These Experimental Treatments Helped Lower Cholesterol for 6 Months to a Year

A male patient looks at a screen with a female physician helping him.
Experimental treatments may help people lower their cholesterol for long periods of time. Leo Patrizi/Getty Images
  • Two experimental treatments offer promise for people who are genetically predisposed to having high cholesterol.
  • One treatment uses the CRISPR gene-editing system to make a small change in a gene involved in the production of LDL (or “bad”) cholesterol.
  • A second study blocks the production of a messenger RNA involved in the manufacture of lipoprotein(a).

Almost two in five American adults have high cholesterol, according to the Centers for Disease Control and Prevention, which increases their risk for heart disease and stroke.

Many factors can lead to high cholesterol, including health conditions such as obesity and type 2 diabetes, as well as smoking, eating a diet high in saturated fat and trans fat, and not getting regular physical activity.

Genetics also plays a role — if you have a close family member with a history of high cholesterol, you are more likely to have it as well. In some cases, people may have dangerously high levels of cholesterol as a result of their genes.

Two experimental treatments target people with this kind of genetic predisposition to high cholesterol, who may struggle to manage their cholesterol levels with diet, exercise and drugs such as statins.

The treatments were described in early-stage research presented Nov. 12 at the American Heart Association’s scientific meeting in Philadelphia.

While the two treatments used different approaches, both led to a reduction in cholesterol levels, which could potentially prevent heart attacks and strokes.

Longer-term clinical trials are needed before these treatments could be approved by the Food and Drug Administration. 

Dr. Spencer Kroll, an internal medicine specialist and lipidologist with the Kroll Medical Group in Morganville, New Jersey, said, “these are very exciting and promising treatments that will target patients who conventional therapy may not be working for.”

In addition, “the length of time that these therapies work is longer than any treatment currently on the market. And in the case of the CRISPR [gene-editing] study, it’s potentially lifelong, which is extremely meaningful,” said Dr. Yu-Ming Ni, a cardiologist and lipidologist at MemorialCare Heart and Vascular Institute at Orange Coast Medical Center in Fountain Valley, Calif.

Neither Kroll nor Ni were involved in the new studies.

Small change to a gene

One study included 10 people with a genetic condition called heterozygous familial hypercholesterolemia, which causes very high levels of cholesterol from birth, and increases the risk of developing coronary artery disease or having a heart attack.

This condition affects an estimated three million adult patients in the United States and Europe, according to Boston-based Verve Therapeutics, Inc., which conducted out the research.

“As a lipidologist, I take care of a lot of patients with [familial hypercholesterolemia], and their risk for cardiovascular disease is quite high,” Ni told Healthline. “Oftentimes, people present with cardiovascular disease before they even know they have familial hypercholesterolemia.”

In the study, researchers used the CRISPR gene-editing system to edit a single base pair in a gene called PCSK9, which is involved in the production of LDL (low-density lipoprotein) cholesterol, sometimes called “bad” cholesterol.

A base pair is the fundamental unit of DNA. This kind of precise gene editing is known as base editing.

The gene-editing medicine was infused into patients and the editing took place in liver cells inside the body. This resulted in the permanent deactivation of the PCSK9 gene.

The main goal of the study was to test the safety of the treatment, so patients were given different doses of the medicine.

Three patients who were given higher doses also saw their LDL cholesterol decrease by up to 55%, which lasted during the 6 months of follow-up.

In an earlier study done in monkeys, the LDL cholesterol reduction lasted 2.5 years after a single treatment.

“Although we have medications that can be given to people with an elevation of LDL cholesterol, this treatment provides a long-term change, so the patients will potentially never need medication again for that,” Kroll told Healthline.

However, he cautions that the study was small, so larger clinical trials will be needed.

While the treatment is promising, the study raised some safety concerns. 

Two participants had heart-related events, including one who died from a heart attack about five weeks after the infusion, and another who had a non-fatal heart attack the day after treatment.

An independent safety board determined that the first event was not related to the treatment, the company reported. The second event, which occurred shortly after dosing, was “potentially related” to the treatment, the board determined.

