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 among 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.

However, while the PCSK9 inhibitors drugs may indeed represent a major breakthrough in cholesterol-lowering, their long-term safety and effectiveness have yet to be established.

Despite the hype it is likely to be several years before doctors will be able to legitimately recommend their use in large numbers of patients.

How Do the PCSK9 Inhibitors Work?

These new 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 are then moved back 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.

The PCSK9 Inhibitors

When PCSK9 was discovered a decade ago, scientists recognized that inhibiting this protein should result in substantially reduced LDL cholesterol levels.

Drug companies immediately 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

Several clinical trials have been conducted with evolucumab (the OSLER trials) and with alirocumab (the ODYSSEY trials), which were 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.

* Read why statin drugs are “different.”

The results in all of these trials were similar - LDL cholesterol was reduced in patients receiving a PCSK9 inhibitor by about 60%, as compared to control groups. While these early trials were not specifically designed to measure improvements in cardiovascular outcomes, patients randomized to a PCSK9 inhibitor had roughly a 50% reduction in major adverse cardiovascular events after one year of treatment (from roughly 2% to roughly 1%).

Side Effects With PCSK9 Inhibitors

A majority of patients in both the treatment and control groups had side effects, including skin reactions at the injection site, muscle pain (similar to the muscle side effects of statins) and neurocognitive problems (specifically, amnesia and memory impairment). This latter side effect was seen in roughly 1% of patients randomized to a PCSK9 inhibitor.

The incidence of cognitive problems, while low, should raise major caution flags. If it is a side effect of the PCSK9 inhibitor drugs themselves, it seems likely that the risk of cognitive difficulties should remain low even with long-term use. However, if it is a side effect of driving cholesterol down to very low levels, then the risk is more likely to increase the longer the drug is used.

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 hype we will be hearing soon, we need to temper our enthusiasm for now.

First, while cardiovascular outcomes with these new drugs seem to be significantly reduced (in relatively short-term studies), the studies assessing long-term clinical outcomes are not completed, and will not be analyzed until about 2018. Until then, we can’t be sure of how much clinical benefit these drugs may provide.

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

Third, while these drugs are being talked about as a substitute for statin therapy, we should all 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.

And finally, while the cognitive problems seen with PCSK9 inhibitors in early clinical trials have been minimized in the press by enthusiastic investigators, they are nonetheless potentially alarming. The incidence, the cause, and the severity of such cognitive problems will need to be well characterized before these drugs can be used in large numbers of patients.


Sabatine MS, Guigliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; DOI:10.1056/NEJMoa1500858.

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.

Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med 2015; DOI:10.1056/NEJM1502192. Editorial

Regeneron. Regeneron and Sanofi report positive top-line results from nine phase 3 trials of alirocumab in people with hypercholesterolemia [press release]. July 30, 2014.

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