Princetonians Weigh In on New Cholesterol Testing Guidelines

On March 13, the American Heart Association released new cholesterol guidelines for the first time since 2018. And for the first time ever, the guidelines included a recommendation that everyone get tested for something called lipoprotein(a), also known as Lp(a) (and pronounced “L-P-little-A”). According to Dr. Dennis Leahy ’69, a retired cardiologist living with elevated Lp(a), the recommendation to test is long overdue. Elevated Lp(a) has been associated with cardiovascular disease for decades, yet it does not respond to diet and exercise, and no drugs are specifically approved to target it. “It got this reputation as an unmodifiable risk factor,” Leahy says. That may be about to change.

Like HDL and LDL, terms readers may be familiar with from standard blood tests, Lp(a) is a molecule that ferries cholesterol around in the blood. LDL is the more recognized villain (commonly known as the “bad” cholesterol reading). Lp(a) deposits cholesterol on the artery walls as well, but it carries an extra protein that makes it a true supervillain: The complex molecule promotes inflammation and interferes with the body’s own blood-clot-dissolving response. As Leahy describes, “This creates a perfect storm setup for heart attacks and most strokes: the sudden disruption of a plaque and clot formation in an inflamed artery.” In addition, unlike LDL, one’s Lp(a) level is impervious to healthy practices like diet and exercise and instead is almost entirely genetically determined — “your Lp(a) level will be roughly the same at ages 5 and 50,” says Leahy.

“With LDL, we see this classic bell curve of numbers in the population,” says Dr. Karen Joynt Maddox ’00, a cardiologist and professor of medicine and public health at Washington University in St. Louis, “but with Lp(a), most people have values around 10 or 15 and then there is a long tail where people can have numbers 10 or 20 times that.” Global epidemiological studies have shown that 20% of the world’s population has high enough Lp(a) levels to double their risks for heart attacks, strokes, and a dangerous narrowing of the aortic valve.

People often discover they are in that 20% after a heart problem that seems to come out of nowhere. “You have the people who do the right things — they’re running and they eat right, yet they come in with aggressive coronary disease,” says Dr. Ajay Kirtane ’94, professor of medicine at Columbia University, “and we think, this person may have elevated Lp(a).”

Long family histories of vascular disease are also suggestive. “I always knew heart problems were in my deck of cards,” says Alison Meloni *95, since both her mother and grandmother suffered aortic valve narrowing, and her father died of a heart attack, “but there was no thought in my mind I would have this.” Meloni is a clinical research medical director at Amgen, one of the pharmaceutical companies with an Lp(a) drug in trials. Though she does not work on the program, hearing people at work talk about it prompted her to get an Lp(a) test. Despite being on a different heart medication that can lower Lp(a) slightly, hers was elevated.

“You have the people who do the right things — they’re running and they eat right, yet they come in with aggressive coronary disease, and we think, this person may have elevated Lp(a).”

— Dr. Ajay Kirtane ’94, Professor of medicine at Columbia University

With no FDA-approved medications to lower Lp(a), there’s been no emphasis on testing in the United States — until now. “The testing numbers have been abysmal,” says Dr. Taher Modarressi ’09, a lipid specialist at Advocare Princeton Cardiometabolic Health. “In New Jersey, it’s 2%, and it’s not like every doctor is testing 2% of patients, but more like a few doctors are doing all of the testing.” Nationally, studies suggest less than 1% of the eligible population has been tested. As Meloni says, “There’s the question of, ‘did you want to know if there’s nothing you can do?’”

But Leahy, who has suffered from cardiac issues since 2007, argues there are some things one can do while waiting for drug approvals. “If one has an elevated Lp(a) level, achieving ultra-low LDL levels can offset or delay its potentially devastating consequences,” he says. Joynt Maddox, who also has elevated Lp(a), says she told her doctor she wanted to go on a statin, even though her LDL was not especially high. The medication has cut her LDL in half. “Everyone has some risk,” she says. “There is the risk you cannot control,” like Lp(a), “and the risk you can control.”

The ability to control Lp(a) may be on the horizon with several drugs in the pivotal, final-stage trials required for FDA approval. Four of the five drugs in development use a novel genomic technology that silences the gene that codes for the protein that makes Lp(a) so dangerous. “The fact that Lp(a) levels are genetically determined opened up an entirely new line of research,” says Dr. Gregory Curfman ’68, executive editor of the Journal of the American Medical Association (JAMA) and JAMA Cardiology. “Now the question is, does reducing Lp(a) actually reduce heart attacks and other events?”

While a “yes” from the trials may seem likely given the strong association between Lp(a) and heart disease, Curfman urges caution. “I’ve seen a lot of promising things not pan out,” he says, like drugs that raised HDL, thought to be cardio protective, but turned out not to decrease heart attacks. And as Rachel Sachs ’09, a professor of law at Washington University in St. Louis specializing in health law and food and drug regulation, points out, the FDA may be intending to learn whether there is a 1-to-1 relationship between Lp(a) lowering and the actual prevention of heart disease. “If one drug lowers Lp(a) by 95% and the other by 85%, how does that difference translate to reducing heart attacks?”

“The fact that Lp(a) levels are genetically determined opened up an entirely new line of research. Now the question is, does reducing Lp(a) actually reduce heart attacks and other events?”

— Dr. Gregory Curfman ’68, Executive editor, Journal of the American Medical Association (JAMA), JAMA Cardiology

If one or more of the new drugs are approved, questions abound. “The new paradigm in cholesterol treatment is factoring in years of exposure to an elevated number,” says Joynt Maddox. “Since people with elevated Lp(a) are born with it, one question is, would you put an adolescent on it for the rest of their life? What will be the risk-benefit tradeoff?” How quickly will secondary trials for people like Meloni, who have elevated Lp(a) but are otherwise healthy, get underway? “As the FDA learns more,” says Sachs, “they might in the future accept trials in which Lp(a) lowering itself is accepted,” because the link between Lp(a) and events like heart attacks and strokes will have already been established, in the same way that blood glucose lowering is accepted to lower the risk for blindness and amputations in diabetes.

These questions, however, do not cast doubt on the value of testing for Lp(a). “I fell in love with lipids because of the promise of prevention,” says Modarressi. “Testing gives us an opportunity to refine cardiovascular risk assessment and personalize treatment approaches.”

“We all know people who just suddenly had a heart attack,” Kirtane says. “If there is testing that can be done to identify these people at an earlier age and perhaps institute preventative therapies, that is beneficial.”