latest cholesterol research 2023

New Cholesterol Guidelines Could Drastically Reduce Statin Use for Millions

Adopting new PREVENT equations could lead to a significant reduction in statin recommendations, impacting 40% of currently eligible U.S. adults, and highlights the importance of precise risk assessment and patient communication in cholesterol management.

If national guidelines were updated to include a new risk equation, approximately 40% fewer individuals may qualify for cholesterol-lowering statins to prevent heart disease, suggests a study involving researchers from the University of Pittsburgh , Beth Israel Deaconess Medical Center , and University of Michigan . The research, published in JAMA Internal Medicine , explores the implications of broadly implementing the PREVENT equations, introduced by the American Heart Association in November 2023. These equations are intended to refine the tools doctors use to estimate a patient’s 10-year risk of a heart attack or stroke.

At a population level, the number of adults recommended for statins could decrease from 45.4 million to 28.3 million. At the same time, the study showed that most people who would be recommended to take statins are not currently taking them.

“This is an opportunity to refocus our efforts and invest resources in the populations of patients at the highest risk,” said lead author Dr. Timothy Anderson, M.D., M.A.S., a primary care physician at UPMC and health services researcher and assistant professor of medicine at Pitt.

Methodology of the Study

For their analysis, the team used nationally representative data from 3,785 adults, ages 40 to 75, who participated in the National Health and Nutrition Examination Survey from January 2017 to March 2020. The researchers estimated the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) using the Predicting Risk of cardiovascular disease EVENTs (PREVENT) equations and compared the results to risk estimated using the previous tool, known as Pooled Cohort Equations (PCE). The PREVENT equations were developed by the American Heart Association to more accurately represent risk across the current U.S. population, as the PCE equations were based on patient data that were decades old and lacked diversity.

PREVENT also reflects more recent insights into the biology of ASCVD. Current statin use as well as metabolic and kidney diseases are incorporated into the new calculation, while race has been removed from it, reflecting a growing awareness that race is a social construct.

Using PREVENT, the team found that among the study’s entire cohort, the 10-year risk of developing ASCVD was 4%, half as high as the risk calculated by the PCE (8%). The difference was even larger for Black adults (5.1% versus 10.9%) and for adults between the ages of 70 and 75 (10.2% versus 22.8%).

An estimated 4.1 million patients who are currently taking statins would no longer be recommended to take them based on PREVENT. For these patients and their physicians, clear and careful communication is key, said Anderson. “We don’t want people to think they were treated incorrectly in the past. They were treated with the best data we had when the PCE was introduced back in 2013. The data have changed.”

At the same time, it’s important to note that everyone’s risk will inevitably change over time, as well, he added. “For a patient who we now know is at lower risk than we previously thought, if we recommend they stop taking statins, they still could be back to a higher risk five years down the road, for the simple reason that everybody’s risk goes up as we get older.”

Reference: “Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations” by Timothy S. Anderson, Linnea M. Wilson and Jeremy B. Sussman, 10 June 2024, JAMA Internal Medicine . DOI: 10.1001/jamainternmed.2024.1302

Other authors on the study were Linnea Wilson, M.P.H., of Beth Israel Deaconess Medical Center, and Jeremy B. Sussman, M.D., M.P.H., of University of Michigan, Ann Arbor.

This research was supported by the National Institute on Aging (#K76AG074878).

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“…, while race has been removed from it, reflecting a growing awareness that race is a social construct.”

Statistics don’t support that naive, woke view. The social ideology behind such decisions may end up costing the lives of minorities who have a predisposition for certain diseases. Whether a particular race has predispositions for certain diseases is well established. What is less well understood is why the predispositions exist. However, be that as it may, pretending that race doesn’t correlate can be deadly because those susceptible may be less alert for symptoms. “The road to Hell is paved with good intentions.”

Everything about this study is useless. Read the article carefully and you will see all of the contradictions. When woke ideologies enter into medical research the results are corrupted .The fact is that statins are useless and dangerous. If you want to take a pill every day to lower cholesterol then take one of many natural supplements that have proven to work as well or better. Garlic and bergamot lowered my cholesterol significantly. The pharmaceutical companies have sponsored bogus studies to lie to the public about the facts. More corporate greed at the expense of our health.

Statins have been around for decades and the side effects, if any, are minimal. It is a proven fact that they are safe. I tend to trust my cardiologist more than conspiracy theories from social media. This article does not change anything for any sane person. Listen to your cardiologist.

If I’m 40 years old, I care about my 40 year risk, not my 10 year risk. Unless you are over 70, 10 year risk is extremely short sighted. My dad has always had marginally high LDL (between 100 and 130). Doctors never prescribed him statins because his 10 year risk was low. Now at age 74 he needs open heart surgery to clear plaques in the artery going to his heart. Meanwhile my mom had LDL above 250 in her 40s and was prescribed statins for decades keeping her LDL around 70-80 and her heart is perfectly fine.

If race is just a social construct, why is it hereditary?

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Researchers solve mystery of how statins improve blood vessel health

Statins designed to lower cholesterol have long been noted to work in mysterious ways to improve other aspects of cardiovascular health. A Stanford Medicine-led study uncovers how they do it.

May 8, 2023 - By Nina Bai

Researchers at Stanford Medicine and their colleagues have discovered how statins improve cardiovascular health beyond lowering cholesterol.  roger ashford/Shutterstock.com

Using new genetic tools to study statins in human cells and mice, Stanford Medicine researchers and collaborators have uncovered how the cholesterol-lowering drugs protect the cells that line blood vessels. 

The findings provide new insight into statins’ curiously wide-ranging benefits, for conditions ranging from arteriosclerosis to diabetes, that have long been observed in the clinic.

“The study gives us an understanding, at a very deep mechanistic level, of why statins have such a positive effect outside of reducing LDL,” said professor of medicine Joseph Wu , MD, PhD, referring to low-density lipoprotein, or “bad” cholesterol. “Given how many people take statins, I think the implications are pretty profound.”

Statins are the most prescribed medications in the country, with more than 40 million Americans taking them. Developed in the 1980s from compounds found in mold and fungi, statins target an enzyme that regulates cholesterol production in the liver. But clinical trials have shown that they also seem to safeguard against cardiovascular disease beyond their ability to lower cholesterol.

Heart failure patients who take statins, for example, are less likely to suffer a second heart attack. They have also been shown to prevent the clogging of arteries, reduce inflammation and even lower cancer risk. Yet these underlying mechanisms are poorly understood.

“Statins were invented to lower cholesterol by targeting the liver. But we didn’t know the targets or the pathways in the cardiovascular system,” said  Chun Liu , PhD, an instructor at the  Stanford Cardiovascular Institute  and co-lead author of the  study  published May 8 in  Nature Cardiovascular Research .  Mengcheng Shen , PhD, and Wilson Tan, PhD, postdoctoral scholars at the Stanford Cardiovascular Institute, are the other co-lead authors, and Wu is the senior author.

Hints from a dish

To take a closer look at statins’ effect on blood vessels, Liu and colleagues tested a common statin, simvastatin, on lab-grown human endothelial cells derived from induced pluripotent stem cells. Endothelial cells make up the lining of blood vessels, but in many diseases they transform into a different cell type, known as mesenchymal cells, which are poor substitutes.

“Mesenchymal cells are less functional and make tissues stiffer so they cannot relax or contract correctly,” Liu said.

The researchers suspected that statins could reduce this harmful transition. Indeed, endothelial cells treated with simvastatin in a dish formed more capillary-like tubes, a sign of their enhanced ability to grow into new blood vessels.

RNA sequencing of the treated cells offered few clues. The researchers saw some changes in gene expression, but they “didn’t find anything interesting,” Liu said.

It was not until they employed a newer technique called ATAC-seq that the role of statins became apparent. ATAC-seq reveals what happens at the epigenetic level, meaning the changes to gene expression that do not involve changes to the genetic sequence.

They found that the changes in gene expression stemmed from the way strings of DNA are packaged inside the cell nucleus. DNA exists in our cells not as loose strands but as a series of tight spools around proteins, together known as chromatin. Whether particular DNA sequences are exposed or hidden in these spools determines how much they are expressed.

“When we adopted the ATAC-seq technology, we were quite surprised to find a really robust epigenetic change of the chromatin,” Liu said.

ATAC-seq revealed that simvastatin-treated cells had closed chromatin structures that reduced the expression of genes that cause the endothelial-to-mesenchymal transition. Working backward, the researchers found that simvastatin prevents a protein known as YAP from entering the nucleus and opening chromatin.

The YAP protein is known to play important roles in development, such as regulating the size of our organs, but also has been implicated in the abnormal cell growth seen in cancer.

A look at diabetes

To see the drug in context, the researchers tested simvastatin on diabetic mice. Diabetes causes subtle changes to blood vessels that mimic the damage commonly seen in people who are prescribed statins — older patients who do not have a cardiovascular condition, Liu said. 

They found that after eight weeks on simvastatin, the diabetic mice had significantly improved vascular function, with arteries that more easily relaxed and contracted.

“If we can understand the mechanism, we can fine-tune this drug to be more specific to rescuing vascular function,” Liu said.

The findings also provide a more detailed picture of the vascular disease process, which could help doctors identify and treat early signs of vascular damage.

“I’ve been taking statins for the past 10 years to keep my cholesterol down. I also knew it has good vascular effects. I just didn’t know how it does it,” said Wu, the Simon H. Stertzer, MD, Professor who is also the director of the Stanford Cardiovascular Institute. “This study explains how.”

Researchers from the University of North Texas and the Ohio State University College of Medicine contributed to this study.

