Heart disease patients taking an investigational class of drugs to achieve very low levels of cholesterol do not experience an increase in adverse events, including memory impairment or nervous system disorders, but may have an increased risk of cataracts, according to a study led by a UI College of Public Health researcher.
However, the researcher says the results will not likely change the use of statins as the primary tool to reduce cholesterol levels and other cardiovascular risks.
The new class of drugs – called PCSK9 inhibitors – were studied in combination with statins to lower LDL cholesterol, or bad cholesterol, in high-risk patients who were unable to achieve desired cholesterol levels using only statins or other lipid-lowering therapies.
The study, led by Jennifer Robinson, UI professor of epidemiology and medicine and director of the UI Preventive Intervention Center, sought to address concerns about how very low levels of LDL cholesterol effect body functions that rely on cholesterol, including hormone production, digestion, and healthy cell structure.
“The safety of these new drugs is critical to patients who have no other means by which to control their life-threatening high cholesterol,” says Robinson. “The long-term effects of very low levels of LDL cholesterol are under evaluation in ongoing large clinical trials.”
The study appears in the Feb. 7, 2017, issue of the Journal of the American College of Cardiology, which was published online Jan. 30, 2017.
Researchers pooled data from 14 randomized, controlled studies that included 5,234 patients treated with the PCSK9 alirocumab for up to two years. They looked for the occurrence of adverse events in patients who achieved two or more consecutive LDL cholesterol values of less than 25 mg/dL or less than 15 mg/dL. An LDL level of 25 md/dL was used because it has been suggested to be the level needed for normal cell function.
The overall incidence of adverse events was similar in patients taking alirocumab versus those taking placebo. Adverse symptoms monitored included musculoskeletal disorders, neurologic and neurocognitive conditions (including memory), and renal or liver problems. There was not an increased incidence of diabetes, despite previous studies showing an excess of diabetes in patients with LDL cholesterol lower than 30mg/dL on statin therapy.
Analyses did show an increased incidence of cataracts in patients with LDL less than 25 versus greater than 25. It was not clear what caused this increase, although researchers said it could be because reducing cholesterol accelerates underlying aging-related changes, contributing to cataracts.
While the investigation suggests the very low levels of LDL cholesterol were well-tolerated in limited trials, the long-term effects of PCSK9 inhibitors remain unknown, according to Robinson. As a result, she says statins remain the mainstay of cardiovascular risk reduction therapy.
“Statins have an excellent record of safety in properly selected patients,” says Robinson. “Therefore, every effort should be made to maximize statin therapy before considering adding a nonstatin such as alirocumab to further reduce LDL-C levels.”
Editor’s Note: This release is adapted from a release prepared by the Journal of the American College of Cardiology.
Jennifer Robinson, CPH professor of epidemiology, has been appointed to fill a vacancy on the National Forum for Heart Disease & Stroke Prevention’s Board of Directors. The National Forum is a multidisciplinary, non-profit health organization addressing cardiovascular health. Its members represent more than 80 national and international organizations from public and private health care organizations, as well as faith, advocacy, academic, and policy settings.
Robinson is a professor in the Departments of Epidemiology and Medicine (Division of Cardiology) and the director of the Prevention Intervention Center at the University of Iowa. She has performed numerous clinical trials sponsored by the National Institutes of Health and the pharmaceutical industry and conducted extensive research on a wide range of anti-atherosclerotic and metabolic agents, including lipid-modifying, anti-inflammatory, antihypertensive, weight loss and diabetic treatments, as well as postmenopausal hormone therapy.
Dr. Robinson is the principal investigator for the Women’s Health Initiative (WHI) at the University of Iowa and has published over 150 peer-reviewed articles in the area of lipids-modifying drugs, cardiovascular risk stratification, and cardiovascular prevention. She is also the chair for the National Forum Cholesterol Risk Awareness Initiative. Prior to her current work, she was vice-chair for the 2013 American Heart Association/American College of Cardiology Cholesterol Guidelines and a member of the 2013 American Heart Association/American College of Cardiology Risk Reduction Guidelines.
