by Mary E. Gearing
figures by Kristen Seim

Heart disease is the number one cause of death in the United States [1]. Today, patients with a family history of heart disease or risk factors such as elevated “bad” cholesterol (low-density lipoprotein or LDL cholesterol) are commonly treated with statin drugs such as Lipitor, which decrease the amount of cholesterol a person makes. Although statins effectively control cholesterol levels in many patients, they are also associated with multiple side effects, notably muscle pain, joint pain, and an increased risk of diabetes. Patients whose cholesterol levels do not respond to statins have limited treatment options [1].

Over the past decade, the buzz has been growing around a new type of heart disease drug. These new drugs, which could enter the market in just a few months, block a protein called PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 lowers the amount of LDL the liver can remove from blood and subsequently break down. When PCSK9 is inhibited, the liver can efficiently metabolize LDL, lowering cholesterol levels in blood. Since it was first associated with high cholesterol levels in 2003, PCSK9 has quickly become an important drug target with multiple clinical trials currently in progress [2-4]. Earlier this year, two studies showed a 50% reduction in cardiovascular events such as heart attack and stroke in patients taking statins with a PCSK9 inhibitor compared to those receiving statins only [4-6]. News media and pharmaceutical companies are hailing PCSK9 inhibitors as the next wonder drugs. Are PCSK9 inhibitors worth the hype?

Cholesterol’s path through the body and the discovery of PCSK9

Cholesterol is an essential molecule in our bodies that is primarily synthesized by the liver. The liver packages cholesterol, fats (triglycerides) and a protein called ApoB together as very low density lipoprotein (VLDL) (Figure 1). As VLDL travels through the bloodstream, it delivers fat to various organs and becomes LDL, which contains more cholesterol and fewer triglycerides (Figure 1). LDL is called “bad” cholesterol because it can stick in the arteries, forming plaques that increase the risk of heart attack and stroke. Lucky for us, the low-density lipoprotein receptor (LDL receptor), located on the surface of liver cells, can bind LDL and clear it from the blood (Fig. 1). A good analogy is to think of the LDL receptor as a mop that cleans up sticky LDL.

Figure 1. Liver cholesterol dynamics. The liver packages VLDL and exports it to the blood, where it delivers fat to other tissues and becomes cholesterol-rich LDL. LDL is then mopped up from the blood by the LDL receptor located on the surface of liver cells.

Mutations can affect the ability of a protein to perform its normal function in the body. You might expect that mutations in the proteins ApoB or LDL receptor could increase an individual’s risk for high cholesterol, and you’d be correct! A severe, inherited form of high cholesterol called familial hypercholesterolemia (FH) can be caused by mutations in either of those two genes. In 2003, scientists showed that two mutations in PCSK9, which had not been previously linked to cholesterol metabolism, can also cause FH [7].

In 2004, scientists studying PCSK9 in mice noticed that it lowered the number of LDL receptors in the liver, decreasing the total amount of LDL mopped up from the blood. After an LDL receptor mops up LDL, it is normally recycled back to cell’s surface to continue its job (Figure 2). However, PCSK9 was found to block that recycling. When PCSK9 is present, LDL receptors are destroyed rather than recycled (Figure 2). Overall, PCSK9 decreases the total amount of LDL receptors, thus increasing LDL cholesterol in blood and raising a person’s risk of heart disease. Considering that PCSK9 was originally discovered as a regulator of cell death in the brain, this function was unexpected to say the least!

Figure 2. PCSK9 can degrade the LDL receptor. If the LDL receptor is not bound to PCSK9, it can be recycled back to the cell surface to continue removing LDL from the blood. If PCSK9 binds, it leads to the degradation of the LDL receptor inside the liver cell.

If high PCSK9 levels increase cholesterol levels, low PCSK9 levels should decrease cholesterol levels and the risk of heart disease. This turned out not only to be true, but more exciting than anyone could have imagined. In 2005, two inactivating, or “loss of function,” mutations in PCSK9 were discovered. Individuals with one functional copy of PCSK9 and one mutated copy (representing about 2% of the study population) had 40% lower cholesterol levels than people carrying two functional copies of PCSK9 (63 vs. 105 milligrams per deciliter of blood) [3,8-9]. For reference, optimal LDL levels are below 100 mg/dL, with 130 marking borderline high levels and a higher risk for heart disease, and 160 or higher associated with an even greater increase in heart disease risk [1]. Inactivated PCSK9 decreases LDL so much that one rare individual with two inactive copies of PCSK9 has LDL levels of 14! [3,8-9]. Researchers then examined a long-term study of heart disease risk to compare risk in participants with and without these inactivating mutations. Not only was an inactivating PCSK9 mutation associated with a 15-28% reduction in LDL, but these patients also had a whopping 47-88% reduction in heart disease risk [3,10]. In addition, their very low cholesterol levels do not appear to cause any negative effects elsewhere in the body. This study, published in 2006 in the New England Journal of Medicine, cemented the status of PCSK9 as a very attractive and potentially lucrative drug target.

What are the new drugs targeting PCSK9?