The study was supported by funding from the National Institutes of Health (grants R01 HL130020, R01 HL150693, R01 HL163680, R01 HL145676, P01 HL141084, R01 HL141371, R01 HL126527, R01 HL15864, R01 HL161002, R01 HL155282 and 18CDA34110293), an American Heart Association SFRN grant, an AHA Career Development Award and the Tobacco-Related Disease Research Program.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

Hope amid crisis

Psychiatry’s new frontiers

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• Published: 01 December 2023

Cholesterol metabolism

New insights into dietary cholesterol absorption

• Jennifer Harman 1  

Nature Reviews Cardiology volume  21 ,  page 70 ( 2024 ) Cite this article

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Research published in Science provides a breakthrough in understanding how dietary cholesterol is absorbed from the gut into the bloodstream. Aster proteins are involved in the non-vesicular transport of cholesterol to the endoplasmic reticulum (ER) in enterocytes. Pharmacological inhibition of the Aster pathway reduced dietary lipid absorption in mice, pointing towards a novel therapeutic target to lower blood cholesterol levels and reduce the risk of cardiovascular events.

Using enteroids (cultures of multiple intestinal epithelial cell types), biochemical analysis and transgenic mouse models, the investigators explored the role of Aster proteins in moving cholesterol during the absorption process. Deletion of Gramd1b and Gramd1c , encoding Aster-B and Aster-C, respectively, reduced cholesterol absorption and attenuated hypercholesterolaemia in mice fed a high-cholesterol diet. Interestingly, the researchers found that the delivery of cholesterol to the ER in enterocytes is not dependent on vesicles, the primary method of cargo delivery in the cell. Instead, the outer (cytoplasmic) and ER membranes are in direct contact. “Asters act sequentially with NPC1L1 in a two-step process of cholesterol uptake from the diet. NPC1L1 was known to deposit micellar cholesterol from the gut lumen into the plasma membrane of intestinal cells. We found that by doing so, NPC1L1 expands the pool of accessible membrane cholesterol available for internalization and simulates Aster recruitment. The recruitment of Asters thus initiates the second step in the uptake process — the movement of cholesterol from the plasma membrane to ER,” explains Ferrari. Pharmacological inhibition of Aster-A, Aster-B and Aster-C using a small molecule (AI-3d) led to cholesterol accumulation at the plasma membrane in mouse and human enteroids and reduced dietary cholesterol absorption in mice.

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Original article

Ferrari, A. et al. Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake. Science https://doi.org/10.1126/science.adf0966 (2023)

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For the first time, gene-editing provides hints for lowering cholesterol

Preliminary results from a study show that gene-editing technology can be used to successfully treat a genetic disorder that increases the risk of heart disease. Gerardo Huitrón/Getty Images hide caption

Preliminary results from a study show that gene-editing technology can be used to successfully treat a genetic disorder that increases the risk of heart disease.

For the first time, researchers have produced evidence that gene-editing can cut high cholesterol, a major risk factor for the nation's leading killer.

Preliminary results from a study involving 10 patients born with a genetic condition that causes very high cholesterol found that editing a gene inside the liver can significantly reduce levels of "bad cholesterol."

The experimental treatment needs to be tested on more patients who would be followed for much longer to confirm the approach is safe and effective. But the results are being hailed as a potential landmark proof-of-concept that could eventually provide a powerful new way to prevent heart attacks and strokes.

"These data are really very exciting," says Dr. Deepak Bhatt , director of the Mount Sinai Fuster Heart Hospital and a professor of cardiovascular medicine at Icahn School of Medicine at Mount Sinai in New York.

Bhatt, who was not involved in the research, stressed that much more research is needed to resolve important open questions. However, "this could have an enormous impact on cardiovascular disease ," Bhatt says.

Shots - Health News

Sickle cell patient's success with gene editing raises hopes and questions, a new way to treat heart disease.

The data from the highly anticipated study, which is being conducted by Verve Therapeutics, Inc. , in Boston, were presented Sunday at an American Heart Association meeting in Philadelphia.

"What we're trying to do is develop an entirely new way to treat heart disease," Dr. Sekar Kathiresan , Verve's executive officer, told NPR in an interview. "We're super excited. This is the first-ever evidence that one can actually rewrite a single DNA letter in the human liver and have a clinical effect. So we're thrilled."

But some other independent scientists also remain cautious.

"Hopefully it will work. But there are many many aspects that are really still fuzzy," including the long-term safety, says Dr. Eric Topol , a cardiologist and professor of molecular medicine at Scripps Research in California. "There's considerable uncertainty here."

Heart disease kills about 695,000 people each year in the U.S.

High levels of a form of cholesterol known as low-density lipoprotein (LDL) cholesterol narrow arteries, blocking blood to the heart and brain and setting the stage for heart attacks and strokes.

Verve studied patients born with familial hypercholesterolemia , a genetic disorder that affects an estimated 1-in-250 people , which causes extremely high LDL.

Patients can take drugs, including a popular class known as statins, to reduce LDL levels. But while those drugs are very safe and effective, many patients fail to take them regularly as needed, leaving them vulnerable. So the hope is the gene-editing treatment could not only treat those with the genetic condition, but also provide a one-time therapy for anyone at risk.

"This same medication should be helpful for any garden-variety patient without the genetic disease," says Kathiresan.

Researchers used a form of gene-editing known as CRISPR , which enables scientists to make very precise changes in DNA much more easily than ever before. Specifically, they used a newer version of CRISPR known as "base-editing," which gives scientists the power to rewrite individual letters in the genetic code.

In this case, the editing occurred in liver cells in the organ inside the body. Other approaches to gene-editing have required removing cells from the body, editing them in the lab and then infusing them back into patients.

For the trial , which is ongoing, scientists are infusing different doses of a CRISPR base-editing molecule that makes it way to the liver to edit a gene called PCSK9 , which is necessary for the production of LDL cholesterol.

Of the 10 patients treated so far, ages 29 to 69, all were in the United Kingdom and New Zealand. Only three of the patients received a dose high enough to cause a beneficial reduction in LDL. Two patients experienced reductions in their LDL levels of 39% and 48%. The one patient who received the highest dose experienced a reduction in LDL of 55% that has lasted at least six months so far.

"This is really the first-ever evidence that one can actually rewrite a single DNA letter in the liver of a living human being and have a clinical effect," Kathiresan.

Mohammed Kahn, 47, of London, was one of the most recent patients treated in the study. Kahn's father died at age 42 and two of his older brothers have already had heart attacks. Kahn's already had a procedure to treat narrowed arteries to his heart.

"It's a brilliant approach," Kahn said in an interview with NPR. "It's fantastic. I hope for the best. I'm very very optimistic that this will be working in my body."

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Cholesterol treatment is just the beginning.

Gene-editing is generating enormous excitement because the technique could lead to new treatments for many genetic diseases, including cancer, heart disease, AIDS, Alzheimer's and other ailments.

In fact, the Food and Drug Administration is poised to approve the first gene-editing treatment next month for the devastating blood disorder sickle cell disease.

"This is exciting for Verve, for the patients, but also more broadly if you look at my entire field," says Fyodor Urnov , professor of molecular therapeutics at University of California, Berkeley.

When he heard about the study's results, Urnov says, "My heart skipped a beat in a good way, in the hopes that these data are the first step towards a future where many peoples heart don't skip a beat and remain healthier for longer."

But others caution this approach faces a higher bar than the sickle cell treatment, especially because both are expected to cost millions of dollars per patient. Unlike for sickle cell, there are already very safe, effective and inexpensive cholesterol-lowering drugs for heart disease.

One key worry is the editing may cause inadvertent genetic changes known as "off-target" effects that could cause health problems years later.

"We don't know much about off-target effects of genome-editing," Topol says. "So even though this is targeting a specific gene that is tied to very high cholesterol, it could have other effects in the genome that are unintended."

"There are a lot of uncertainties. This is a very bold approach but we'll have to see," Topol says.

Statins vs. supplements: New study finds one is 'vastly superior' to cut cholesterol

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• gene editing

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• An updated test measures how well "good cholesterol" works

An updated test measures how well "good cholesterol" works

It’s the cholesterol we love to love – and for good reason.

High-density lipoprotein (HDL) cholesterol, often called “good cholesterol,” removes extra cholesterol from the arteries by gobbling up early-forming plaque and transporting it to the liver, which flushes it out of the body. It’s an essential job: when too much plaque accumulates in the arteries, it can narrow blood vessels and impede blood flow, or even rupture. This can lead to severe events, including heart attacks and stroke.

Measuring how much HDL cholesterol we have in our bodies to do these tasks has long been a mainstay of the annual physical. However, within the past decade, researchers have also found that measuring whether HDL cholesterol is doing these tasks effectively can be just as valuable. The stronger the signs that a person’s “good cholesterol” is working well, they’ve discovered, the more likely they appear to have reduced risks for heart disease in the future.

There’s been one main challenge, however. Measuring HDL function is limited to research labs and isn’t conducive to large-scale testing by routine clinical laboratories. To try to solve that problem, researchers from NHLBI’s Lipoprotein Metabolism Laboratory created a new diagnostic test.

“This is going to quicken the pace of basic research,” said Edward B. Neufeld, Ph.D. , a scientist in the lab who, along with Masaki Sato, Ph.D., developed the test. “It increases the number of samples that you can study. It increases the number of experiments you can do.”

Current HDL functional assessments require researchers to harvest cells in the lab. This has to be done in small batches, often requires extra materials like radioactive cholesterol, and can take days to process. The cell-free test that Neufeld and researchers developed could be easily replicated in labs, automated to process larger samples, and provide readings in about an hour. Importantly, they have shown in clinical studies that their test can predict cardiovascular disease risk better than HDL cholesterol, which is currently used to assess such risk. They published these findings in the Journal of Clinical Investigation .

To perform the test, a person’s plasma, which contains HDL, is separated from their blood. The plasma is added to donor particles coated with a lipid mixture that resembles plaque, and a fluorescent-tagged phospholipid that can only be removed by HDL. The fluorescent signal obtained by HDL is then measured. A brighter signal reflects optimal HDL lipid removal function. A dim light indicates reduced function.

