When a new class of cholesterol drugs called PCSK9 inhibitors was introduced three years ago, it was heralded as a potential breakthrough, particularly for people at high risk of heart attack or stroke. Those powerful new drugs can dramatically reduce LDL (bad) cholesterol, even in people with a genetic condition resulting in very high LDL levels.
But the bigger question has been whether, like statins, they can prevent cardiovascular complications and result in additional benefit on top of a high-intensity statin. That issue has now become clearer.
What the research says
A major clinical study found that one PCSK9 inhibitor, evolocumab (Repatha), when added to a statin, reduced patients’ risk of heart attack, stroke, or death from cardiovascular causes by 20 percent over two years versus taking a statin alone.
All study participants were at high risk of complications because they had a history of heart attack, stroke, or symptomatic peripheral artery disease (pain in the legs and feet caused by narrowed arteries). They also had additional risk factors such as high blood pressure and diabetes.
The findings, published in The New England Journal of Medicine in 2017, were hailed as proof that PCSK9 inhibitors could deliver on their promise. At the same time, there is reason for caution: The benefits of evolocumab were not as dramatic as heart experts had hoped. And no one yet knows how PCSK9 inhibitors will stack up over time, in terms of both benefits and side effects.
There is also a looming practical issue — PCSK9 inhibitors cost nearly $14,000 a year, and insurers have largely balked at paying, unless a patient is deemed to be high risk and still has elevated LDL cholesterol while on the highest tolerated conventional lipid-lowering therapy. Statins, widely available as generics, are a fraction of the cost.
Here is what’s known, and what still needs to be understood, about the new cholesterol medications.
How they work
PCSK9 inhibitors were developed based on research showing that a protein in the blood, proprotein convertase subtilisin–kexin type 9 (PCSK9), is key to the liver’s ability to clear LDL cholesterol from the body. The medications are monoclonal antibodies that bind to PCSK9 proteins in the blood and in the liver, allowing more LDL to be shed from the body.
Besides evolocumab, the U.S. Food and Drug Administration in 2015 also approved another PCSK9 inhibitor, alirocumab (Praluent). Both are administered by injection, either every two weeks or once a month. FDA approval came after studies showed that the drugs reduced LDL cholesterol levels by up to 70 percent.
Officially, the medications are approved for people with familial hypercholesterolemia—a genetic condition that causes very high LDL — and patients with clinical atherosclerosis (such as a history of heart attack or stroke) who need additional lowering of their LDL cholesterol. The drugs are intended to be used with a statin at the highest tolerable dose, along with dietary changes.
Measuring the benefits
While PCSK9 inhibitors can clearly drive down LDL cholesterol levels, the critical question remained: Can they prevent heart attacks and strokes? The answer, at least with evolocumab, seems to be yes.
The evolocumab study was a randomized control trial known as FOURIER. The trial, funded by Amgen, the drug manufacturer, involved more than 27,000 patients with clinical atherosclerosis and LDL cholesterol levels of 70 mg/dL or higher. All were already on statin therapy. Researchers randomly assigned them to add either evolocumab or placebo injections.
Over the next two years, out of roughly 13,780 patients in each group, 816 evolocumab patients — or just under 6 percent—had a heart attack or stroke, or died of cardiovascular causes. That compared with 1,013 placebo patients—or just over 7 percent.
Patients taking evolocumab also fared better when it came to a broader measure of cardiovascular complications. It included not only heart attacks and strokes but also unstable angina and the need for angioplasty or bypass surgery.
Evolocumab patients were 15 percent less likely to suffer one of those problems—1,344 patients, or just under 10 percent, did so, versus 1,563 placebo patients, a little over 11 percent.
Examining the risks
While the FOURIER trial showed that adding evolocumab to a statin can be beneficial, the difference in those complication rates between the two groups was relatively small. So is the potential benefit worthwhile? To help figure that out, the risks must be considered.
During the study, skin reactions around the injection site were the only side effect seen. Patients on the drug had no higher rate of muscle pain or weakness. They also did not show a higher rate of new onset diabetes, which is important since statins have been linked to a slightly heightened risk of that disease. The trial found no evidence of so-called neurocognitive effects such as memory loss or confusion, at two years of follow-up.
However, other research suggests there is still reason for concern. An analysis of 11 studies published in 2017 in Circulation: Cardiovascular Quality & Outcomes revealed a slightly higher rate of neurocognitive problems among patients given PCSK9 inhibitors versus those on other cholesterol drugs or a placebo.
The risk turned up in two large trials designed to follow the safety of evolocumab and alirocumab for up to 1.5 years. Few patients developed memory or thinking problems—there were just 45 reports of neurocognitive “events” among more than 4,500 patients on the PCSK9 inhibitors.
These events included delirium, cognitive and attention disorders, and disturbances in thinking and perception, with no evidence those conditions were caused by the PCSK9 inhibitors. Still, that compared with only eight reports among the 2,227 patients who were not on the drugs. Thus the findings raise a potential safety issue that needs further study.
The price tag
At this point, PCSK9 inhibitors have not been widely prescribed. That is partly because doctors have been waiting for evidence that the drugs actually prevent heart attacks and strokes on top of standard therapy. But it’s also because the drugs are expensive and not all insurance plans provide coverage for them.
With the results of the FOURIER trial, the tide may shift. Amgen, the drug’s maker, has even offered insurers an unusual money-back guarantee: If a patient suffers a heart attack after a certain period on the drug, Amgen will reimburse the cost of the drug.
However, it’s still not clear how PCSK9 inhibitors will ultimately fit into standard care. Results from an ongoing trial of alirocumab have not yet been published.
And a study published in 2017 in PLOS One argued that for PCSK9 inhibitors to be financially worthwhile, their cost will have to be substantially lowered — by more than 70 percent to about $4,000 a year. Only time will tell how the battle for insurance coverage will play out.
Are the new drugs for you?
Statins remain the standard of care for most people with high cholesterol levels. But for others at high risk, it is reasonable to consider adding a PCSK9 inhibitor.
A prime candidate would be someone with clinical cardiovascular disease—such as a history of heart attack, unstable angina, or stroke—whose LDL-C levels have not responded as well as expected to statin therapy at the highest tolerable dose.
The American College of Cardiology (ACC) recommends that those patients might need additional therapy if statins fail to cut their LDL in half. Our medical experts recommend trying a statin plus ezetimibe first, along with improving lifestyle habits. If this fails to reduce LDL-C, injections of a PCSK9 inhibitor could be considered.