In August 2025, I wrote a piece for KevinMD titled “Are we repeating the statin playbook with lipoprotein(a)?” I was skeptical of the excitement surrounding a new generation of drugs that could lower Lp(a) by 80 to 90 percent. Not because I knew they wouldn’t work, but because nobody had demonstrated that lowering Lp(a) actually prevented heart attacks.
I had seen this movie before with HDL cholesterol. We spent years developing drugs that raised HDL beautifully, only to discover that patients didn’t live longer or have fewer cardiovascular events. I suggested we might be making the same mistake with Lp(a).
Well, the results are in.
On November 7, the New England Journal of Medicine published the long-awaited Lp(a)HORIZON trial. More than 8,300 patients with established cardiovascular disease and elevated Lp(a) were randomized to monthly injections of pelacarsen or placebo.
The drug did exactly what it was supposed to do. It lowered Lp(a) by approximately 78 percent. That’s an extraordinary biochemical achievement.
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Unfortunately, after nearly five years, the cardiovascular outcomes were virtually identical. Major cardiovascular events occurred in 12.3 percent of patients receiving pelacarsen compared with 12.1 percent receiving placebo. The absolute risk reduction was zero. Technically, the treated group did slightly worse, although the difference was not statistically significant. Even patients with the highest baseline Lp(a) levels derived no detectable benefit.
Let that sink in. We took a molecule that epidemiologists and geneticists have spent decades telling us is an important causal risk factor for cardiovascular disease. We developed an extraordinarily sophisticated drug that reduced it by nearly 80 percent. We treated thousands of high-risk patients for almost five years.
And nothing happened. No fewer heart attacks. No fewer strokes. No cardiovascular benefit.
Novartis has now abandoned further development of pelacarsen for atherosclerotic cardiovascular disease. I don’t take pleasure in seeing a promising therapy fail. I would much rather have another effective tool to prevent heart attacks.
But I do take some satisfaction in seeing a hypothesis subjected to a proper randomized trial before we commit another generation of patients to treating a laboratory number. This is precisely what I was questioning in my original article.
I have been a lipidologist for much of my 35-year medical career. I even spent years hosting a radio program called Lipid Luminations. I understand the lipid hypothesis as well as most physicians, and I certainly spent enough time promoting it.
But somewhere along the way, I began to question our tendency to confuse risk factors with causes and causes with useful treatment targets. Those are three different things.
An elevated Lp(a) is associated with cardiovascular disease. Genetic studies provide compelling evidence that it contributes causally to atherosclerosis. But neither observation guarantees that lowering Lp(a) in a sixty-year-old with established coronary disease will prevent another heart attack. HORIZON demonstrated that distinction rather convincingly.
Of course, the lipid community is already offering explanations. Perhaps we intervened too late. Perhaps the drug didn’t lower Lp(a) enough. Perhaps another technology will work better. Perhaps patients need to be treated for ten or twenty years. All reasonable possibilities. But they are hypotheses. Again.
I find myself wondering whether we’ve become so enamored with identifying and manipulating individual molecules that we’ve lost sight of the disease itself. Why does atherosclerosis begin? What injures the endothelium? Why does inflammation become chronic? What role might infection and the immune response play?
I have written extensively about the possibility that chronic infection contributes to atherosclerosis. That theory remains unproven, and pelacarsen’s failure certainly doesn’t establish it. But I would argue that we should be spending considerably more intellectual energy investigating what initiates arterial injury rather than continually developing more sophisticated ways to remove particles from the bloodstream.
I’ve also wondered why Lp(a) exists in the first place. Its evolutionary history and relationship to plasminogen suggest that its biology may involve wound healing, thrombosis, and host defense. Perhaps it’s doing more than simply depositing cholesterol in an artery. We don’t know nearly as much as we pretend to.
To be clear, HORIZON does not prove that Lp(a) is innocent. Other Lp(a)-lowering trials are underway, and perhaps one will demonstrate a meaningful clinical benefit. I hope it does. But we now have the first large randomized outcomes trial of a drug specifically designed to lower Lp(a), and the result is unequivocally disappointing.
The drug worked on the biomarker. It failed on the disease. I think that’s worth remembering the next time we hear about a revolutionary new treatment that lowers some cardiovascular risk marker by an astonishing percentage.
Show me the absolute risk reduction. Show me the number needed to treat. Show me fewer heart attacks, strokes, or deaths. Then I’ll get excited.
Until then, I remain a lipidologist in recovery, increasingly convinced that we understand less about the origins of atherosclerosis than our guidelines would have us believe. And perhaps that’s not such a bad place for science to begin.
Larry Kaskel is an internist and “lipidologist in recovery” who has been practicing medicine for more than thirty-five years. He runs a concierge practice in the Chicago area and serves on the teaching faculty at the Northwestern University Feinberg School of Medicine. He is also affiliated with Northwestern Lake Forest Hospital.
Before podcasts were even a thing, Dr. Kaskel hosted Lipid Luminations on ReachMD, building a library of more than four hundred shows featuring thought leaders in cardiology, lipidology, and preventive medicine.
He is the author of Dr. Kaskel’s Living in Wellness, Volume One: Let Food Be Thy Medicine, a book that blends evidence-based medicine with practical strategies for a longer healthspan. His current work focuses on rethinking the cholesterol hypothesis and exploring the infectious roots of atherosclerosis. More information is available at larrykaskel.com.