The test is still years away from potential use in a medical setting, but it holds promise for physicians looking to gather additional information that could help inform their treatment decisions. For example, a patient with intermediate risk for having a heart attack or stroke in 10 years , also found to have reduced HDL function, may emerge as a stronger candidate for treatment or for having additional assessments to measure how much atherosclerotic plaque they have. “Any additional information that we could get in terms of assigning stratification would be of great benefit,” said Neufeld. He explained that many adults have medium-level risks.

NIH has now patented the test and will work with an outside company to purchase the rights to license and manufacture the diagnostic material. “Other people may modify this or come up with better versions, which is fine with us,” said Neufeld. “We just really wanted to tackle this problem of evaluating HDL function.”

Neufeld and his colleagues believe the test could also be used for multiple purposes in research, which could lead to clinical applications, such as use in the doctor’s office. This excites them, but they caution that they still have a lot to learn. “HDL cholesterol is important, but we still don’t fully understand it,” said Alan T. Remaley, M.D., Ph.D. , a senior investigator in the Lipoprotein Metabolism Laboratory. “Biology is full of mysteries.”

Remaley explained that while HDL cholesterol research has transformed cardiovascular research, therapeutic advancements to improve HDL cholesterol haven’t followed. “Someday we may have a drug that modulates HDL and turns out to be beneficial, but right now we don’t have that,” said Remaley.

“There’s a long tradition in the field of knowing that research takes time,” Remaley explained. Like for other disciplines, incremental advancements in lipoprotein research have led to novel discoveries. 

He and Neufeld envision that the updated HDL function test, which builds on previous findings, will support similar advancements. “This could open up new opportunities to gain further insights, such as with drug development, that have been difficult to achieve,” said Neufeld.

To learn about cholesterol, visit https://www.nhlbi.nih.gov/health/blood-cholesterol .

To learn about the Laboratory of Lipoprotein Metabolism, visit  https://www.nhlbi.nih.gov/science/lipoprotein-metabolism .

Related Health Topics

Related news & features.

Statin alternative significantly reduces heart disease deaths, new study finds

An alternative to statins may help reduce deaths from heart disease among people with high levels of LDL, or “bad” cholesterol, new research finds.

When taken as a daily pill, bempedoic acid lowered LDL cholesterol and showed a significant 39% reduction in heart disease deaths and heart attacks, researchers reported Saturday at the American Diabetes Association’s annual meeting. The findings were simultaneously published in JAMA.

“What we saw really surprised me,” said the study’s lead author, Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic. “I hope this will be a wake-up call for patients and physicians.”  

Right now, fewer than half the people who should be prescribed a cholesterol-lowering medication because of heart disease risk are getting it, according to Nissen. That needs to change, he said.

“Treating people who have risk factors before their first cardiovascular event would have large benefits,” not just in preventing complications but also in preventing deaths, he said.

What is a healthy level of cholesterol?

Bempedoic acid, which was approved in 2020 by the Food and Drug Administration , is not as effective as statins, which are considered the gold standard in treating high cholesterol. However, many people stop or refuse to take statins because of possible side effects such as muscle pain, headaches, sleep problems and digestive problems.

Recent research found that about 20% of people at high risk for heart disease refuse to take statins when prescribed by their doctor. Women in particular were less likely to accept a statin prescription, according to the study published in JAMA Network Open.

Although the new study looked at only the impact of bempedoic acid on people who had adverse reactions to statins, it found that lowering cholesterol resulted in a significant decrease in heart attacks and heart-disease related deaths.

What's most important is to get blood cholesterol to healthy levels, whether by taking a statin or bempedoic acid or other lipid-lowering medication, Nissen said in an interview.

More on heart health

• 'Good' cholesterol may not protect against heart disease as much as thought
• Covid infection raises cholesterol levels, even in people with no prior problem
• Too many people stop their lifesaving statins, research shows

LDL, or low density lipoprotein, is the type of cholesterol that contributes to the buildup of fatty deposits in the arteries and raises the risk of cardiovascular events, such as heart attack and stroke. According to the American Heart Association , the optimal total cholesterol level for an adult is about 150 mg/dL, with LDL levels at or below 100 mg/dL.

The 4,206 patients enrolled in the new study are part of a larger group described in a New England Journal of Medicine article in March. The NEJM study included both patients who had experienced a cardiovascular event, such as a stroke or heart attack, as well as those who only had risk factors.

In the new research, Nissen and his colleagues focused only on participants who had never been diagnosed with heart disease, but were at high risk because of factors such as high LDL, diabetes and hypertension.

The average age of the participants in the new study was 68, and 59% were women. Two-thirds had diabetes. At the outset, the average LDL level in the participants was 142.5 mg/dL.

Six months into the study, compared with patients taking a placebo, participants who received a daily dose of bempedoic acid experienced a 23.2% reduction in LDL cholesterol and a 22.7% decrease in inflammation caused by a protein in the blood associated with heart and stroke risk.

Other key findings of the study, which tracked most participants for a little more than three years, showed that:

• Risk of heart attacks among people who received the medication were cut by 39%.
• Risk of heart disease-related death had been reduced by 39%.
• The combined risk of a patient dying, having a heart attack or a stroke had been cut by 36%.

There was a small increased risk of complications in those who were treated with bempedoic acid versus placebo, including the development of gout and gallstones.

Statins as 'first-line therapy'

While bempedoic acid may not cause as many muscle-related symptoms, it is more expensive than generic statins, Dr. Druv S. Kazi, a cardiologist, noted in an editorial accompanying the JAMA study.

"Patients are likely to face substantially higher out-of-pocket costs for bempedoic acid than for a generic statin," Kazi wrote.

Sheldon Koenig, CEO and president of Esperion, which makes the medication sold as Nexletol and funded the study, said the drug is now covered by many insurance companies.

“For Medicare, the company has preferred status and the copay is generally only $45 per month,” Koenig said.

The new findings are “exciting and very promising,” said Dr. Marc Eisenberg, a cardiologist and an associate professor of medicine at Columbia University’s Vagalos College of Physicians and Surgeons. “But statins should still be offered and tried as a first-line therapy.” Eisenberg was not associated with the new study.

While the study is “well designed,” Eisenberg said, “we still need more studies.”

These “are very important findings,” said Dr. Robert Rosenson, director of metabolism and lipids for the Mount Sinai Health System and a professor of medicine at the Icahn School of Medicine at Mount Sinai.

The benefits seen in the new study are greater than you would expect simply based on the reductions seen in LDL level, said Rosenson, who was not associated with the research.

The new study reinforces the idea that “targeting LDL cholesterol reduces cardiovascular risk,” said Dr. Jeffrey Berger, director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health.

Patients with risk factors, such as high LDL and diabetes, but who haven’t yet been diagnosed with cardiovascular disease “are the largest group of patients we take care of,” Berger said. Berger was not part of the new study.   

For people who can’t or won't take statins, bempedoic acid offers an alternative, Berger said.

“But I do think it’s important to recognize that there are important side effects with this drug. Like everything in medicine, there are risks and benefits,” Berger said.

CORRECTION (June 25, 2023, 6:56 p.m. ET): A previous version of this article misspelled Dr. Marc Eisenberg’s affiliation. It is Columbia University Vagelos College of Physicians and Surgeons, not Columbia University’s Vegelos College of Physicians and Surgeons.

Linda Carroll is a regular health contributor to NBC News. She is coauthor of "The Concussion Crisis: Anatomy of a Silent Epidemic" and "Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings." 

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2023: The year in cardiovascular disease – the year of new and prospective lipid lowering therapies. Can we render dyslipidemia a rare disease by 2024?

Maciej banach.

1 Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland

2 Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland

3 Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

4 Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Stanisław Surma

5 Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland

Peter P. Toth

6 CGH Medical Center, 101 East Miller Road, Sterling, IL, USA

In 2023 there are still even 75% of patients over the target of low-density lipoprotein cholesterol (LDL-C), and hypercholesterolemia is the most common and the worst monitored cardiovascular risk factor. How it is possible, considering the knowledge we have on the role of cholesterol in the process of atherosclerosis, atherosclerotic cardiovascular disease (ASCVD) and its complications, on the methods of lipid disorders diagnosis, prevention, and treatment. Nowadays, almost 4 million deaths per year are attributed to LDL-C, and even 2/3 of all CVD deaths to ASCVD, therefore hypothetically we should easily prevent few to several million of deaths with early diagnosis, and early and intensive non-pharmacological and pharmacological therapies. Moreover, lipidology is now, besides oncology, the area with the highest number of new and ongoing trials with new effective and safe medications that have already appeared and will soon be available. Therefore, we have no doubt that year 2023 should be called the year of new and prospective lipid lowering therapies (LLTs). In this State-of-the-Art paper we summarized the most important trials, studies, and recommendations on the new and prospective LLTs, with suitable graphical summaries that might be helpful for the physicians in their practice with a look to the nearest future with prospective therapies being still under investigation. Let’s hope all those medications helps to render dyslipidemia a rare disease in next few years.

Introduction

Lipid disorders, mainly hypercholesterolemia, are in terms of prevalence, the third – after elevated blood pressure and dietary risks- most common cardiovascular risk factor in the world [ 1 ], while in Poland and in most European countries they rank first (current data indicate that 70% of Poles – 21 million – suffer from hypercholesterolemia) [ 2 – 4 ]. Elevated serum low-density lipoprotein cholesterol (LDL-C) concentration has persisted as a leading modifiable risk factor and is one of the most closely linked markers of atherosclerotic cardiovascular disease (ASCVD) [ 5 ]. In 2021, 3.81 million (95% CI: 2.17–5.42 million) cardiovascular (CV) deaths and 3.81 million (95% CI: 2.17–5.42 million) deaths overall were attributed to elevated LDL-C serum concentrations, and these data may represent underestimates [ 6 ]. Between 1990 and 2019, the prevalence of CVD increased significantly from 271 million to 523 million. At the same time, the number of CVD-related deaths also increased from 12.1 million to 18.6 million [ 1 ]. In 2020, approximately 19.1 million deaths were attributed to CVD globally [ 4 ]. Almost 2/3 (67.3%) of all CVDs are attributable to ASCVD, mainly CAD, ischemic stroke, and peripheral arterial disease, and, therefore in many cases a significant percentage of this mortality might be preventable [ 1 ]. In this context, lipid disorders and ASCVD are the leading cause of premature death worldwide [ 7 ].

