Daily statin use to lower cholesterol may soon be a thing of the past. A new study reveals how a vaccine successfully lowered "bad" cholesterol in mice and reduced atherosclerosis, which is a narrowing of the arteries caused by a buildup of plaque.
The vaccine is called AT04A and has already entered a human clinical trial, which is expected to deliver results by the end of this year.
If the vaccine is found to be safe and effective in humans, researchers say that it would offer a long-term therapeutic strategy for high cholesterol; rather than taking statins every day, patients could simply have an initial injection, followed by an annual booster.
LDL cholesterol is often referred to as "bad" cholesterol; high LDL levels can lead to atherosclerosis. This is the accumulation of fatty deposits, or plaque, in the arteries. Over time, plaque buildup can cause the arteries to narrow, restricting blood flow.
Vaccine targets PCSK9 enzyme
High LDL cholesterol is a major risk factor for cardiovascular diseases. Statistics show that people with high LDL cholesterol are around twice as likely to develop heart disease - the leading cause of death in the U.S. - than those with lower LDL cholesterol.
Lifestyle changes, such as adopting a healthful diet and partaking in regular exercise, can help to lower LDL cholesterol levels, but some patients may also require medication.
Statins remain the gold standard of cholesterol-lowering therapy. This class of drugs helps to lower LDL cholesterol by inhibiting a cholesterol-producing enzyme in the liver called HMG-CoA reductase.
While statins are effective for lowering cholesterol, they are not without risk, with side effects including muscle pain and liver damage. What is more, statins need to be taken on a daily basis, a regimen that is hard for some patients to follow.
In the new study - recently published in the European Heart Journal - Dr. Günther Staffler and colleagues describe the development of a vaccine that targets and blocks the activity of an enzyme called Proprotein convertase subtilisin/kexin type 9 (PCSK9).
Produced by the liver, PCSK9 is known to bind to LDL cholesterol receptors. This stops these receptors from clearing LDL cholesterol from the blood. As such, blocking PCSK9 is considered a promising strategy to lower LDL cholesterol.
Total cholesterol levels halved in mice
Dr. Staffler and team reveal how, when injected, their AT04A vaccine produces antibodies that target PCSK9 and stop it from functioning. This increases LDL receptor activity, enabling them to clear LDL cholesterol from the blood.
The researchers tested the vaccine in mice that had high LDL cholesterol and atherosclerosis, induced by consumption of a high-fat, Western-style diet.
When injected under the skin of the rodents, the team found that the AT04A vaccine led to a 53 percent reduction in total cholesterol levels, compared with unvaccinated mice, as well as a 64 percent reduction in atherosclerosis-related blood vessel damage.
What is more, the vaccine led to a 21 to 28 percent reduction in biological markers of blood vessel inflammation.
Importantly, the researchers found that the antibodies produced by the vaccine remained high and functional throughout the entire 18-week study period, suggesting that it has long-term benefits.
"As antibody concentrations remained high at the end of the study, it can be assumed they would continue to reduce cholesterol levels for some time afterwards, resulting in a long-lasting effect, as has been shown in previous studies," says Dr. Staffler.
Human clinical trials started
Based on the success of AT04A in mouse studies, a phase I clinical trial of the vaccine began in 2015, which involves 72 healthy adults. The trial is due to be complete by the end of this year.
"If these findings translate successfully into humans, this could mean that, as the induced antibodies persist for months after a vaccination, we could develop a long-lasting therapy that, after the first vaccination, just needs an annual booster," says Dr. Staffler.
"This would result in an effective and more convenient treatment for patients, as well as higher patient compliance."
Dr. Günther Staffler
While the AT04A vaccine shows promise, researchers stress that it is very important to determine the long-term safety of this therapeutic strategy.
"In particular, reductions in total cholesterol via statins and other drugs are associated with an increase in new-onset diabetes," write Prof. Ulrich Laufs, of Saarland University in Germany, and Prof. Brian Ference, of the University of Bristol in the United Kingdom, in an editorial linked to the study.
"Therefore, one potential safety concern for long-term lowering of LDL cholesterol with a vaccine directed against PCSK9 is the potential for an increased risk of new-onset diabetes," they add. "In the short-term, the LDL cholesterol-lowering effect of statins and PCSK9 inhibitors appears to far outweigh the risks of new-onset diabetes."