A clinical trial rocked the cardiology community this week — not for what it showed, but for what it didn’t. On September 4, Novartis announced that pelacarsen, a drug targeting the cholesterol particle known as lipoprotein(a), or Lp(a), failed to significantly reduce the risk of cardiovascular death, heart attack, or stroke. One of the most anticipated drugs in cardiology turned out to be a dud.
Just this year, new cholesterol guidelines from the American Heart Association and American College of Cardiology recommended that all adults get their lipoprotein(a) checked at least once in their lifetime. The reason? Decades of research have shown that high levels of this cholesterol particle—which is genetically determined and minimally impacted by diet or exercise—strongly predict future risk of heart attack and stroke. Because drugs that lower other harmful cholesterol particles, like LDL, reduce cardiovascular risk, scientists hoped that lowering lipoprotein(a) would do the same.
Over the past decade, several such drugs emerged. Pelacarsen and others in development—including olpasiran and lepodisiran—have been shown to reduce lipoprotein(a) levels by 80% or more. Until now, though, no one knew whether that actually translated into fewer heart attacks and strokes. The trial of pelacarsen, known as Lp(a)HORIZON, enrolled more than 8,300 patients with established cardiovascular disease and elevated lipoprotein(a), randomized them to pelacarsen or placebo on top of existing standard-of-care, and followed them over several years. The negative result raises a real possibility: lipoprotein(a) might just be a marker of cardiovascular risk rather than a cause. In other words, we might be turning off the fire alarm rather than extinguishing the fire.
Cardiologists have been burned by this kind of reasoning before. Higher levels of HDL, the “good” cholesterol, are associated with lower cardiovascular risk. But niacin, a drug that raises HDL, failed to reduce heart attacks or strokes in large clinical trials.
Only the top-line results from the pelacarsen trial have been released so far; full data are expected later this year, and it’s possible it will still show benefit in some subgroup. It’s also possible that the medication offers benefits, but not when all other risk factors have already been optimized—patients in this trial were already on aggressive background therapy, with a well-controlled median LDL cholesterol of 66 mg/dL. Longer follow-up or earlier intervention might yield a different result. Time will tell. In addition, clinical trials of the other Lp(a)-lowering drugs are ongoing and may have different results—perhaps by enrolling different patient types or achieving more significant Lp(a) reduction
For now, the tried-and-true advice for preventing heart disease hasn’t changed: control blood pressure, cholesterol, and blood sugar through lifestyle and, when needed, medication; eat a diet rich in fruits, vegetables, nuts, and legumes; exercise often; avoid tobacco; limit alcohol; and prioritize consistent, quality sleep.
Christopher Rehbeck Kelly, M.D., M.S. is a cardiologist at UNC Rex Hospital in Raleigh, NC. He serves on the board of the American Heart Association in North Carolina and is the founder of Exact Healthcare. He graduated from the Columbia University College of Physicians and Surgeons and served as an intern, resident, and chief resident at NewYork-Presbyterian Hospital/Columbia University Irving Medical Center. He is co-author of the book, Am I Dying?!: A Complete Guide To Your Symptoms, and What to Do Next.
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