Lipid-lowering therapy is the most efficacious approach to primary and secondary prevention of ASCVD [ 2 , 3 ]. Lipid-lowering therapy in primary prevention is associated with a reduction in the risk of death from any cause by 11%, CV death by 20%, acute coronary syndrome by 38%, stroke by 17%, unstable CAD by 25% and major CV events by 26% [ 8 ]. In secondary prevention, lipid-lowering treatment leads to a reduction in the risk of death from any cause by 22%, death from CV causes by 31%, acute coronary syndrome by 38%, the need for coronary revascularization by 44% and cerebrovascular events by 25% [ 9 ]. At the same time statin therapy and lipid lowering combination therapy (with an adherence of 97–100% for PCSK9 inhibitors and inclisiran) are among the most well tolerated medications used to manage CVD. Remarkably, 93-95% of patients can be treated without safety concerns [ 10 – 14 ].

Patients accrue the greatest benefits from lipid-lowering treatment in accordance with three key principles. First, the earlier we start treatment of lipid disorders, the better (“the earlier the better”). The study by Domanski et al, which included 4958 participants aged 18–30 years followed for 16 years, found that the risk of ASCVD was higher in those who were exposed to elevated serum LDL-C concentrations at a younger age compared to people exposed to elevated LDL-C in old age, which emphasizes the importance of optimal control of serum LDL-C concentration from an early age [ 15 ]. This is also confirmed by the results of a study by Zhang et al, including 18,288 participants, which concluded that cumulative LDL-C exposure during young adulthood and middle age were associated with the risk of incident ASCVD, independent of midlife LDL-C serum concentrations [ 16 ]. Second, the treatment of lipid disorders should be intensive, according to the principle “the lower the better” with a number of studies, trials and meta-analyses confirming this relationship [ 17 – 20 ]. The greater benefits of more intensive lipid-lowering treatment are also confirmed by a meta-analysis of 18 randomized clinical trials (RCTs) which shows that more intensive reduction of LDL-C was associated with an additional reduction in the risk of CVD events by 24% (RR = 0.76; 95% CI: 0.68–0.85) and the risk of death from any cause by 10% (0.90; 0.83–0.97) [ 21 ]. Third, lipid-lowering treatment should be ongoing for a lifetime, according to the principle “the longer the better”. Each 1% reduction in serum LDL-C is associated with an approximately 1% reduction in cardiovascular risk. After 5 years, the risk decreases by approximately 20–25%, and after 40 years by even 50–55% for each mmol/l of LDL-C reduction [ 20 ]. A meta-analysis of 21 studies also showed that the longer lipid-lowering treatment lasts, the greater the cardiovascular benefits. Each mmol/l reduction in serum LDL-C is associated with a 12% (95% CI: 8–16%) reduction in the risk of major CV events at year 1, 20% (16–24%) in year 3, 23% (18–27%) in year 5, and 29% (14–42%) in year 7 of lipid-lowering treatment [ 22 ]. Figure 1 summarizes the most important information regarding lipid-lowering treatment.

Basics of lipid-lowering treatment – method of management, impact on prognosis, safety, and biological mechanisms. Based on information from [ 2 , 3 , 8 , 11 – 18 ]

CVD – cardiovascular disease, LLT – lipid-lowering treatment, CV – cardiovascular, ASCVD – atherosclerotic cardiovascular disease, SI – statin intolerance, OR – odds ratio, LDL-C – low density lipoprotein cholesterol.

It should be emphasized that, in addition to the control of LDL-C concentration in serum, it is also very important to assess the levels of other lipid parameters, such as: triglycerides, lipoprotein (a) [Lp(a)], non-HDL-C cholesterol and apolipoprotein B (apoB), in order to reduce residual CVD risk [ 3 , 23 ].

Despite the data demonstrating that lipid-lowering treatment prolongs the life of most patients in the primary and secondary prevention of ASCVD, risk-stratified, guideline directed control of LDL-C is not the case in 75% individuals [ 24 – 27 ]. Only 1/3 patients in Europe, and 1/4 in Poland and Central and Eastern Europe, reach their LDL-C targets [ 24 , 25 ]. The therapeutic goal for patients with very high cardiovascular risk (i.e, < 55 mg/dl/< 1.4 mmol/l) is achieved only in 18% of the European population, 17% in Poland and only 13% in the countries of Central and Eastern Europe [ 24 , 25 ]. In turn, the LDL-C target in the group of patients with extreme cardiovascular risk (i.e, < 40 mg/dl; < 1 mmol/l) is achieved by less than 10% of patients [ 24 , 25 ]. When trying to find the most common reasons for this low rate of therapeutic success, two issues seem to be the most important: use of moderately intensive statin therapy in over 50% of patients and severe underutilization of lipid lowering combination therapy (< 10%) [ 24 – 29 ]. The more recent SANTORINI study, which included 9044 patients with high or very high cardiovascular risk from 14 western European countries, showed only a slight improvement, as only 20.1% achieved the LDL-C target (24% of high-risk patients and 18.6% of very high-risk patients) [ 28 ]. Moreover, it was found that 21.8% of patients did not receive any lipid-lowering treatment (23.5% and 21.1%). In this study, 54.3% of patients (58.4% and 52.5%) used statin monotherapy and combination therapy was used in 24% of patients (18.1% and 26.4%). The most commonly used combination was a statin with ezetimibe [ 28 ].

We have many effective lipid lowering therapies (LLTs) at our disposal. This offers the possibility of therapy personalization after considering the presence of concomitant risk factors and specific forms of dyslipidemia/mixed dyslipidemia. New medications for the management of dyslipidemia will continue to be developed, and available lipid-lowering treatment are so effective that most patients should be able to achieve their therapeutic goals. We believe inadequately treated dyslipidemias should be a rare event. we have no doubt that 2023 should be established as the year of new and prospective lipid lowering therapies. Figure 2 shows the mechanism of action of lipid-lowering drugs, therapeutic strategies, and nutraceuticals available or under investigation.

Mechanism of action of lipid-lowering drugs (available and in clinical trials), major nutraceuticals and other therapeutic strategies

Apo(a) – apolipoprotein (a), mRNA – messenger ribonucleic acid, ANGPTL3 – angiopoietin like protein 3, CRISPR-Cas9 – clustered regularly interspaced short palindromic repeats – caspase 9, ASGPR –asialoglycoprotein receptor, ApoC-III – apolipoprotein CIII, ApoB100 – apolipoprotein B100, PCSK9 – proprotein convertase subtilisin/kexin 9, VLDL – very low-density lipoprotein, LDL-R – low-density lipoprotein receptor, Lp(a) – lipoprotein (a), TG – triglycerides, MTP – microsomal triglyceride transfer protein, IDL-R – intermediate-density lipoprotein receptor (VLDL remnants), LDL – low-density lipoprotein, CETP – cholesterol ester transfer protein, HDL – high-density lipoprotein, ApoA-I – apolipoprotein A-I, LRP1 – low density lipoprotein receptor-related protein 1, LPL – lipoprotein lipase, HL – hepatic lipase, IDL – intermediate-density lipoprotein (VLDL remnants), ABCG5/8 – ATP binding cassette subfamily G member 5/8, acetyl-CoA – acetyl coenzyme A, FDC – fixed dose combination, HMG-CoA – β-hydroxy β-methylglutaryl-CoA, FA – fatty acid, NPC1L1 – Niemann-Pick C1-Like 1, ACSVL1 – very long-chain acyl-CoA synthetase, ChMR – chylomicron remnants, ChM – chylomicron, PPARa – peroxisome proliferator-activated receptor α, FFA – free fatty acid, ApoA-II – apolipoprotein A-II, DGAT – diglyceride acyltransferase, PPARg – peroxisome proliferator-activated receptor g, PPARd – peroxisome proliferator-activated receptor d, SC-A – scavenger receptor A, CD36 – cluster of differentiation 36, IsmA – intestinal sterol metabolism A. Modified and updated with permission based on: Surma S, Burchardt P, Banach M, Leki hipolipemizujące. In: Kardiologia - Podręcznik Polskiego Towarzystwa Kardiologicznego. Wydanie II, Via Medica 2023, Rycina 2.1.13.1, page 133.

