Lp(a)HORIZON, Oral PCSK9s, and 2027 Lipid Trials, with Kausik Ray, MD, MBChB, MPhil

Human genetics has long supported lipoprotein(a) [Lp(a)] as a causal cardiovascular risk factor, but the first outcomes trial of a targeted Lp(a)-lowering therapy did not deliver the expected result.

The phase 3 Lp(a)HORIZON trial enrolled 8,323 patients with established cardiovascular disease and Lp(a) levels of 70 mg/dL or higher. Pelacarsen did not significantly reduce the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization vs placebo, according to data presented at the American Heart Association Scientific Sessions 2026.1

While this trial has dominated headlines from the meeting, the world of lipidology has welcomed several signfiicant advances in the last year, including the approval of enlicitide (Lipfendra) in July 2026—marking the first approval for an oral PCSK9 inhibitor. In 2 placebo-controlled trials of 3,207 adults receiving maximally tolerated statins, enlicitide lowered LDL-C by approximately 56% and 59% at week 24. However, the approval for enlicitide arrived before cardiovascular outcomes data for the agent.

Investigators are also comparing add-on options for patients above their LDL-C goal. The phase 3 MEDICI trial is randomizing approximately 426 patients at high to very high cardiovascular risk across Europe to obicetrapib 10 mg or bempedoic acid 180 mg. Both agents are added to maximally tolerated lipid-lowering therapy, with percent change in LDL-C at day 84 as the primary end point.3

Kausik Ray, MD, MBChB, MPhil, professor of public health at Imperial College London and director of the Imperial Centre for Cardiovascular Disease Prevention, has led several pivotal lipid-lowering trials and sat down with HCPLive at the AHA 2026 to discuss Lp(a)HORIZON, remnant cholesterol targets, enlicitide, and the lipid trials to watch in 2027.

Q&A: Lp(a), remnant cholesterol, and oral PCSK9 inhibitors

HCPLive: How does Lp(a)HORIZON influence how you think about lipoprotein(a) as a modifiable risk factor?

Kausik Ray, MD, MBChB, MPhil: It doesn't change whether I think Lp(a) is a causal risk factor or not. The biology and the human genetics are there for why we should be thinking about it. What it changes is my thinking about whether I will be able to modify what I ultimately want to change, which is clinical events. The answer now is probably that it depends on the circumstances. Lp(a) clearly can't behave like LDL cholesterol, so it might be, for example, changing plaque stability rather than the amount of plaque, which is what LDL is changing. What that means is that maybe these treatments we're developing are going to work much faster because of the relevance of high Lp(a) in a primary prevention setting. But it also means we're going to have to have a reset in identifying who among secondary prevention patients, where we've thrown various other things at them in terms of risk factor control, would still benefit. Is it a question of having to go to even higher Lp(a) levels? Is it only going to work in terms of modifying disease when other risk factors are uncontrolled, because I'm laying down new plaque and it's vulnerable? Or, because I've waited so long, am I going to have to go even further in terms of duration of treatment? What it also tells me as a clinician managing patients is that, at the moment, I'm going to manage conventional risk factors very aggressively, as I have been doing, to try to mitigate the risk of a high Lp(a).

HCPLive: With new ApoC3, ANGPTL3, and ANGPTL4 data at this meeting, is remnant cholesterol the next major target?

Kausik Ray, MD, MBChB, MPhil: It is, because of the human genetics supporting the pathway. But the problem with remnant cholesterol is there are lots of different stages, and there are lots of things that can modify it. What we don't know is which of those is going to work or is the best. The genetics tells you pathways giving you higher levels are associated with worse outcomes. We've seen genetically that some of the things people are now targeting would also give you lower risk and better outcomes. So we've targeted those, but the problem is they're so interrelated. If you target ANGPTL3, some of this is going to go onto ANGPTL4, for example, so maybe the effect is going to be more modest just from inhibiting that. The same is true if you inhibit ANGPTL4. You're going to get a certain amount of reduction, but some of it will go onto ANGPTL3. Then you've got ApoC3. I think the one obvious one, the easy win, is in pancreatitis, and we've seen that consistently now. It's great that you see it in severe hypertriglyceridemia and in FCS, and that clearly is now the treatment of choice in that patient population. But for ASCVD, we're still not certain. There was also some data a few years back on the ANGPTL3/8 complex, and that actually might be the right target to go for when you're targeting remnant cholesterol, because you're now getting complete inhibition and a much bigger change in ApoB as a result. That's really where I think this field has to go. Somebody's going to have to either take a leap of faith on one of these targets and go that little bit further, or we work through the biology a little bit more and then pick the right target to go forward with, which, you know, I'm hedging much more toward ANGPTL3/8.