Drugs come in many different shapes and sizes; the new PCSK9 inhibitors belong to a class of drugs called antibodies.You may have heard that antibodies help our immune system fight off infections; they do this job by recognizing and binding to specific proteins found in viruses and bacteria. (Generally speaking, an antibody can bind only one protein, so we have many different antibodies.) The PCSK9 inhibitor antibodies were designed to cover part of PCSK9 that usually interacts with the LDL receptor. When the antibody is bound to PCSK9, PCSK9 can’t bind the LDL receptor, so the receptor is recycled to the cell’s surface, ready to mop up more LDL (Figure 3). Antibodies are an example of targeted therapy: they interact with a specific protein and may cause fewer side effects than other drugs. Unfortunately, antibodies can’t be taken in pill form, as they would be destroyed during digestion. Instead, they must be injected, which is less convenient than oral administration and may also cause pain at the injection site.

Figure 3. PCSK9 inhibitors work differently than statins. Statins block the liver from producing cholesterol. Since the liver can no longer make cholesterol, it must take it up from the blood using its LDL receptors. PCSK9 inhibitors directly block PCSK9 binding to the LDL receptor to prevent LDL receptor degradation. LDL receptor levels are higher with PCSK9 inhibition than with statin treatment.

Clinical trial data published earlier this year can help us compare statins, the standard therapy for heart disease, and PCSK9 inhibitors. Amgen conducted a clinical trial of over 4,000 patients, assigning them to receive a statin or a statin with a PCSK9 antibody inhibitor. The results were striking: LDL levels in the PCSK9 group were about 1/3 of those in the statin only group (48 vs. 120 mg/dl), marking an improvement to optimal levels from borderline high levels. After only 11 months of monitoring, the risk of cardiovascular events such as heart attack or stroke was decreased by 50% in the PCSK9 group (0.95% vs. 2.18% of patients suffered an event) [4,5]. Sanofi’s trial of a different PCSK9 antibody in over 2,000 patients showed equally strong results: treatment with a statin and a PCSK9 inhibitor reduced cholesterol by 62% compared to a statin with a placebo. They initially planned to just examine cholesterol levels, but when they analyzed the data, they found a similar 50% reduction in cardiovascular events (1.7% vs 3.3%) [4,6]. These preliminary data indicate that PCSK9 inhibitors are effective in combination with statins in patients at a high risk for heart disease.

How soon will PCSK9 inhibitors be available?

For the 55-60% of patients who respond well to statins, there is no reason to switch treatment course until we have much more information about these PCSK9 inhibitors. Statins and their side effects are well understood, and inexpensive generic versions are available. PCSK9 inhibitors, on the other hand, will likely be very expensive, and thus limited to patients at highest risk for cardiovascular events.

Metabolism is very complex, and we do not yet have the data to understand the long-term effects of PCSK9 inhibition. Given that humans with PCSK9-inactivating mutations are healthy, drug companies are optimistic that PCSK9 inhibitors (and the very low LDL levels they enable) will be safe. However, one area of concern is neurocognitive effects, including delirium and dementia, which are associated in low frequencies with statin treatment. These effects seemed to occur more frequently with PCSK9 inhibitor treatment, but they were still limited to a small population (Amgen – 0.9% vs. 0.3%; Sanofi – 1.2% vs. 0.5%). The total number of neurocognitive events across both studies was small (PCSK9 inhibitors – 45/4526; statin only – 8/2277), but larger trials will help drug companies and the FDA to determine the safety profile of these PCSK9 inhibitors, and if adverse effects are more common in certain groups [4-6]. Other drug companies are pursuing different strategies of PCSK9 inhibition, so other approaches may win the safety and efficacy challenge.

Although much remains to be learned, PCSK9 inhibitors have already cleared a number of hurdles, and they may someday be widely used to prevent heart disease. This summer, the FDA will decide whether to approve Amgen and Sanofi’s PCSK9 inhibitors. It’s hard to believe that just twenty years ago, no one knew PCSK9 played a role in cholesterol metabolism (Figure 4). The story of PCSK9 is a testament to the role of basic science research in developing new therapies to treat human disease.

Figure 4. A timeline of PCSK9 biology. 20 years ago, PCSK9 was not known to influence cholesterol levels. Today, it’s a major drug target that could change the way we treat heart disease. PCSK9 could be a true biomedical science success story, with important contributions from human genetics and other basic science fields paving the way for rational drug development.

Mary E. Gearing is a Ph.D. candidate in the Biological and Biomedical Sciences Program at Harvard University.


Numerous healthcare organizations, including the Mayo Clinic (ref. 1) and the American Heart Association, have excellent resources on statins and heart disease.

The New York Times has covered PCSK9 research very thoroughly ( For the latest PCSK9 drug news, try FierceBiotech ( If you’d like a detailed review of PCSK9 research, please read “The PCSK9 decade” (ref. 2).

1. Mayo Clinic. Diseases and Conditions: Heart disease. (2014).

2. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. (2012). Journal of Lipid Research. (free article)

3. Kolata G. Rare mutation ignites race for cholesterol drug. (13 July 2013). New York Times.

4. Pollack A. Tests of cholesterol drugs offer hope of reducing heart attacks and strokes. (15 March 2015) New York Times.

5. Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. (2015). New England Journal of Medicine.

6. Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New England Journal of Medicine. (2015).

7. Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics. (2003).

8. Cohen J, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genetics. (2005).

9. Hall SS. Genetics: A gene of rare effect. (2013). (free summary article)

10. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine. (2006). (free article)

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