Upfront lipid lowering combination therapy of high intensity statin (HIS) therapy with ezetimibe

In patients with very high and extremely high CV risk, LLT should be started with combination therapy (preferably a fixed dose combination (FDC) of high intensity statin (HIS) with ezetimibe – Figure 2 ) [ 29 , 30 ]. A meta-analysis of 14 studies showed that the use of HIS with ezetimibe versus HIS monotherapy allowed for an additional reduction in serum LDL-C concentration by 14% and more patients attaining their LDL-C goal [ 31 ]. The RAndomized Comparison of Efficacy and Safety of Lipid-lowerING With Statin Monotherapy Versus Statin Ezetimibe Combination for High-risk Cardiovascular Diseases (RACING) trial, which included 3780 patients with ASCVD during a 3-year follow-up, showed that the use of combination therapy with a moderate intensity statin (MIS; rosuvastatin 10 mg) and ezetimibe was associated with a higher percentage of achieving serum LDL-C concentrations < 70 mg/dl (1.8 mmol/l) compared to rosuvastatin 20 mg in monotherapy (72% vs. 58%, p < 0.0001) [ 32 ]. Moreover, combination therapy was associated with a significantly lower risk of therapy discontinuation or drug dose reduction (4.8% vs. 8.2%, p < 0.0001), while maintaining the same cardiovascular benefits (with the reduction trend – the absolute difference between group was –0.78%) [ 32 ]. Older people have a higher risk of intolerance, nonadherence, and discontinuation with HIS therapy [ 33 ]. In a subgroup analysis of the RACING study including patients with ASCVD aged ≥ 75 years, it was found that the use of combination therapy with a MIS with ezetimibe for 3 years was associated with a lower risk of intolerance compared to HIS monotherapy (2.3% vs. 7.2 %, p = 0.01), while maintaining the same cardiovascular benefits (HR = 0.87; 95% CI: 0.54–1.42) [ 34 ]. Another group at greater risk of intolerance to lipid-lowering treatment are diabetic patients [ 13 , 35 ]. In a subgroup analysis of the RACING study with 1398 diabetic patients, it was found that the use of lipid lowering combination therapy was associated with a lower incidence of intolerance (5.2% vs. 8.7%, p = 0.014), and higher percentage of goal attainment < 70 mg/dl (1.8 mmol/) (79.9% vs. 66.8%, p < 0.0001) [ 36 ]. In this concept, it is worth mentioning the study that used the inclusion criteria of the RACING trial that investigated the role of lipid lowering combination therapy in patients who underwent percutaneous coronary intervention (PCI) [ 37 ]. The study included 72,050 patients and showed that the use of MIS combination therapy with ezetimibe vs. HIS monotherapy was associated with a lower risk of the primary endpoint of CVD death, myocardial infarction (MI), coronary artery revascularization, hospitalization for heart failure (HF) treatment, or nonfatal stroke (HR = 0.75; 95% CI: 0.70–0.79), lower risk of discontinuation of therapy (0.85; 95% CI: 0.78–0.94), and lower risk of new onset diabetes (NOD) (0.80; 95% CI: 0.72–0.88) [ 37 ]. In a recent study by Lewek et al , including 38,023 patients with a history of an ACS from the Polish Registry of Acute Coronary Syndromes (PL-ACS), the impact of statin combination therapy with ezetimibe vs. statin monotherapy (mostly on HIS) on long-term prognosis was analyzed [ 38 ]. After 3-year follow-up the authors showed that upfront combination therapy was associated with a significantly greater reduction in the risk of all-cause mortality compared to statin monotherapy (OR = 0.526; 95% CI: 0.378–0.733) with absolute risk reduction (ARR) of 4.7% and number needed to treat (NNT) = 21. It is worth emphasizing that the significant reduction in mortality appeared after only 52 days of the lipid lowering combination therapy (ARR 1%, p = 0.032) [ 38 ].

In an RCT by Mehta et al. (EPIC-STEMI) with ST segment elevating myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI), the effect of HIS with alirocumab vs. HIS on serum LDL-C concentrations was assessed. It was shown that early use of alirocumab allowed for an additional reduction in serum LDL-C concentration by 22.3% after 45 days after PCI. This resulted in a higher percentage of patients achieving the LDL-C target in the HIS + alirocumab group (92.1% vs. 56.7%, p < 0.001). Adding alirocumab to HIS after PCI also allowed for a faster lipid-lowering effect (during the first 24 h – 0.01 mmol/l/h, p = 0.03) compared to HIS monotherapy [ 39 ]. In the Virginia Commonwealth University Alirocumab Response Trial (VCU-AlirocRT), the addition of alirocumab to HIS was assessed in patients with non-ST segment elevating myocardial infarction (NSTEMI) within 24 h of diagnosis [ 40 ]. After 72 h, the serum LDL-C concentration was significantly lower in the group that received alirocumab (73 mg/dl vs. 94 mg/dl, p = 0.02). It was shown that early addition of alirocumab allowed for an additional reduction in serum LDL-C concentration by 62 mg/dl 14 days after administration (28 mg/dl vs. 90 mg/dl, p < 0.001) [ 40 ].

The Evolocumab in Acute Coronary Syndrome (EVACS) trial, including 57 patients with type 1 NSTEMI, evaluated the effect of administering evolocumab as an add-on to HIS within 24 h of diagnosis [ 41 ]. It was shown that LDL-C was significantly reduced just 24 h after evolocumab administration (91.5 mg/dl vs. 70.4 mg/dl, p < 0.01). Moreover, 3 days after the administration of evolocumab, some patients were already at therapeutic goal of < 70 mg/dL (LDL-C 49.2 mg/dl vs. 76.1 mg/dl, p = 0.02). After 30 days, the LDL-C reduction was significantly lower in patients who received evolocumab in addition to HIS (35.9 mg/dl vs. 64.5 mg/dl, p < 0.01) [ 41 ]. Similar results were provided by the EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients with Acute Coronary Syndromes (EVOPACS) trial, including 308 patients with ACS. It was shown that the use of HIS with evolocumab, compared to HIS monotherapy, led to a reduction in serum LDL-C concentration after 8 weeks by 40.7%, which was related to the fact that 95.7% of patients were in at the therapeutic target (vs. 37.6% in HIS monotherapy) [ 42 ]. Recent evidence also demonstrated the benefits of early PCSK9 inhibitors in lipid reduction, plaque stabilization, and short-term or long-term cardiovascular event prevention [ 43 ].

All the aforementioned results are reflected in the 2023 ESC guidelines on the management of patients with ACS [ 44 ], in which for the first time the recommendation of the upfront lipid lowering combination therapy was indicated with a IIb class of recommendations. We might be arguing that the level should be IIa at least, but nevertheless it is a critically important step forward to recommend effective LLT in very high risk and extremely high-risk patients with ACS [ 44 ].

Despite the proven effectiveness of HIS combination therapy with ezetimibe and PCSK9 inhibitors, 24% of physicians deescalate the statin dose by adding ezetimibe or PCSK9i [ 45 , 46 ], thereby reducing the expected percentage of patients reaching their risk-stratified goal for LDL-C. Thus, it is critically important to emphasize that while adding ezetimibe or PCSK9i to HIS, the statin dose not be reduced unless the patient is experiencing statin-related side effects [ 47 – 49 ].

To sum up, in 2023 we have no doubt that immediate treatment with two drugs or even three drugs (if it is allowed by the reimbursement criteria) is a treatment that results in significantly more patients being at or below LDL-C goal with significantly fewer side effects and therapy discontinuation. As long as effort is made to prevent treatment discontinuation and de-escalation, the management of dyslipidemia with multiple drug regimens will result in substantial improvement in CVD event rate reductions compared to drug monotherapy ( Figures 2 – 4 ).

Lipid-lowering combination therapy in very high cardiovascular risk patients now, and the possible prospective combinations, including drugs being under investigations (*for some of the presented combinations the suggested reduction is assumption based on the available data)

ASCVD – atherosclerotic cardiovascular disease, ACS – acute coronary syndrome, PAD – peripheral artery disease, HeFH - heterozygous familial hypercholesterolemia, FDC – fixed dose combination, HIS – high intensity statin, EZE – ezetimibe, BA – bempedoic acid, OBICE – obicetrapib, PCSK9m – proprotein convertase subtilisin/kexin 9 modulator.

Bempedoic acid

Bempedoic acid, first in-class adenosine 5’-diphosphate (ATP) citrate lyase inhibitor ( Figure 2 ), reduces the serum concentration of total cholesterol by an average of 15%, non-HDL-C by 18%, LDL-C by 23% (19–27%; approx. 40% in combination with ezetimibe), apoB by 15%, HDL-C by 6%, triglycerides by 1.5%, and apoA-I by 1.83%. The unique effect of this drug is also the reduction of high sensitivity C-reactive protein (hsCRP) by an average of 27% (> 40% in participants with high baseline hsCRP concentrations) [ 50 , 51 ]. Recent analyses suggest that a stronger lipid-lowering effect of bempedoic acid is observed in women [ 52 ], and the anti-inflammatory effect of bempedoic acid is independent of background statin therapy [ 53 ]. The effect of bempedoic acid on cardiovascular risk was first assessed in the CLEAR Outcomes randomized trial, which included 13,970 patients at high cardiovascular risk with statin intolerance. Bempedoic acid 180 mg/day over a 40.6-month follow-up period was associated with a 13% reduction in the risk of the primary 4-component endpoint. In addition, fatal or non-fatal myocardial infarction (HR = 0.77; 95% CI: 0.66–0.91) and the need for coronary revascularization (0.81; 0.72–0.92) were reduced significantly as pre-specified independent endpoints [ 54 ]. This effect was even pronounced in relation to the total (not the first) number of events for primary (0.80; 0.72–0.89) and secondary endpoints (0.83; 0.73–0.93), as well as for risk reduction of 2 nd (0.74; 0.63–0.87), 3 rd (0.69; 0.51–0.93) and ≥ 4 th CVD events (0.52; 0.31–0.88) [ 55 ]. A meta-analysis of phase-3 studies showed a beneficial effect of bempedoic acid on glycemic parameters and even significant reduction in the risk of de novo diabetes (OR = 0.59; 95% CI: 0.39–0.90) [ 56 ]. The pooled analysis also indicated that in patients with existing diabetes and lipid disorders, bempedoic acid improved glycemic control (reduced HbA 1c percentage) with more patients with HbA 1c < 6.5% ( p = 0.03) [ 57 ]. The CLEAR Outcomes study also confirmed the observed neutral effect on glycemic parameters as well as the lack of NOD risk increase (with total 3% absolute NOD risk reduction) [ 54 ] and the most recent subgroup analysis confirmed this indicating the largest benefit of CVD events reduction (MACE-4 endpoint) in patients with diabetes (HR = 0.83; 0.72–0.85; ARR = 2.4%) in comparison to those without (0.84; 0.63–1.10; ARR = 1.9%) and with pre-diabetes (0.94; 0.81–1.09; ARR = 0.6%) [ 58 ].

