Dr Eliot A. Brinton: Perspectives on PCSK9 Inhibitors

Results from the FOURIER trial have provided convincing data that there is no downside to aggressively lowering cholesterol with PCSK9 inhibitors, and studies have shown there are cardiovascular benefits associated with Repatha, but reimbursement remains challenging, said Eliot A. Brinton, MD, FAHA, FNLA, president of the Utah Lipid Center.

What do the recent results published in The Lancet and presented at the European Society of Cardiology imply about the advantages of PCSK9 inhibitors?

The FOURIER trial, which was the main study of one of the PCSK9 inhibitors, evolocumab, is a landmark trial. It is the first clinical cardiovascular outcomes trial looking at this new class—there’s another on its way; we’re going to have results in the next few months—but just taking the FOURIER trial, first, what we see is proof of principle. Adding a PCSK9 to a statin is helpful in terms of additional risk reduction beyond what is available with a statin alone. But then, a very large piece, and this is both clinically and scientifically important, is the question of the relationship between LDL cholesterol measured by whatever means—usually the Friedewald—the relationship between LDL cholesterol on treatment and cardiovascular outcomes. The biggest question here is: Can LDL be too low? Is there harm, or maybe lack of benefit, in having that LDL go ever lower? And the answer from the FOURIER data is “no.”¹⁰ The benefit is there, and the harm is not there. There appears to be no such thing as [an LDL] cholesterol that is too low.

[This is] in contrast to glucose, where we have hypoglycemia, a very serious concern clinically, and hypotension, also very serious. [Those] are life-threatening situations if we are not careful. [But] for LDL cholesterol, we don’t appear to have any downside for getting that LDL below 40 [mg/dL] or even below 20 [mg/dL]. FOURIER has really given us convincing data for additional benefit and no additional harm, even for an LDL in the less-than-20 [mg/dL] range. We’ve been concerned about this. I think FOURIER is of an adequate size and adequate power to give us confidence as we go forward to ever-more-aggressive LDL-lowering treatment.

At the American College of Cardiology Scientific Sessions in March, physicians took note of the cardiovascular benefits that were seen with Repatha, as well as studies that showed the difficulty clinicians experience when prescribing PCSK9 inhibitors. Has the reimbursement experience changed in recent months for this class of therapy?

We have a wonderful new tool in the field of lipid management and that is this new class of drugs, the PCSK9 inhibitors. They are marvelous because they are so effective in lowering LDL. They work really nicely on top of a statin; if we have someone who is statin-intolerant we are still allowed to use them as long as we have given statins a fair chance. So, then the question is: Can we actually have access to these drugs? And because they are expensive, access has been a big issue. The managed-care people are able to put a few roadblocks in the way—a little extra paperwork—that does make it harder for clinicians to write a PCSK9 inhibitor. Is that getting better? Is it still an issue?

The quick answer is, in my experience, it has changed very little. Maybe we have changed a little in terms of our approach to this, possibly some of the payers are little more relaxed. We do have convincing trial data now with the FOURIER study with evolocumab; we should have similar data soon with the other drug, which is alirocumab. I’m hopeful that this will become less of an issue. But it remains a very important fact that just simply writing a prescription for a PCSK9 inhibitor does not give one immediate access to the drug. On the one hand, we know that we shouldn’t just be using this drug widely for everyone who happens to have high cholesterol. On the flip side, if we have patients who really need additional LDL lowering, [if] we have done everything possible with a statin, we’re certainly considering, in most of these cases, use of ezetimibe. [That] has now gone generic, so we have greater access to ezetimibe. In the case where patients still have a high residual LDL cholesterol level and they have high residual cardiovascular risk, then adding a PCSK9 inhibitor is a good thing to do, and access remains an important issue.