Cardiovascular disease is the leading cause of death in the United States. According to the U.S. Centers for Disease Control, cardiovascular disease killed 611,000 Americans in 2013. But hundreds of thousands of people have the power to prevent cardiac events by managing their blood cholesterol levels, says Jennifer Robinson, MD, MPH, professor of epidemiology in the College of Public Health and professor of internal medicine in the Carver College of Medicine.
Robinson has performed numerous clinical trials sponsored by the National Institutes of Health and the pharmaceutical industry, and she serves as the chair of the Cholesterol Awareness Initiative of the National Forum for Heart Disease & Stroke Prevention. She was a member of the panel that recently revised the blood cholesterol guidelines of the American College of Cardiology and the American Heart Association. Robinson has also worked as a lead researcher in the development of a powerful new class of cholesterol drugs called PCSK9 inhibitors.
What important changes came out of the effort to establish new blood cholesterol guidelines?
We did a systematic review of the evidence, and it told us something new: What we really need to do is treat people based on risk rather than focus solely on blood cholesterol numbers. You need your doctor to look at all of your risk factors — age, sex, blood pressure, whether you smoke — along with cholesterol levels. If you have more than a 1-in-20 chance of having a heart attack or stroke in the next 10 years, you will benefit from treatment.
What kind of treatment?
A healthy lifestyle is the foundation for preventing heart attack and stroke. As we age, and for people with genetically high cholesterol levels, drug treatment often needs to be added. We have very safe cholesterol-lowering drugs called statins. We have studied statins in clinical trials in a wide range of people, from people with heart disease all the way to low-risk populations with low cholesterol levels. Across the board, statins prevented heart attacks, strokes, and deaths. We’ve learned from the science and have come up with better ways of doing things.
How were the new recommendations received?
Some scientists looked at them and said, “That can’t be right. Let’s look at our data.” And every time they’ve applied our new guidelines versus the old way, the new way based on patient risk is better. One study looked at an application to the U.S. population and found that our new guidelines would prevent 450,000 more heart attacks and strokes over 10 years.
What are PCSK9 inhibitors, and what role do they play in all of this?
They’re a new class of drugs that enhance the body’s natural machinery for getting rid of low-density lipoprotein, also known as LDL or “bad” cholesterol. Liver cells have receptors that pull LDL out of the blood so that it can be excreted from the body. PCSK9 is a protein, and its molecules bind to those LDL receptors and cause them to break down. PCSK9 inhibitors are antibodies that you inject every two weeks to protect those LDL receptors so they can keep taking cholesterol out of the blood. This lowers LDL another 50 to 65 percent on top of what statins do. So you’re getting LDL levels closer to 50 instead of 200 or higher.
But this is high-tech stuff. It’s expensive. The health payers are already saying they can’t afford to give PCSK9 inhibitors to everybody who could benefit from them. They’re the right choice for people who have genetic high cholesterol. You need to treat those people any way you can — cost is not a consideration. Now we’re struggling to determine the appropriate use beyond that, since some patients with cardiovascular disease may not be able to tolerate a statin.
Can the average person manage blood cholesterol without drugs?
It would be great if everybody had a healthy lifestyle — eating a heart-healthy diet, getting regular physical activity, controlling their weight, avoiding smoking, and encouraging kids to adopt healthy habits. But unfortunately that’s not where most Americans are. So in addition to lifestyle, everybody should get a cholesterol screen. Kids should have their cholesterol checked between ages 8 and 11, and adults should have been screened at least once by age 21, and then again every five years.
Screening is the only way to find out if you have genetic high cholesterol. One in 300 people has it. It’s the most common genetic disorder, and it’s a silent killer. Those people need a statin drug, starting as early as we can find them.
Then let’s talk about the other 299 people. Most of the heart attacks and strokes occur in those other 299 out of 300. Get checked out and have a conversation with your doctor about your risk factors, including cholesterol levels. We want to catch people before their first heart attack. A third of the time, the first heart attack is fatal.
Certainly, follow a healthy lifestyle. But by age 50, you’ve got enough cholesterol buildup in your arteries that lifestyle by itself may not be enough. Take a statin and stick with it. Statins are the best way to lower cholesterol and are proven to reduce heart attack, stroke, and death. It’s such easy insurance.
This article originally appeared in the Fall 2015 issue of InSight.