PCSK9 inhibitors, a new type of therapy, have arrived and appear to be an effective therapy for lowering LDL cholesterol to a level that exceeds the current standard of care.
Recently, the results from a clinical trial at Brigham and Women’s Hospital showed that the drug evolocumab, when combined with statins, significantly and safely reduced the risk of cardiovascular events. Today we will take a look at the new study and their strategy of lowering LDL cholesterol.
So what is evolocumab?
Evolocumab is a human monoclonal antibody that works by inhibiting proprotein convertase subtilisin-kexin 9 (PCSK9), a protein that reduces the liver’s ability to remove LDL cholesterol from the blood.
The drug was approved for use in the United States in 2016 as a co-therapy with statins and lifestyle changes for lowering LDL cholesterol in some adults with cardiovascular disease. The drug costs approximately $14,000 annually and is made by Amgen.
How low can you go?
In a new study, researchers investigated if there was a threshold level of LDL cholesterol below which reducing it had no added health benefit. They also wanted to find out if very low levels of LDL were harmful to health.
The data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) showed that patients treated with statins and evolocumab had a 20 percent reduction in the risk of death from heart attack or stroke.
The researchers found that the risk over 2.2 years declined steadily as LDL cholesterol levels fell below 20 mg/dL (0.5 mmol/L), and patients with under 10 mg/dL (0.26 mmol/L) had a forty percent lower risk of cardiovascular events than those with LDL cholesterol of 100 mg/dL or higher.
The researchers suggest, based on their findings, that there is no lower threshold level, and that the lower the level of LDL cholesterol, the lower the risk. The researchers found no negative impact on cognitive ability, reaction time or memory resulting from ultra-low LDL cholesterol levels. They also checked nine other safety indicators and found no issues.
How do reductions of LDL cholesterol slow cardiovascular aging?
As we grow older and the various damages that drive the aging process progress, inflammation and oxidative stress rise steadily, leading to the production of damaged and oxidized cholesterols that then enter the bloodstream.
These damaged molecules cause inflammation in the blood vessel walls, which prompts macrophages to arrive and clear up these molecules by engulfing and consuming them.
However, sometimes the macrophages fail and become overwhelmed by the amount of damaged cholesterol and either die outright or become immobilized and dysfunctional, lodged in the blood vessel wall. This then creates more inflammation and draws in more macrophages, which can also suffer the same fate. Over time, the numbers of macrophages stuck in the blood vessel walls grow and are the basis of plaques and the age-related disease atherosclerosis.
The end result is these plaques narrow the blood vessels, raising blood pressure and reducing the flexibility of the tissue, and they can break off and cause heart attacks and strokes. Such cardiovascular events then lead to crippling injuries that can leave people disabled or kill them outright.
The formation of these plaques cannot be avoided completely regardless of diet and lifestyle; they accumulate sooner or later in everyone who lives long enough. Slowing the formation of these plaques is only really delaying that, not resolving the underlying problem.
One possible solution would be to find ways to break down the plaques directly and safely dissolve them to reduce inflammation and open the blood vessels again to reduce blood pressure once more. These are the approaches that rejuvenation biotechnology is developing to tackle the problem at the root cause.
Therapies like PCSK9 inhibitors are an intriguing line of research and are indeed better than nothing, as interfering in the process of plaque formation does delay the inevitable. However, only by targeting the core reasons that plaques form in the first place might we achieve the best outcome – the permanent eradication of heart disease.
 Giugliano, R. P., Pedersen, T. R., Park, J. G., De Ferrari, G. M., Gaciong, Z. A., Ceska, R., … & Mach, F. (2017). Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. The Lancet.