One of the most anticipated developments this year in the world of cardiology, and specifically prevention, is the first large clinical trial to ask a deceptively simple question: If we substantially lower lipoprotein(a), or Lp(a), can we reduce cardiovascular events?
The answer from the Lp(a)HORIZON trial is, at least for now, not as clear as we had hoped. This month, we wanted to dig into what we observed from the limited announcement regarding outcomes, and how we should be thinking about Lp(a) moving forward.
Why does Lp(a) matter?
Lp(a) is a cholesterol-carrying particle that is largely determined by genetics. About one in five people has an elevated level, which is independently associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Unlike LDL cholesterol, Lp(a) is minimally affected by diet, exercise, or weight loss.
This makes Lp(a) an important piece of the cardiovascular-risk puzzle, especially for young people. It can help explain why some people develop heart disease despite apparently favorable traditional risk factors and optimal lifestyle.
What did HORIZON test?
HORIZON enrolled 8,323 people with established cardiovascular disease and elevated Lp(a). Participants had previously experienced a heart attack, ischemic stroke or symptomatic peripheral artery disease, and their Lp(a) was at least 70 mg/dL (with a normal cutoff of <29mg/dL). They were randomized to monthly injections of pelacarsen — an antisense medication designed to reduce production of Lp(a) — or placebo. Importantly, everyone continued receiving guideline-directed cardiovascular care, including lipid-lowering and blood-pressure treatment.
Though we don’t have exact data regarding trial participants in HORIZON phase 3 (outcomes), we can assume similar baseline characteristics as phase 2, which noted >80% of participants on a statin, ~50% on ezetimibe and roughly 20% were on a PCSK9 inhibitor. Bottom line: we believe these patients were already on good treatment.
The trial followed patients for years and asked whether lowering Lp(a) would reduce the risk of cardiovascular death, heart attack, stroke or urgent coronary revascularization.
What Did We Learn?
Pelacarsen successfully lowered Lp(a), but that did not translate into a statistically significant reduction in cardiovascular events.
What Now? How are we Thinking About These Results?
The positive: We now have powerful evidence that Lp(a) can be dramatically lowered with medications. This proof of concept will be helpful for future studies.
The negative: Simply lowering Lp(a) did not reduce cardiovascular events in this high-risk population receiving care with guideline directed medical therapy.
The puzzling: Why would a biomarker so strongly associated with cardiovascular disease fail to produce an obvious benefit when we lower it? We don’t yet know. What we do know is that treating known risk factors (including cholesterol, blood pressure, stress, sleep apnea, insulin resistance) aggressively is highly effective in lowering risk of cardiovascular event risk.
The question to ask may simply be whether lowering Lp(a) in an already well-treated individual will produce better cardiovascular outcomes. Additionally, there may be variability in this population based on the degree of Lp(a) elevation, as well as the presence of other risk enhancing conditions.
The full HORIZON dataset and results from other Lp(a)-lowering trials (ongoing) will be particularly important and interesting.
What should we do today?
The HORIZON results do not make elevated Lp(a) irrelevant. Quite the opposite: Lp(a) remains an important inherited risk marker, and current guidelines recommend measuring it at least once in adulthood. When Lp(a) is elevated, the best-established strategy is to be especially aggressive about the risk factors we can change — particularly ApoB (and LDL) cholesterol, blood pressure, glucose/metabolic health, smoking, exercise and nutrition.
For patients with established cardiovascular disease who have not reached LDL/Apo treatment goals despite maximally tolerated statin therapy, current guidelines recommend considering additional therapy such as a PCSK9 inhibitor, which can also modestly lower Lp(a).
And this is where an important principle of the BaleDoneen Method comes into focus. For decades, we have been testing, measuring, and optimizing the modifiable drivers of vascular disease in our patients, rather than waiting for a single new medication to solve the entire risk problem. Additionally, Vitamin B3 continues to be recognized as an important supplement for patients with Lipoprotein(a).
Lp(a) may be inherited, but overall cardiovascular risk is not determined by Lp(a) alone. HORIZON reminds us that sophisticated prevention is about understanding the whole risk picture and aggressively addressing every factor we can influence.
The Lp(a) story is not over. But while we await the next chapters, there is already plenty we can do to protect our arteries today.