The latest International Lipid Expert Panel (ILEP) guidelines from 2023, published simultaneously with the CLEAR Outcomes study, indicate that bempedoic acid is recommended in combination with statins and other lipid-lowering drugs in ASCVD when the LDL-C treatment targets are not met (class of recommendations: I; level: A), in combination with statins and other lipid-lowering drugs in heterozygous familial hypercholesterolaemia (heFH) when the LDL-C treatment targets are not met (class of recommendations: I; level: A); in combination with maximally tolerated statins and other non-statin agents to enable patients with partial statin intolerance to reach therapeutic goals (class of recommendations: I; level: A); in monotherapy or in combination with ezetimibe (FDC) and other non-statin drugs to enable patients with complete statin intolerance to reach their therapeutic goals (class of recommendations: I; level: A) [ 59 ]. Based on the available results the ILEP experts also recommended to consider bempedoic acid in primary prevention patients at high and very high cardiovascular risk, who despite optimal, maximally tolerated doses of statins and ezetimbe, have not achieved their LDL-C target (class of recommendation: IIb; level: B); in patients at high and very high cardiovascular risk with elevated hsCRP levels (class of recommendation: IIb; level: B), and in patients with high and very high cardiovascular risk with prediabetes and diabetes to reduce the risk of NOD and improve glycaemia (class of recommendation: IIb; level: B) ( Figures 2 – 4 ) [ 59 – 61 ].

Obicetrapib

Another drug with interesting properties and lipid disorders management benefits is obicetrapib – a new cholesterol ester transfer protein (CETP) inhibitor ( Figure 2 ). The results of available studies suggest that the drug has a potential to be used in the next step (after statins and ezetimbe) of intensifying lipid-lowering treatment. In a recent phase-2 RCT (ROSE-2 trial) by Ballantyne et al, including 119 patients receiving HIS, it was found that the addition of obicetrapib 10 mg reduced serum LDL-C concentrations by 43.5%, and obicetrapib plus ezetimibe by 63.4%. LDL-C serum concentrations of < 100, < 70, and < 55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Moreover, obicetrapib and its combination with ezetimibe significantly reduced concentrations of non-HDL-C, apoB, and total and small LDL particles [ 62 ]. The ROSE study also showed obicetrapib treatment to significantly decrease apoB (by up to 30%) and non-HDL-C serum concentration (by up to 44%), and significantly increased HDL-C serum concentration (by up to 165%) [ 63 ]. Based on the available data obicetrapib (10 mg) can be also a great adding value for patients with elevated levels of Lp(a) with the possibility to reduce it by up to 50% [ 63 , 64 ]. Additionally, the use of CETP inhibitors, including obicetrapib, reduces the risk of new onset diabetes (RR = 0.84; 95% CI: 0.78–0.91), which means that it can be considered in patients with metabolic disturbances and the risk of diabetes or existing diabetes [ 65 , 66 ]. Ongoing phase-2 and phase-3 trials – OCEAN ( {"type":"clinical-trial","attrs":{"text":"NCT04770389","term_id":"NCT04770389"}} NCT04770389 ; phase-2 study on the combination of obicetrapib and ezetimibe), BROOKLYN ( {"type":"clinical-trial","attrs":{"text":"NCT05425745","term_id":"NCT05425745"}} NCT05425745 ; phase 3, HeFH), BROADWAY ( {"type":"clinical-trial","attrs":{"text":"NCT05142722","term_id":"NCT05142722"}} NCT05142722 ; phase 3, HeFH and/or ASCVD), TANDEM ( {"type":"clinical-trial","attrs":{"text":"NCT06005597","term_id":"NCT06005597"}} NCT06005597 ; phase 3, HeFH and/or ASCVD or multiple ASCVD risk factors), and the cardiovascular outcome trial PREVAIL ( {"type":"clinical-trial","attrs":{"text":"NCT05202509","term_id":"NCT05202509"}} NCT05202509 ) - will address how best to configure obicetrapib in lipid lowering management ( Figures 2 , ​ ,3). 3 ). It is also worth mentioning the proof-of-concept study on the role of obicetrapib in early Alzheimer’s disease (AD) ( {"type":"clinical-trial","attrs":{"text":"NCT05161715","term_id":"NCT05161715"}} NCT05161715 , phase 2a), in which it was observed that obicetrapib reduced cerebrospinal fluid (CSF) levels of 24- and 27-hydroxycholesterol, the oxysterols that may be linked to neuroinflammation and Alzheimer’s pathology [ 67 ]. The authors also observed that the reduction in 24- and 27-hydroxycholesterol was paired with an 8% improvement in the plasma β-amyloid (Aβ) 42/40 ratio. Based on these results, it is believed that obicetrapib might offer an advancement for a high-risk patient population for AD development ( Figures 2 – 4 ) [ 67 ].

Lipid-lowering treatment algorithm in patients with high or very high cardiovascular risk now and the possible prospective management, including drugs being under investigations

1 Pitavastatin is preferable in patients with risk factors of diabetes or with diabetes; 2IPE is still not available in most of the countries in Europe. *In patients with severe hypertriglyceridemia and/or familial chylomicronaemia syndrome (FCS). FDC – fixed dose combination, LLT – lipid lowering treatment, TGs – triglycerides, PCSK9m – proprotein convertase subtilisin/kexin 9 modulator.

Inclisiran is a silencing ribonucleic acid (siRNA) that reduces expression of the PCSK9 gene ( Figures 2 – 4 ). The administration of inclisiran, compared to placebo, allows for a reduction in the serum concentration of LDL-C by 45–55%, triglycerides by 7–13%, Lp(a) by 17–26% and an increase in the concentration of HDL-C in the serum by 3–6% [ 68 , 69 ]. In a meta-analysis of 3 randomized clinical trials, including 3660 patients with hypercholesterolemia, it was found that the use of inclisiran reduced serum LDL-C levels by 51% and, more importantly, reduced the risk of major cardiovascular events by 24% (RR = 0.76; 95% CI: 0.61–0.92). It also significantly decreased total cholesterol by 37%, apolipoprotein B by 41%, and non-HDL-C by 45% [ 70 ]. In the first real world data with inclisiran the observed effectiveness of inclisiran seems to be less than in the RCTs. In the recent RWE analysis Mulder et al. showed that at 3 months, patients who newly started inclisiran showed an LDL-C decrease of 38% (–49; –33%), patients who used statins as co-medication had a higher median LDL-C decrease compared to those without statin use (45% vs. 38 %), however, those who switched from mAbs to inclisiran surprisingly had an increase in LDL-C of 38% (+4; +97%) [ 71 ]. At the ESC Congress 2023 in Amsterdam – the results of the ORION-8 study were presented that was aimed to assess the long-term efficacy and safety of inclisiran in patients who entered the open-label extension after completing either ORION-3, ORION-9, ORION-10, or ORION-11. The longest exposure of inclisiran was 6.84 years, and a quarter of patients were exposed to inclisiran for over 4.45 years [ 72 ]. Mean LDL-C reduction was 49.4% with even 51% (–52.2; –49.9%) in ASCVD patients and 42.4% in those with ASCVD risk equivalent (–45.0; –39.9%). At the end of study 78.4% of patients achieved the prespecified LDL-C goal with 79.4% of ASCVD patients being at the goal of < 70 mg/dl (1.8 mmol/l) and 74.3% of individuals with ASCVD risk equivalent at the goal of < 100 mg/dl (2.5 mmol/l) [ 72 ]. In the recently published ORION-5 study inclisiran treatment did not reduce LDL-C levels in patients with hoFH (–1.68%; –29.19 to 25.83%; p = 0.90), despite substantial lowering of PCSK9 levels [ 73 ]. We need obviously to wait for the results of the ORION-4 ( {"type":"clinical-trial","attrs":{"text":"NCT03705234","term_id":"NCT03705234"}} NCT03705234 ) and the VICTORION-2P ( {"type":"clinical-trial","attrs":{"text":"NCT05030428","term_id":"NCT05030428"}} NCT05030428 ) to see how the efficacy of inclisiran and way of administration may result in reduction of CVD outcomes. In the most recent meta-analysis of 3 randomized clinical trials ORION-9 to 11, including 3713 patients, it was found that inclisiran may reduce the risk of ACS by 32% (0.68; 0.48–0.96) [ 74 ].

Lp(a) lowering drugs

Elevated serum Lp(a) concentration is an LDL-C-independent risk factor for ASCVD [ 64 , 75 , 76 ]. Olpasiran, a siRNA that silences the expression of the LPA gene encoding apolipoprotein (a) [apo(a)] ( Figures 2 , ​ ,5), 5 ), necessary for the synthesis of Lp(a), in a RCT by O’Donoghue et al, including 281 patients with ASCVD, induced an up to even 100% reduction in serum Lp(a) concentrations [ 77 ]. A recent study evaluated the association of elevated Lp(a) with CVD outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial ( {"type":"clinical-trial","attrs":{"text":"NCT05581303","term_id":"NCT05581303"}} NCT05581303 ) main enrolment criteria [ 78 ]. In a total of 3142 patients who met the eligibility criteria with median follow-up of 12.2 years, the primary composite outcome occurred more frequently in patients with versus without elevated Lp(a) (by 33%; adjHR = 1.33, 95% CI: 1.12–1.58, p = 0.001) [ 78 ]. Zerlasiran (SLN360) has similar effectiveness – it reduces the concentration of Lp(a) in serum by > 95% [ 79 ]. Pelacarsen, which is an antisense oligonucleotide that blocks apo(a) synthesis, is slightly less effective. This drug reduces serum Lp(a) concentration by approximately 80–90% [ 64 ]. Muvalaplin is the newest drug to lower Lp(a) concentrations in serum and blocks the covalent attachment of apo(a) with the apoB 100 moiety of LDL particles ( Figures 2 , ​ ,5). 5 ). Based on the first presented data the drug reduces the concentration of Lp(a) in serum by 65% [ 80 ]. Before we have targeted drugs to effectively lower Lp(a), we need to assess the outcomes in ongoing prospective, randomized clinical trials with these drugs ( Figure 5 ) [ 76 ].

