New oral drug may become alternative to statins to lower cholesterol

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Scientists are working on new treatments that could help lower cholesterol. People Images/Getty Images
  • Researchers tested an experimental cholesterol drug on cell lines and mice.
  • The drug lowered LDL cholesterol by 70% in high cholesterol mouse models.
  • The researchers noted that their new drug could one day provide an alternative strategy for lowering cholesterol.

Almost 40% of adults in the United States have high cholesterol, which increases the risk of several health problems, including heart disease and stroke.

Statins are the most common treatment for high cholesterol, followed by PCSK-9 inhibitors. PCSK-9 is an enzyme that marks low-density lipoprotein (LDL) receptors for degradation.

LDL receptors sit on the surface of liver cells to remove cholesterol from the blood. Thus, PCSK-9 inhibitors lower cholesterol levels by maintaining higher levels of LDL receptors that remove cholesterol from the blood.

Currently, PCSK-9 inhibitors are limited in use because they must be administered as injections. Further research on them could expand their use as an alternative to statins.

Recently, researchers conducted preliminary research into the ability of a nitric oxide-derived molecule to lower cholesterol by inhibiting PCSK-9 enzymes in cell and mouse models.

Their experimental treatment lowered PCSK9 levels and lowered LDL cholesterol in mice by 70%.

“This is of exceptional importance because so far we have only seen benefits from nitric oxide-based therapies for blood vessel health,” said Dr. Rigved Tadwalkar, a board-certified cardiologist at Providence Saint John’s Health Center in Santa Monica, California, who was not involved in the study, told WebMD. Medical News Today.

“Since some people have or experience side effects from statin medications, this could be an alternative, although we first need to see how the drug would compare to other established therapies when it comes to longer-term clinical outcomes.”
— dr. Rigved Tadwalkar

The study is published in Cell reports.

Nitric oxide (NO) reduces cardiovascular risk by improving blood vessel function, blood pressureand diabetes mellitus. However, studies suggest that NO has little impact on cholesterol.

Previous research shows that an NO-derived molecule regulates cellular lipid biosynthesis in yeast.

So the researchers sought to see if a similar molecule could regulate blood lipid levels in human cell lines and mice.

To begin with, they investigated the effects of an NO-derived compound on human cell lines. They found that the molecule could moderate PCSK9 levels.

The researchers next examined the effects of an NO-derived molecule – AL-1576 – on mouse models. After four weeks of oral treatment, their LDL and HDL cholesterol had dropped by 50% and 20%.

They then tested the compound on high-cholesterol mouse models. After eight weeks of treatment, their LDL and HDL cholesterol dropped by 70% and 25%, respectively.

The researchers wrote that their findings suggest that orally administered PCSK-9 inhibitory molecules could potentially treat high cholesterol.

To understand how the new treatment works, MNT talked toDr. Murray W. Huff, professor emeritus in the Departments of Medicine and Biochemistry at the University of Western Ontario, who was also not involved in the study.

Dr. Huff noted that the drug observed in this study works by targeting an enzyme in the liver that leads to a cascade of cellular events that prevents PCSK9 from being secreted.

He said this lowers circulating levels of PCSK9, which in turn reduces the number of LDL receptors that are “turned off,” leaving more LDL receptors that lower LDL cholesterol levels.

“Our drug works by increasing a molecule called nitric oxide, which is known to prevent heart attacks by widening blood vessels. We show that nitric oxide inactivates PCSK9, increasing the removal of bad cholesterol,” said Dr. Jonathan Stamler, a professor of cardiovascular innovation and medicine and biochemistry at Case Western Reserve University School of Medicine, the study’s lead author. MNT.

When asked how PCSK9 inhibitors work differently than statins, Dr. Robert Salazar, a cardiologist at Memorial Hermann in Houston, Texas, who was not involved in the study, MNT:

“PCSK9 inhibitors lower cholesterol levels by increasing the removal of bad cholesterol (LDL-C) already circulating from the liver into the blood. This is a different mechanism from statin drugs, which lower cholesterol levels by decreasing the liver’s production of cholesterol from dietary fat.”

Dr. Tadwalkar added that while PCSK9 inhibitors and statins work in different ways, the “result is the same, that is [increased numbers] of LDL receptors.’

When asked about the study’s limitations, Dr. Rob Hegele, professor of medicine and biochemistry at Western University, who was not involved in the study, MNT:

“The authors mainly describe a new pathway in the liver that regulates cholesterol levels. The effect of their new drug is almost an afterthought. The overall work is very basic and is still in a very early stage.”

“The studies have been done mainly in mice with no human studies, so it’s not even clear if these pathways are relevant in humans. There are dozens of examples in the cholesterol field of mechanisms and drugs that looked promising in animals but then failed and were lost in translation to humans,” he said.

“The biggest question I have about this approach is specificity for PCSK9, as I imagine other proteins are affected by SCoR2 and, therefore, by his inhibition. This raises questions about the safety of this approach, which clearly needs preclinical and clinical testing.”
— dr. Dan Rader, a professor of molecular medicine at Penn Medicine, also not involved in the study, speaks with MNT

Dr. Subroto Chatterjee, a professor of pediatrics and director of the Sphingolipid Signaling and Vascular Biology Laboratory, who was not involved in the study, told MNT:

“A consistent decrease (20-25%) in HDL, the ‘good cholesterol’ […] should be discussed in light of the reduced level of HDL in aging/postmenopausal women, men and a large group of patients with ‘metabolic syndrome’, type 2 diabetes and obesity.”

Low HDL cholesterol is linked to higher cholesterol cardiovascular risk and risk for different forms of cancer.

The researchers said their findings could extend beyond cholesterol and impact cancer treatments as well.

“PCSK9 doesn’t just target LDL receptors for degradation; it also mediates the breakdown of MHC 1 on lymphocytes, which is used for cancer cell recognition. PCSK9 effectively prevents your lymphocytes from recognizing cancer cells. So if you inhibit PCSK9, you can boost the body’s cancer surveillance,” said Dr. Stamler.

“Maybe one day there will be an opportunity to apply these new drugs to that need,” he added.

Dr. Chattergee said that while PCSK-9 can break down MHC-1 on lymphocytes, reducing PCSK-9 can also reduce cancer cell recognition. However, he continued, studies show that PCSK-9 improves the efficacy of certain colorectal cancer treatments.

“Cholesterol is necessary for tumor growth and metastasis. Thus, lowering cholesterol levels in cancerous tissue may be beneficial. But statin therapy has not been helpful in cancer,” he said.

“In addition, studies show that alirocumab, an antibody against PCSK-9, does not affect inflammation, [thickening of scar tissue], [formation of new blood vessels] etc. So the jury is out to determine the use of PCSK-9 inhibition in cancer therapy,” he added.

Dr. Shannon Hoos-Thompson, a cardiologist at The University of Kansas Health System, who was not involved in the study, saidthat more research is needed before the drug becomes a potential treatment for cholesterol.

“Cancer and heart disease have many similar risk factors. The hypothesis here is entirely a hypothesis and has not proven cause/effect at this point,” she said MNT.

“The bottom line is that this lab science is nowhere near becoming a potential therapy in everyday medical practice for heart disease or anything else. Science always builds on what we have learned before and how we can better understand and use it.”
— dr. Shannon Hoos-Thompson

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