HCPLive: How do you weigh the potential benefit of enlicitide, the newly approved oral PCSK9 inhibitor, before outcomes data are available?

Kausik Ray, MD, MBChB, MPhil: LDL lowering by 5 different pathways has shown cardiovascular benefits. We know that if you lower PCSK9 or inhibit the ability of PCSK9 to interact with the LDL receptor, you will lower LDL. We've got monoclonals that have shown that, and we know next year we'll have 2 inclisiran outcome trials. If those show a benefit, are we going to look back and say it wasn't the LDL? Clearly not. Enlicitide does exactly what it's designed to do. It interferes with the interaction between PCSK9 and the LDL receptor, and as a result, it lowers LDL cholesterol. The benefits will relate to the absolute change in LDL, and that's your relative risk reduction: 38 mg/dL, 22% benefit.

HCPLive: Which lipid trials should clinicians keep an eye on heading into 2027?

Kausik Ray, MD, MBChB, MPhil: We will get the ORION-4 data early next year. It's scheduled for the first quarter; the exact date is not known, but that's what we expect. That's the first cardiovascular outcome trial with inclisiran. In the second half of the year, we should get VICTORION-2 PREVENT, which is a global trial of secondary prevention. ORION-4 is US and UK; this is a global one in secondary prevention. Those 2 together will absolutely answer that question. There's [VICTORION-PLAQUE], which was the imaging study with inclisiran looking at intravascular ultrasound. Then we'll see the [AZD0780] data, which is the other oral PCSK9 inhibitor, but it works differently. Enlicitide is much more like a monoclonal, working in the plasma. This one works inside the hepatocyte, stopping the LDL receptor from being degraded, so it's much more like inclisiran. We've seen some good phase 1 and phase 2 data, and we'll see the first phase 3 data probably in the first quarter of next year.

I'm not sure yet when I'll be presenting it, but I'm completing a trial called MEDICI, which is a head-to-head trial of obicetrapib compared against bempedoic acid in people in Europe, across multiple countries and multiple sites, looking at those people above goal and which of these options is the best next add-on. That'll be important, and we're looking forward to the approval of obicetrapib in the UK, having another shot at goal. In the absence of treatments that lower Lp(a), we sometimes use PCSK9-directed therapies in a lot of our patients because these people have a higher residual risk. The number goes down, and psychologically, the patients feel a bit better, but you're doing it because of the overall risk profile. So I could see obicetrapib being used a lot more in those patients, because it gives the LDL reduction, particularly when it's combined with ezetimibe, but also gives you added reductions for some of those patients who are worried about their Lp(a). Those are some of the main ones. We're also going to see some real-world initiation studies with inclisiran.

The other one I'm really looking forward to is EVOLVE-MI. This year, we had a trial called AMUNDSEN, and I wrote the editorial for it. The problem with it was it was too short. It's 2000 patients post-ACS. A lot of people got the wrong end of the stick: You get to an LDL of 16, so why doesn't that show you a benefit at 1 year compared with standard of care? Well, you've only treated them for 1 year. It's a marathon and not a sprint. EVOLVE-MI, which should report out at ESC, will be 6000 patients, with total events over 1600, and I predicted from some of the models we've used it would give you somewhere between a 15% and 20% cardiovascular risk reduction. That means your standard of care becomes: You come to the hospital, you've had your ACS, and you go out on a PCSK9 therapy. In this case, it's evolocumab being studied with a statin, and that's your care. No LDL gatekeeper; irrespective of LDL, you're giving combination therapy. That's a trial I actually wanted to do about 8 years ago, but people were not sure about it, and now it's being done anyway. I think it's incredibly important, because that trial changes guidelines and care pathways. None of this stepwise nonsense. There's lots to look forward to next year.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Novartis. Novartis announces Lp(a)HORIZON phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD). Published September 4, 2026. Accessed November 8, 2026. https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd

2. US Food and Drug Administration. FDA approves first oral PCSK9 inhibitor to lower LDL cholesterol in adults with high cholesterol. Published July 17, 2026. Accessed November 8, 2026. https://www.biospace.com/press-releases/fda-approves-first-oral-pcsk9-inhibitor-to-lower-ldl-cholesterol-in-adults-with-high-cholesterol

3. A. Menarini International Licensing S.A. Obicetrapib versus bempedoic acid to treat dyslipidemia in patients at high to very high cardiovascular risk (MEDICI). EU Clinical Trials Information System identifier: 2025-524265-24-00. Accessed November 8, 2026. https://ctis.eu/trial/2025-524265-24-00