The suggested pathway of management with patients with elevated Lp(a) concentration. Based on Banach M. Eur Heart J Open 2023; 3: oead080 [ 76 ] with License Permission No. 5658420691033

Angiopoietin-like protein 3 (ANGPTL3) is involved in the regulation of triglyceride-enriched lipoproteins (TRLs) ANGPTL3 inhibits lipoprotein lipase (LPL), thereby reducing the clearance of TRLs from the plasma, which include small very-low density lipoproteins and intermediate density lipoproteins [ 81 – 83 ]. Therefore, inhibition of this protein may be important in patients with familial hypercholesterolemia and/or hypertriglyceridemia. Currently, inhibition of the ANGPTL3 protein is possible using evinacumab (an anti-ANGPTL3 monoclonal antibody) or vupanorsen (an antisense oligonucleotide that reduces the synthesis of ANGPTL3 in the liver) ( Figure 2 ), however, for the latter, based on the results from the TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in AdulTs with dyslipidEmia (TRANSLATE-TIMI 70) trial, in which the magnitude of non-HDL-C and TG reduction observed did not support continuation of the clinical development program for CV risk reduction or severe hipertriglicerydemia (SHTG) the clinical development program was discontinued [ 84 ]. Another reason was the safety concerns, as vupanorsen was associated with dose-dependent significant increases in liver fat, and higher doses were associated with elevations in the liver enzymes [ 84 ]. Evinacumab reduces the concentration of multiple lipoprotein fractions in serum: LDL-C by 33–49%, triglycerides by 51% and HDL-C by 13%. In patients with homozygous FH, evinacumab has a potential to reduce serum concentrations of total cholesterol by 47%, triglycerides by 55%, non-HDL-C by 50%, apoB by 41%, apoC-III by 84%, Lp(a) by 6% [ 85 ]. It appears to do this by both promoting the clearance of TRLs via the VLDL and LDL receptor related protein-1 and reducing hepatic VLDL production and secretion. Evinacumab also proved to be effective and safe in the treatment of children with HoFH – within the follow-up of 24 weeks LDL-C was reduced by mean 48.3%, ApoB by 41.3% non-HDL-C by 48.9%, and total cholesterol by almost 50%. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events were considered to be treatment-related (nausea and abdominal pain) [ 86 ]. This drug allows for long-term control of the lipid profile in patients with resistant hypercholesterolemia [ 87 ]. Despite lack of registration for treating hypertriglyceridemia, evinacumab may be effective (in phase-2 trial in patients with severe hypertriglyceridemia (SHTG; triglycerides > 500 mg/dl) with a history of hospitalization for acute pancreatitis evinacumab reduced triglycerides by mean 27.1%); however, we need to wait for additional data to confirm its efficacy in subjects with SHTG, especially in those with a history of SHTG-associated acute pancreatitis (except familial chylomicronemia [FCS] patients lacking functional LPL) [ 88 , 89 ].

Olezarsen and volanesorsen

ApoC-III is present on TRL and inhibits LPL, thereby slowing down the clearance of these lipoproteins from plasma. Olezarsen and volanesorsen are antisense oligonucleotides that inhibit apoC-III production in the liver ( Figure 2 ). In patients with hypertriglyceridemia, volanesorsen reduces the serum concentration of triglycerides by 74%, apoB48 by 69%, VLDL-C by 71%, apoC-III by 80%, and increases the serum concentration of HDL-C by 45% and LDL-C by 69%. This drug does not affect the concentration of apoB 100 in serum [ 90 ]. Based on the recent data from the UK Early Access to Medicines Scheme (EAMS) analysis (drug exposure ranged from 6 to 51 months), volanesorsen therapy among treatment-naive patients resulted in an averaged median 52% reduction (–10.6 mmol/l) from baseline (26.4 mmol/l) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47–55% reductions). A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before and during Volanesorsen treatment [ 91 ]. In patients with hypertriglyceridemia, olezarsen a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide – reduces serum concentrations of triglycerides by 60%, apoC-III by 74%, VLDL-C by 58%, total cholesterol by 8%, non-HDL-C by 20% and apoB by 12–17%, while it increases the serum concentration of: HDL-C by 33–40%, LDL-C by 16% and apoA-I by 14–18% [ 92 ]. This drug seems to have very large potential for patients with high and severe hypertriglyceridemia and FCS due to its efficacy and safety and significant ApoB reduction. We await results for outcomes with olezarsen. Multiple randomized, prospective studies are underway, and include: CORE CS5 ( {"type":"clinical-trial","attrs":{"text":"NCT05079919","term_id":"NCT05079919"}} NCT05079919 , SHTG ≥ 500 mg/dl/5.65 mmol/l), CORE2 CS6 ( {"type":"clinical-trial","attrs":{"text":"NCT05552326","term_id":"NCT05552326"}} NCT05552326 , SHTG ≥ 500 mg/dl/5.65 mmol/l), CS8 – TIMI 73a ( {"type":"clinical-trial","attrs":{"text":"NCT05355402","term_id":"NCT05355402"}} NCT05355402 , moderate hypertriglyceridemia ≥ 150 mg/dl/1.69 mmol/l and established or increased risk for ASCVD or SHTG) and ESSENCE CS9 – TIMI 73b ( {"type":"clinical-trial","attrs":{"text":"NCT05610280","term_id":"NCT05610280"}} NCT05610280 , moderate hypertriglyceridemia ≥ 150 mg/dl/1.69 mmol/l and established or increased risk for ASCVD or SHTG) ( Figures 2 , ​ ,3 3 ).

Conclusions and perspectives

It is unacceptable for patients to be treated ineffectively for lipid disorders. We have many classes of LLTs at our disposal. Patients continue to be underdiagnosed and undertreated despite the widespread availability of effective and safe therapies. Physician inertia and failure to treat to risk stratified lipoprotein goals should become issues relegated to the past. Of special importance is ongoing education of patients to increase medication adherence and long-term compliance according to the well-known rule that the more educated the patient, the more adherent the patient. Well-designed media and social-media campaigns (we are failing the fight with anti-statin and anti-LDL-theory movements in social media) should be initiated at the local and national levels. It is also important for medical leaders to establish effective collaboration with government officials in order to increase funding for and availability of dyslipidemia screening programs and drug therapies for patients in need [ 93 – 96 ]. Only then can we cross out the word hypothetically from the statement that lipid disorders patients should be considered as those with rare diseases.

Acknowledgments

Drs Banach and Surma equally contributed to this paper.

Conflict of interest

M.B. – speakers bureau: Amgen, Daiichi Sankyo, KRKA, Pfizer, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Adamed, Amgen, Daiichi Sankyo, Esperion, MSD, NewAmsterdam, Novartis, Novo-Nordisk, Sanofi-Aventis; Grants from Amgen, Daiichi Sankyo, Viatris, and Sanofi, CMO at the Nomi Biotech Corporation and Dairy Biotechnologies; S.S. – honoraria from Sandoz/Novartis; Pro.Med.; P.P.T. – speakers bureau for Amgen.

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Cholesterol: Latest Research

High cholesterol raises your risk of heart disease , heart attack , and stroke . A healthy diet and lifestyle can improve your levels. Medication can help, too. Still, doctors and scientists keep studying cholesterol to see what else they can learn about it.

Here’s some progress they’ve made in the ways they think about, prevent, and treat high cholesterol.

A More Personal Approach

Doctors used to think everyone’s cholesterol level should be about the same. Now, your doctor will look at your numbers along with other risk factors you have for heart disease. Those factors include blood pressure , blood sugar , age, and weight . The higher your risk for heart issues, the lower your doctor may suggest you try to get your cholesterol levels .

Prescription for Exercise

If you have high cholesterol and mildly high blood pressure , but you have a low overall risk of heart disease, your doctor may not prescribe medication right away. New guidelines from the American Heart Association advise sitting less and moving more as the first treatment.

Physical activity can reduce LDL (low-density lipoprotein, or “bad”) cholesterol by 3 to 6 milligrams per deciliter (mg/dL) in your blood. It also lowers your blood pressure.

About 150 minutes of moderate exercise per week is ideal. But you could see a difference in your cholesterol levels with as few as 5 to 10 minutes of movement each day.

Beyond Statins

Doctors often prescribe statins to treat high cholesterol, but not everyone does well on these drugs. People who don’t respond to this type of medicine, or who have unpleasant side effects, now have some other options, such as:

• PCSK9 inhibitors: PCSK9 is a protein that your liver makes. The more you have, the harder it is for your body to get rid of LDL cholesterol . A new class of drugs called PCSK9 inhibitors can block PCSK9. That way, it won’t interfere with cholesterol. You can take these medications by themselves or with statins . You get them through a shot, usually about every 2 weeks.

If you have a genetic condition called familial hypercholesterolemia , PCSK9 inhibitors may work better for you than statins do.

• SiRNA therapy: SiRNA (small interfering RNA) therapy can treat some health conditions by changing how some of your genes work. A new medication called inclisiran ( Leqvio ) uses this technology to treat adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) who need additional LDL lowering. It lowers your LDL levels by disrupting the gene that makes PCSK9. Inclisiran comes in the form of shots, taken several months apart. You can use this medication along with other cholesterol-lowering treatments or alone.
• Bempedoic acid: Like statins, this new medication makes it harder for cholesterol to form in your body. Bempedoic acid, which is a pill you swallow, may lower your LDL levels by up to 15%. For now, you can get a prescription only if you have a family history of high cholesterol or you have atherosclerotic cardiovascular disease (ACD).

Nanotech That ‘Eats’ Plaque

Cholesterol can cause fatty deposits called plaque to form inside your arteries . Over time, it can start to block your blood flow. This condition, called atherosclerosis , raises your risk of heart problems and stroke . Scientists have recently created a nanoparticle -- a tiny object that the naked eye cannot see -- to eat away at this waxy buildup. It’s still in testing mode, but in the future, a drug that contains this nanoparticle could be part of atherosclerosis treatment.