The company will continue to follow participants in this study for another 14 years, as required by the FDA for gene-editing therapies.

One concern with gene-editing treatments is the occurrence of “off-target” edits, changes in other locations in the genome, or DNA. This could potentially disrupt or activate another gene, which might lead to a harmful outcome such as cancer.

Verve reported that liver cells treated in the lab with the gene-editing medicine showed no evidence of off-target editing.

Another question is whether the benefits of this kind of gene-editing treatment outweighs the risks and cost, especially when considering alternative treatments.

Other gene therapies have focused on conditions where there are few highly-effective treatments. For example, the FDA is poised to approve a gene-editing treatment for sickle cell disease later this year.

But there are already safe, effective and low-cost drugs that lower cholesterol and reduce the risk of heart disease.

In spite of that, Ni thinks there is still a need for better treatments for people with familial hypercholesterolemia, because some patients may not be able to tolerate the current drugs long-term, requiring them to undergo more intensive treatments.

“I find it really challenging at times to manage patients with familial hypercholesterolemia, but it’s gotten easier because we have more options available,” he said. “So there’s therapeutic value in something like this, even for patients where there are other treatments available.”

Targeting product of gene

The second study, which was published Nov. 12 in JAMA, included 48 people with high levels of lipoprotein(a)

Lipoprotein(a) causes plaques to accumulate in the arteries, which increases the risk of having a heart attack or stroke. Levels of this molecule are approximately 70% to 90% due to genetics, so lifestyle changes such as diet and exercise have little effect.

The heart-related risks of high levels of lipoprotein(a) are so strong that Ni tests many of his patients for this marker. He also encourages others to talk with their doctor about whether they should get tested, especially those with a family history of early-onset cardiovascular disease, or who have very high cholesterol.

In an early-stage clinical trial presented at the AHA meeting, participants were given an injection of lepodisiran, which reduced their level of lipoprotein(a) by as much as 96% within two weeks, with levels remaining up to 94% below baseline for 48 weeks. The results above were seen with the highest (608 mg) dose of lepodisiran.

“What’s nice about this is that [a single dose of] the medication is effective for a long time,” said Ni, “in this case for almost a year, which is really remarkable.”

In addition, Kroll thinks lepodisiran may hold promise for more immediate use, because gene-editing therapies may take longer to be approved by the FDA due to safety concerns.

This treatment also targets people whose genes increase their cholesterol levels, but in a different way than the first study.

Lepodisiran is a small interfering RNA (siRNA), which blocks the messenger mRNA (mRNA) needed to make a key part of lipoprotein(a) in the liver.

mRNA is a molecule found in cells that corresponds to a single gene, and provides instructions for making a specific protein. So by blocking this mRNA, lepodisiran blocks the production of a protein needed to make lipoprotein(a).

This study was meant to test the safety of lepodisiran. No safety issues were identified, with the main adverse effects being mild reactions at the injection site.

The study was sponsored by drugmaker Eli Lilly and Company.

Impact on heart attack and stroke risk

Although both new treatments were able to lower LDL or lipoprotein(a) levels, neither study looked at whether this also reduced people’s risk of heart attack and stroke.

Based on how the drugs work, these kinds of longer-term heart-related benefits might be expected. In fact, cholesterol-lowering statins have been shown to also reduce the risk of cardiovascular disease events.

However, Kroll cautions that not every promising drug works that way.

“We’ve had lots of therapies that we know lower LDL cholesterol, but some of them have been shown to not actually lower a person’s cardiovascular risk,” he said.

Additional long-term studies are needed to “know that the medication is not just changing the LDL level, but that people are having fewer heart attacks, strokes and hospitalizations,” he said.


Two studies presented at the American Heart Association’s annual scientific meeting highlighted experimental treatments targeted at people genetically predisposed to having high cholesterol.

One treatment uses the CRISPR gene-editing platform to change a single base pair in a gene involved in the production of LDL cholesterol, also known as “bad” cholesterol. This reduction lasted up to 6 months.

The second treatment blocked the production of a messenger (RNA) that contains instructions for a protein needed for making lipoprotein(a). The effects lasted for almost a year.

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