A new oral drug could become an alternative to statins to lower cholesterol

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Scientists are working on new treatments that can help lower cholesterol. PeopleImages/Getty Images
  • Researchers studied an experimental cholesterol drug in cell lines and mice.
  • The drug reduced LDL cholesterol by 70% in mouse models of hypercholesterolemia.
  • The researchers noted that their new drug may 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 hypercholesterolemia, followed by PCSK-9 inhibitors. PCSK-9 is an enzyme that marks low-density lipoprotein (LDL) receptors for degradation.

LDL receptors are found on the surface of liver cells to remove cholesterol from the blood. PCSK-9 inhibitors thus reduce cholesterol levels by maintaining higher levels of LDL receptors that remove cholesterol from the blood.

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

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

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

“This is of exceptional interest because so far we have only seen the benefits of nitric oxide therapies on blood vessel health,” said Dr. Rigved Tadwalkar, board-certified cardiologist at Providence Saint John’s Health Center in Santa Monica, Calif., which was not involved in the study, says Medical News Today.

“Given that some people have or perceive side effects from statins, this could be an alternative, although we would first need to see how the drug would fare against other established therapies with respect to clinical outcomes at longer term.”
Dr. Rigveda Tadwalkar

The study was published in Cell reports.

Nitric oxide (NO) reduces cardiovascular risk by improving function of blood vessels, arterial pressureand Diabetes. However, studies suggest that NO has little impact on cholesterol.

Previous research demonstrates that a molecule derived from NO regulates cellular lipid biosynthesis in yeast.

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

To begin, they studied the effects of a compound derived from NO on human cell lines. They found that the molecule could moderate PCSK9 levels.

The researchers then explored the effects of a molecule derived from NO, AL-1576, on mouse models. After four weeks of oral treatment, their LDL and HDL cholesterol were reduced by 50% and 20%.

They then tested the compound in mouse models of hypercholesterolemia. 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 inhibitor molecules could potentially treat hypercholesterolemia.

To understand how the new treatment works, DTM speak withDr. 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 prevent PCSK9 secretion.

He said this decreases circulating levels of PCSK9, which in turn reduces the number of LDL receptors that are “turned off” and leaves 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 dilating blood vessels. We show that nitric oxide inactivates PCSK9, thereby increasing the removal of bad cholesterol,” said Dr. Jonathan Stamler, Professor of Cardiovascular Innovation, Medicine and Biochemistry at Case Western Reserve University School of Medicine, lead author of the study. DTM.

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, said DTM:

“PCSK9 inhibitors reduce cholesterol levels by increasing the removal of bad cholesterol (LDL-C) already circulating in the blood by the liver. This is a different mechanism than statins, which lower cholesterol levels by reducing the liver’s production of cholesterol from dietary fat.

Dr. Tadwalkar added that although PCSK9 inhibitors and statins work in different ways, the “outcome is the same, i.e. [increased numbers] LDL receptors.’

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

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

“The studies were mostly done 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 seemed promising in animals but then didn’t work and got lost in translation in humans,” he said.

“The biggest question I have about this approach is the specificity of PCSK9, as I imagine other proteins are influenced by SCoR2 and, So, by his inhibition. This raises questions about the safety of this approach, which clearly should be tested preclinically and clinically.
– Dr. Dan Rader, professor of molecular medicine at Penn Medicine, also not involved in the study, speaking to DTM

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

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

Low HDL cholesterol levels are linked to an increase cardiovascular risk and the risk to various forms of cancer.

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

“PCSK9 not only targets LDL receptors for degradation; it is also involved in the degradation of MHC 1 on lymphocytes, which is used for the recognition of cancer cells. PCSK9 effectively prevents your lymphocytes from recognizing cancer cells. So if you inhibit PCSK9, you can strengthen the body’s cancer surveillance,” Dr. Stamler said.

“There may be an opportunity one day to apply these new drugs to this need,” he added.

Dr. Chattergee said that while PCSK-9 can degrade MHC-1 on lymphocytes, reducing PCSK-9 can also reduce cancer cell recognition. He added, however, that studies show that PCSK-9 improves the effectiveness of some colorectal cancer treatments.

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

“Furthermore, studies show that alirocumab, an antibody against PCSK-9, does not affect inflammation, [thickening of scar tissue], [formation of new blood vessels] etc The jury is therefore out on the use of PCSK-9 inhibition in the treatment of cancer,” 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 cholesterol treatment.

“Cancer and heart disease have many similar risk factors. The hypothesis here is entirely a hypothesis and has no proven cause/effect at this time,” she said. DTM.

“The bottom line is that this lab science is still a long way from becoming a potential therapy in everyday medical practice for heart disease or anything else. The science still builds on what we’ve learned previously and on how we can better understand and use it.
— Dr. Shannon Hoos-Thompson

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