Are PCSK9 Inhibitors the New Cholesterol "Miracle" Drugs?

PCSK9 inhibitors show promise, but we need a lot more information


A new class of anti-cholesterol drugs—the PCSK9 inhibitors—is creating a lot of buzz within the cardiology community, and various reports suggest these new drugs may be a great alternative for patients who have difficulty taking statins. The first two PCSK9 inhibitors—Repatha (evolucumab) and Praluent (alirocumab)—were approved for use in 2015.

The PCSK9 inhibitor drugs may indeed represent a major breakthrough in cholesterol-lowering.

However, their long-term safety and effectiveness are not yet fully established. That, and their very high cost, leaves most doctors still unsure today of their proper place in clinical medicine.

How Do the PCSK9 Inhibitors Work?

These drugs inhibit the cholesterol regulator called "proprotein convertase subtilisin/kexin 9" (PCSK9) in the liver. The surface of liver cells contain LDL receptors, which bind circulating LDL particles (which contain LDL cholesterol) and remove them from the blood. Both the LDL particles and the LDL receptors are then moved into the liver cells, where the LDL particles are broken apart. The LDL receptors then return to the surface of the liver cells, where they can “trap” more LDL particles.

PCSK9 is a regulatory protein which also binds to LDL receptors. LDL receptors bound by PCSK9 are not recycled back to the cell surface, but instead are broken down inside the cell.

Therefore, PCSK9 limits the ability of the liver to remove LDL cholesterol from the bloodstream. By inhibiting PCSK9, these new drugs effectively improve the liver’s ability to remove LDL cholesterol, and reduce LDL blood levels.

When a PCSK9 inhibitor is added to high-dose statin therapy, LDL cholesterol levels are routinely driven below 50 mg/dL, and often to 25 mg/dL or less.


The PCSK9 Inhibitors

When the PCSK9 regulatory protein was discovered in the early 2000s, scientists immediately recognized that inhibiting this protein should result in substantially reduced LDL cholesterol levels. Drug companies instantly launched into a race to develop PCSK9 inhibitors.

Remarkably, two of these drugs have already been developed and tested in clinical trials: evolucumab (Repatha, developed by Amgen) and alirocumab (Praluent, developed by Sanofi and Regeneron). Both of these drugs are monoclonal antibodies, designed to have an effect only on PCSK9, and (theoretically, at least) nowhere else. They are both administered by subcutaneous injection (like insulin therapy), and are given once or twice per month.

Clinical Trials With PCSK9 Inhibitors

Early clinical trials were conducted with evolucumab (the OSLER trials) and with alirocumab (the ODYSSEY trials), designed to assess the safety and tolerability of these new drugs.

In these trials, over 4500 patients whose cholesterol levels had proven difficult to treat received one or the other of these drugs.

Patients were randomized to receive either a PCSK9 inhibitor along with a statin drug, or a statin drug alone. Note that no patients were treated only with the PCSK9 inhibitor. All study participants received statins.

The results in all of these trials were similar—LDL cholesterol was reduced in patients receiving a PCSK9 inhibitor by about 60 percent, as compared to control groups treated with a statin alone. These early trials were not specifically designed to measure improvements in cardiovascular outcomes, but the observed outcomes in people randomized to receive a PCSK9 inhibitor looked promising. 

In late 2016 the GLAGOV study showed that, in 968 people with coronary artery disease (CAD) who were randomized to treatment with either evolocumab plus a statin or a statin alone, those receiving evolocumab experienced (on average) a 1 percent reduction in the volume of their atherosclerotic plaques—a quite favorable outcome.

The first major trial designed to evaluate clinical outcomes on a PCSK9 inhibitor, the FOURIER trial, was published in early 2017. This large study enrolled over 27,000 people with CAD, and again randomized them to receive evolocumab plus a statin versus a statin alone. After an average follow-up time of 22 months, clinical outcomes in the evolocumab group were significantly improved from a statistical standpoint, though only to a modest extent. Specifically, the risk of a heart attack was reduced by 1.5 percent, the risk of needing invasive medical therapy also by 1.5 percent, and the risk of stroke by 0.4 percent. The incidence of death was not significantly reduced. While it is likely that the magnitude of clinical benefit will improve with longer follow-up times, documenting for certain that is the case will take a few more years.

Side Effects With PCSK9 Inhibitors

In clinical studies with PCSK9 inhibitors, a majority of patients had at least some side effects—mainly skin reactions at the injection site, but adverse reactions also included muscle pain (similar to the muscle side effects of statins) and neurocognitive problems (specifically, amnesia and memory impairment). In the initial studies this latter side effect was seen in roughly 1 percent of patients randomized to a PCSK9 inhibitor.

The incidence of cognitive problems, while low, has raised some cautionary flags. In a sub-study of the FOURIER trial, there were no significant differences in cognitive function between people receiving evolocumab plus a statin, when compared to people receiving a statin alone. However, the question remains whether driving cholesterol levels to very low levels for a long period of time may increase the risk of cognitive decline, whatever drugs are used to do so. Again, longer term follow-up is needed to get a better handle on this important question.

PCSK9 Inhibitors in Perspective

The PCSK9 inhibitors may indeed turn out to be a major breakthrough in treating cholesterol, and in reducing cardiovascular risk. However, despite all the enthusiasm being expressed by many cardiologists, we should keep things in proper perspective for now.

First, while cardiovascular outcomes with these new drugs seem to be significantly improved (in relatively short-term studies), the magnitude of the improvement so far is not very large. Longer-term follow-up will be necessary to really see how much benefit these drugs produce—and, in particular, whether they will eventually provide a long-term mortality benefit. 

Second, like all modern “designer drugs” (drugs tailor-made for a specific molecular target), the PCSK9 inhibitors are very, very expensive. Their usage, at least in the initial years, will almost certainly be limited to people who are at very high risk, and whose risk cannot be substantially reduced with statins—such as people with familial hypercholesterolemia.

Third, while these drugs are being talked about as a substitute for statin therapy, we should carefully note that the clinical trials to date have used them in addition to statins, and not instead of statins. So, we actually have no clinical data to tell us whether they may turn out to be viable statin substitutes.

Fourth, while the safety profile of the PCSK9 drugs so far looks promising, there remain open questions; in particular, as to whether driving cholesterol to ultra-low levels for a long period of time may turn out to be at least partially counterproductive, especially as regards cognitive function.


Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-treated Patients. The GLAGOV Randomized Clinical Trial. JAMA 2016. DOI:10.1001/jama.2016.16951

Robinson JG, Farnier M, Krempf M, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015; DOI:10.1056/NEJMoa501031.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; DOI:10.1056/NEJMoa1615664. 

Sabatine MS, Guigliano RP, Wiviott SD, et al. Efficacy and Eafety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015; DOI:10.1056/NEJMoa1500858.

Stone NJ, Lloyd-Jones DM. Lowering LDL Cholesterol is Good, but How and in Whom? N Engl J Med 2015; DOI:10.1056/NEJM1502192.

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