PCSK9 Inhibitors: A Novel Treatment for High Cholesterol

Illustrated by Parveen Dhanoa

High cholesterol is one of the most prevalent health issues in the U.S. and is a major risk factor for heart disease, which is the leading cause of death in this country. According to the CDC, about one-third of American adults have high or borderline high levels of cholesterol (1). Of the three components of cholesterol— triglycerides, high-density lipoproteins and low-density lipoproteins—high levels of low-density lipoproteins (LDL) is known to increase the risk of developing heart problems. LDL cholesterol is known as “bad” cholesterol since it can build up in the walls of arteries, causing them to become hard and narrow. This reduces blood flow and increases the risk of artery blockage, which can cause a heart attack or stroke. Current treatments for high cholesterol, while generally effective, can cause significant side effects for many patients. The development of a new therapeutic agent, utilizing PCSK9 inhibitors, has given high hopes to researchers to address this major concern since these inhibitors are able to significantly reduce LDL levels and potentially reduce the risk of heart disease. 

Currently, statins, a class of cholesterol-lowering drugs, are prescribed for people with high cholesterol. These drugs have been around since the 1980s and have proven to be quite reliable and effective for most people. Despite this, many patients are unable to reach optimal LDL cholesterol levels. One study of over 9950 patients with coronary heart disease revealed that only 37 percent were able to achieve optimal levels of LDL cholesterol even though most of them were on statin therapy (2). Some patients are unable to achieve these treatment goals due to factors that limit the effect of statins in the body, such as type 2 diabetes, and adverse effects such as muscle aches and liver damage, which leads patients to stop taking statin drugs. Others, such as those with familial hypercholesterolemia, a genetic disorder resulting in high levels of LDL cholesterol, are likewise unable to achieve optimal levels of LDL cholesterol even with high intensity statin treatment (3). Due to these unmet needs, a new treatment is needed to ensure that optimal LDL cholesterol levels are attainable. 

PCSK9 inhibitors are a new class of drugs that allow patients to achieve these optimal LDL levels. PCSK9 is an enzyme in the liver that binds to and degrades specific receptors on the liver cells that are needed to break down LDL. With less of these receptors, LDL levels remain high. PCSK9 inhibitors work by inactivating the PCSK9 enzyme, resulting in an increase in receptor availability which increases capture and break down of LDL (4). There are multiple approaches that are able to inhibit the PCSK9 enzyme; however, the most successful approach has used monoclonal antibodies. Since the antibodies in testing are fully human monoclonal antibodies, the likelihood that an immune response occurs in response to the antibody and the development of antibody inhibitors is low (4). This quality improves the safety and effectiveness of this treatment.

The results of several clinical trials using PCSK9 inhibitors to lower LDL cholesterol have shown remarkable success and have established these inhibitors as a viable alternative to statins. One recent phase 3 trial involving 27,564 patients with atherosclerosis, who were not at optimal LDL cholesterol levels and were receiving statin therapy, revealed that the PCSK9 inhibitor reduced LDL cholesterol levels by approximately 60 percent. About 87 percent of the patients were able to achieve optimal LDL cholesterol levels. PCSK9 inhibitors were also able to reduce the risk of heart attack, stroke, and other heart complications by 21 to 27 percent, indicating that this therapeutic is able to reduce the risk of cardiovascular events. A two year follow-up further revealed that optimal LDL cholesterol levels were sustained (5). Another clinical trial evaluating PCSK9 inhibitors in 803 patients with hypercholesterolemia revealed a reduction in LDL cholesterol levels by 52 percent in patients not receiving statin therapy and 59 percent in patients who were (6). Together, these results provide evidence of the effectiveness of PCSK9 inhibitors, especially in patients who do not respond well to statins. 

The results of these clinical trials have enabled PCSK9 inhibitors to gain approval by the FDA and be available on the market. In 2015, the FDA approved the first PCSK9 inhibitor alirocumab which was followed by evolocumab later that year. Since 2019, both of these drugs have been approved to prevent heart attack and stroke (7). These treatments would consist of a subcutaneous injection that can be self-administered once or twice a month. Inclisiran, a new PCSK9 inhibitor still pending approval, would only need to be taken once or twice a year (8). Statins, on the other hand, must be taken daily. Overall, alirocumab and evolocumab are considered to be quite safe with only minor side effects, of which the most common are redness, pain or itching near the injection site (5). Currently, one of the biggest limitations to these inhibitors are their high costs. While prices have been reduced by 60 percent since they have been released, they are still relatively high and cost much more than statins (9). The low cost of statins makes it unlikely that PCSK9 inhibitors will become the standard of care anytime soon.

Given the prevalence of high cholesterol and heart disease, the development of PCSK9 inhibitors as a new form of cholesterol management is crucial in improving cardiovascular health and outcomes. PCSK9 inhibitors represent an effective treatment addressing the unmet needs of many patients in the case where statins have shown to be ineffective. With PCSK9 inhibitors as a viable alternative to statins, more patients are able to achieve optimal LDL cholesterol levels and maintain their cardiovascular health. Perhaps in the future, given further price reductions, these inhibitors will become the new standard for lowering cholesterol. While they might be limited to certain at risk groups currently, PCSK9 inhibitors provide a lot of hope for improving cardiovascular outcomes in future patient populations.

Written by: Rehan Mehta
Edited by: Soyi Sarkar
Illustrated by: Parveen Dhanoa

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