PCSK 9 Inhibitors: A Short History and a New Era of Lipid-lowering Therapy

INTRODUCTION

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD).

The discovery of the relationship between lipids, cholesterol, and atherosclerosis was made in the 1960s,[1] leading to the discovery of lipid-lowering drugs, including statins (co-enzyme A reductase inhibitors). Statins are the most common drug that lowers cholesterol, but they do not work for everyone. Statins are effective at lowering cholesterol and protecting against a heart attack and stroke, but they may lead to side effects for some people such as:

1. Muscle pain – One of the most common complaints of people taking statins is muscle pain. Researchers have found a “nocebo” effect, i.e. people who have negative expectations about a medication report experiencing the side effect at higher rates than the drug should cause. It has been found that the actual risk of developing muscle pain with statins is about 5% or less compared with taking a drug that does not contain statin. An interesting finding is that nearly 30% of people stopped taking statin because of muscle aches even when they were taking a placebo. Therefore, a strong predictor patients' experience muscle aches when taking statins could be whether or not could be if they read about the potential side effect

2. Liver damage – Liver function test may be high, but liver problems are rare

3. Type 2 diabetes – The increase in blood sugar is mild, and patients should not stop taking statins because of a mild increase in blood sugar

4. Neurological side effects – The Food and Drug Administration (FDA) warns on statin labels that some people might develop memory loss or confusion, but there is limited evidence to prove a cause–effect relationship. There is evidence that statins may actually help with the brain function such as people with dementia, but this finding is still being studied.

Some patients who are at high risk of developing CVD and who are on statins just stop taking the drug because of perceived side effects (especially muscle pain) or their cholesterol is resistant to statins. Hence, there is a need for alternative potent lipid-lowering agents.

PCSK9: A brief history

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is interesting. Nabil Seidah, a researcher in Montreal, Canada, identified PCSK9 encoded by a gene on chromosome 1.[1] Collaborating with a French group, they found out that a gain-of-function mutation in that gene was responsible for familial hypercholesterolemia in a French family. This was followed by similar findings from other researchers, in particular, from Oslo, Norway.[2]

In contrast, findings from the Dallas Heart Study showed that loss-of-function mutations in PCSK9 gene in a subset of Afro-Americans were associated with very low cholesterol levels and markedly reduced incidence of CVD.[3]

The above-mentioned exciting findings were followed by the development of several strategies to inhibit the protein or RNA using monoclonal antibodies. Hence, the search for inhibiting PCSK9 pathway continues.

A new era of lipid-lowering therapy

PCSK9 inhibitors are a new class of drugs that lower low-density lipoprotein (LDL), or “bad,” cholesterol. PCSK9 inhibitors are set to revolutionize the management of atherosclerotic risk. There are two FDA-approved medications: alirocumab (Praluent) and evolocumab (Repatha).

Studies show that PCSK9 inhibitors have a powerful effect and in some cases can actually prevent heart attacks or strokes. They can be taken on their own or in addition to a statin. However, they are also much more expensive than other cholesterol drugs.

Guideline recommendations and consensus statements now endorse the use of PCSK9 inhibitors as appropriate second- or third-line agents or as an alternative therapy in cases of complete statin intolerance, for patients with established atherosclerotic CVD or familial hypercholesterolemia with persistent hypercholesterolemia.

The importance of cholesterol and other lipoproteins

Cholesterol is vital to health and well-being, but excess cholesterol in the bloodstream is a key contributor to artery-clogging plaque, which can accumulate and set the stage for a heart attack. Most cholesterol in the body is made in the liver and the intestines. Both the liver and intestines make about 80% of the cholesterol needed to stay health. Only about 20% comes from food. Although we measure cholesterol production in the blood, it is found in every cell of the body. It is also used to make Vitamin D, hormones (including testosterone and estrogen), and fat-dissolving bile acids.

Our bodies' package cholesterol and other lipids into protein-covered particles (lipoproteins) that mix easily with blood and move cholesterol and other fats throughout the body. Cholesterol and other lipids circulate in the bloodstream in several different forms (very LDL, LDL, high-density lipoprotein).

The liver clears cholesterol and LDL build-up from the body.

Mechanism of action of PCSK9 inhibition

PCSK9 is found in chromosome 1 and mutation in that gene causes familial hypercholesterolemia.[1] Since this fact has been confirmed by numerous investigators, strategies to inhibit PCSK9 are therefore highly desirable. The enzyme encoded by the PCSK9 gene is primarily expressed in the liver.

PCSK9 is a proprotein convertase which is involved in the degradation of LDL receptors in the liver. Mutations in the PCSK9 gene cause familial hypercholesterolemia in a subset of patients by reducing the number of LDL receptors on the surface of hepatocytes. This decreases their ability to clear LDL-cholesterol from plasma. Conversely, other PCSK9 mutations result in unusually low concentrations of plasma LDL-cholesterol and a reduced risk of atherosclerotic disease. Blocking the activity of PCSK9 with monoclonal antibodies reduces the degradation of LDL receptors and increases the clearance of LDL-cholesterol. An injection of PCSK9-specific antibody suppresses LDL-cholesterol concentrations for several weeks.[4]

Receptors in the liver that remove cholesterol are destroyed by PCSK9, which increases cholesterol level. Inhibiting or blocking PCSK9 protein from acting will free more receptors to clear away LDL-cholesterol, thus lowering the amount of cholesterol measured in the bloodstream. PCSK9 inhibitors cut cholesterol levels by an average of 50%–60%.

The two FDA-approved medications are alirocumab (Praluent) and evolocumab (Repatha). They are given as shots every 2–4 weeks. The drugs were shown to reduce the risk of heart attack by 27%.[5]

CONCLUSION

As evidence supporting their ability to improve cardiovascular outcomes continues to mount, PCSK9 inhibition use will undoubtedly continue to expand, given the size of the target population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.