease affecting small vessels. That disease can be caused by high blood pressure and diabetes. Stabilizing cholesterol could actually reduce dementia related to vascular disease. As for concerns that PCSK9 inhibitors could make lipid levels too low and have an effect on cognition, look at the LDL levels in an infant.

Could you please explain?

When your brain is forming, in your first year of life, your LDL level is 40. So from an evolutionary point of view, that is a good level. Whether it rises depends on diet. In some cultures it stays at 40.

There have been concerns that so far PCSK9 inhibitors have not been shown to prevent cardiac events. Are these legitimate concerns at this stage?

Actually there are preliminary study results—though they weren’t high power studies-- showing about a 50% reduction in cardiac events. That is encouraging though they weren’t endpoint studies.

The drugs are designed to be injected, not taken as pills. How big a concern is that?

If will be an impediment, though the drug companies are working on ways to make it easier for patients. The fact that it is only necessary once every two weeks could help—but at the same time it could make it too easy for patients to forget it was time to do it.

At what LDL level do you think patients should be considered PCSK9 inhibitor candidates?

Realistically, insurance companies will set that because these drugs are going to be expensive. But except for patients with the familial high cholesterol, I’d say an LDL of around 70, though some patients would need it at a lower LDL level.

Is statin intolerance a real thing, or does it have a psychological component?

Anyone in clinical practice sees a wide range of patient responses. Some patients say they have symptoms but there is no evidence, but I believe it is not fair to characterize them as having only a mental response. I generally believe patients are telling me what’s going on.

If the drugs are approved, when will you start prescribing them?

This is an exciting time in cardiology and these drugs could have a very, very, important impact—initially for a small group but eventually greater. If they are approved Friday, I think I’ll be hearing from a patient [who wants them] on Monday.