Gut Health Could Help

Researchers have thought for some time that gut health plays a role in cholesterol levels , but it hasn’t been clear exactly how. But they now know that probiotics (“good” live bacteria) and prebiotics (which feed useful germs in your gut) can lower LDL cholesterol and triglycerides , another type of blood fat. These gut bacteria may also increase high-density lipoprotein (HDL, or “good”) cholesterol.

Talk to your doctor if you’re interested in trying probiotics or prebiotics. The amount you need in order to get results is still under review, and too much could lead to an upset stomach .

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Millions fewer people may need statins, a new study suggests. But guidelines have yet to agree

By Elizabeth Cooney June 10, 2024

I t’s a familiar scene for patients during a routine primary care visit. The doctor scans blood test results, notes high cholesterol flagged by a standard calculator to assess risk of heart attack or stroke, then decides — and ideally discusses — whether to recommend taking a statin to cut the risk over time.

That conversation may happen less often if changes in the risk model presented by the American Heart Association in November translate into new guidelines for prescribing statins. Those guidelines haven’t been recalibrated yet, but a new analysis suggests that the new risk model could mean far fewer Americans — as many as 40% less than current calculators say — would be candidates for cholesterol-lowering drugs to prevent cardiovascular disease.

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To reach this conclusion, published Monday in a JAMA Internal Medicine study , researchers analyzed data from 3,785 adults who were 40 to 75 years old and took part in the National Health and Nutrition Examination Survey from January 2017 to March 2020. Their 10-year risk of artery-narrowing cardiovascular disease was computed using the AHA’s Predicting Risk of cardiovascular disease EVENTs (PREVENT) equations from 2023 and then compared to risk estimates using the previous tool from 2013, the Pooled Cohort Equations (PCE) on which current guidelines are based.

Those 2013 equations were widely criticized as overestimating risk . The 2023 version, drawing on billing and electronic health record data from a more diverse real-world population, incorporated current statin use as well as metabolic and kidney diseases.

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Chiadi Ndumele, chair of the American Heart Association’s CKM Scientific Advisory Group, emphasized that the actual PREVENT risk thresholds for statin use in cardiovascular prevention will need to be decided in clinical guidelines, and that has not yet occurred. He also acknowledged criticism of the earlier risk model.

“We updated the AHA risk prediction model to PREVENT reflecting the growing influence of inter-related metabolic risk factors (obesity, diabetes, metabolic syndrome) and chronic kidney disease on cardiovascular disease risk,” Ndumele, director of obesity and cardiometabolic research at Johns Hopkins University, told STAT in an email. “It is therefore not surprising that the investigators found about twice the predicted event rate for the PCEs vs. PREVENT, reflecting this difference.”

Under the current guidelines, most people with a 10-year risk of 7.5% or more for developing cardiovascular disease are advised to take a statin, while at a 5% risk, they’re told only that they and their doctors should consider doing so.

“Analyses are underway,” Ndumele said. “Guidelines will have to consider whether and how to update recommendations to include PREVENT risk thresholds to guide clinical decision making.”

Related: Reversing progress, stroke rates are rising, especially in working-age adults

What’s changed in the JAMA Internal Medicine analysis is how many people might be at risk, based on the new components put into the calculator. Overall, 4% of people had a 10-year risk of developing cardiovascular disease, compared to the 8% previously predicted by the PCE. The number of adults recommended for statins could drop from 45.4 million to 28.3 million.

Race, now recognized as a social not biological construct, was excluded in the newer equations. That meant 5.1% of Black adults were computed to be at risk, compared to 10.9% from the previous calculator. For older adults ages 70 to 75, the proportion at risk was 10.2%, down from 22.8%.

In a paradox, the study found that while fewer people might be eligible for statins, which now can cost as little as $40 a year, the estimates also say most people who would be advised to take them aren’t doing so.

“The prior risk equations and the PREVENT equations that we focus on in this study really seek to give doctors and patients sort of a starting percentage to say, is it worth having a conversation about statins?” lead study author Timothy Anderson, a primary care physician and an assistant professor of medicine at University of Pittsburgh Medical Center, told STAT. “When we’re seeing risk rates cut in half, I think that really is something that’s likely to impact how doctors and patients talk about these meds.”

The biggest predictor of risk remains age, Anderson said. “If you’re a borderline risk now, you’re likely to be higher risk in five years. And that’s a complicated set of conversations for primary care doctors and patients to have.”

That concerns Steven Nissen, a cardiologist at the Cleveland Clinic, who was not part of the study. “Age is the most powerful factor in the calculators, so if you wait until somebody is 60 or 65, you’re playing catch-up,” he said. “I tend to lean toward treating rather than not treating when it’s a borderline case, but only when the patient and I have a conversation.”

Nissen has been leading an effort in collaboration with AstraZeneca to make the 5-milligram dose of its drug, rosuvastatin, available without a prescription. He urged shared decision-making between doctor and patient, aware that busy primary care physicians may be pressed for time.

“Good medicine involves judgment. And the calculator is not a replacement for good medical judgment, which may come to a different conclusion,” he said. “I’m not very supportive of either calculator because I think that in general, it’s good to have a lower LDL,” or “bad” cholesterol.

There are a multitude of factors affecting cardiovascular health, and statins are just one piece, said Gregg Fonarow, chief of cardiology at UCLA, citing the AHA’s recent projection that 61% of the U.S. population will likely have cardiovascular disease. He did not take part in the current study.

Related: Decline in heart failure deaths has been undone, led by people under 45

“So many cardiovascular events are preventable, not just through medication but through lifestyle modification. We need to do such a better job with prevention,” Fonarow said. “This really represents an opportunity to use the new enhanced PREVENT risk score and better inform individuals of risk, but importantly, not just for 10-year risk, but their lifelong risk for disease.”

Ndumele said PREVENT will help guide use of preventive therapies beyond statins, relevant for people with cardiovascular-kidney-metabolic syndrome, a disorder in which metabolic risk factors, chronic kidney disease, and the cardiovascular system interact to cause multi-organ dysfunction and poor cardiovascular outcomes.

“I think the challenge with this paper is the assumption that the same threshold will be used for the recommendation of statin use,” Ndumele said. “Risk estimates from PREVENT are much closer to what is observed in reality than they were for PCEs, but there is need for discussion about the optimal risk threshold for preventive statin use in guidelines.”

Nissen said any changes should be thought through carefully, with this caveat: “The take-home message is that any of these calculators are the best guess about risk,” he said, “but the decision to treat is different from simply calculating a risk.”

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies . Our financial supporters are not involved in any decisions about our journalism.

About the Author Reprints

Elizabeth cooney.

Cardiovascular Disease Reporter

Elizabeth Cooney is a cardiovascular disease reporter at STAT, covering heart, stroke, and metabolic conditions.

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New Cholesterol Guidelines Personalize Risk and Add Treatments

• JAMA Clinical Guidelines Synopsis Management of Blood Cholesterol Francis J. Alenghat, MD, PhD; Andrew M. Davis, MD, MPH JAMA
• Medical News & Perspectives Highlights From the American College of Cardiology’s Scientific Sessions—New Heart Failure Management Guidelines, Alirocumab After a Myocardial Infarction, and Treating Mild Chronic Hypertension in Pregnancy Jennifer Abbasi JAMA

Last November, more than 15 000 clinicians alighted on Chicago for the American Heart Association (AHA) Scientific Sessions, the group’s annual flagship conference. The meeting featured the release of the federal government’s physical activity guidelines and results from several high-profile clinical trials, like VITAL and REDUCE-IT and DECLARE-TIMI 58 . The announcements also included new cholesterol clinical practice guidelines from the AHA, the American College of Cardiology (ACC), and several other organizations, the first update since 2013.

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Abbasi J. New Cholesterol Guidelines Personalize Risk and Add Treatments. JAMA. 2019;321(8):731–732. doi:10.1001/jama.2018.21019

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UK dietary saturated fat guidance supported by study

by University of Reading

A new study from the University of Reading has provided strong support for current U.K. dietary guidelines on saturated fat consumption, while also highlighting the potential for personalized nutritional advice in the future.

The research , published this month in The American Journal of Clinical Nutrition , simulated the effects of switching from a diet high in saturated fats to one that aligns with U.K. dietary fat recommendations—lower in saturated fats and higher in unsaturated fats .

Key findings include:

• On average, reductions in total and LDL—cholesterol (often called "bad" cholesterol) levels were seen in the middle-aged male participants.
• The ratio of LDL to HDL ("good" cholesterol) improved.
• Individual responses varied significantly, with some participants showing dramatic improvements while others had minimal changes.

Professor Julie Lovegrove, lead researcher on the study, commented, "Our results strongly support current U.K. dietary guidelines to reduce saturated fat intake to no more than 10% of total energy and replace it with unsaturated fats. However, the variation in individual responses is fascinating and opens up exciting possibilities for personalized nutrition ."

Several ways in which dietary saturated fats affect blood cholesterol levels were examined in this human study. One important pathway for the uptake of bad (LDL) cholesterol by the liver was increased when saturated fats were replaced with unsaturated fats in the diet, but the large variation in response between participants was not solely explained by this pathway.

"How our bodies respond to dietary change is very complex and involves a number of different bodily processes" said Dr. Kim Jackson, co-investigator on the study. "It emphasizes the need for further research to identify reliable blood markers that can predict an individual's response to reducing saturated fat intake."

The research team is currently conducting a follow-up study to investigate other factors that could explain the variation in responses to dietary fat changes.

"Once we can identify those who would respond most significantly to saturated fat reduction, we can provide more targeted, personalized dietary advice," Professor Lovegrove explained. "This could lead to more effective dietary interventions and better health outcomes in the future."

This study is part of ongoing research at the University of Reading's Hugh Sinclair Unit of Human Nutrition, which aims to improve human health through nutrition.

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