Commentary|Articles|November 12, 2026

Oral Enlicitide Could Close Primary Prevention Gap: Christie Ballantyne, MD

Author(s)Pearl Steinzor, Christie Ballantyne, MD

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In this Q&A, Christie Ballantyne, MD, explains why consistent LDL-C lowering with oral enlicitide could expand PCSK9 use in primary prevention.

Uptake of nonstatin therapies in primary prevention has lagged behind their use in patients who have already had a heart attack or stroke, and a once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor that is simple to prescribe could help change that, said Christie M. Ballantyne, MD, chief of the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine, in an interview with The American Journal of Managed Care^® (AJMC^®).

New analyses presented at the American Heart Association (AHA) Scientific Sessions 2026 found that enlicitide (Lipfendra; Merck) reduced low-density lipoprotein cholesterol (LDL-C) by 57% to 63% vs placebo across AHA Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) risk categories in the phase 3 CORALreef Lipids (NCT05952856) trial. In an open-label extension with no control group, reductions were sustained through week 104.¹ The FDA approved the once-daily 20-mg tablet in July 2026 as the first oral PCSK9 inhibitor.²

In this Q&A, Ballantyne explains why consistent results across risk groups are reassuring, why he urges clinicians to weigh 30-year risk in younger patients, how a simple daily pill could fit into routine care, and what the ongoing outcomes trial will add.

AJMC: Can you give some background on the study, including its efficacy findings and what care gap in primary prevention led to this analysis?

Ballantyne: CORALreef Lipids is a study looking at high-risk individuals, a mixture of secondary and primary prevention. They had to have some risk factors for their primary prevention side, and they were randomized 2:1 to enlicitide 20 mg or placebo. Overall, there was about a 60% reduction in LDL cholesterol, very good reductions in non-HDL [high-density lipoprotein] cholesterol, 52% [to] 53%, and apolipoprotein B [apoB] of about 50%. It was a 52-week duration study.

AJMC: Can you talk about the study population, particularly the participants in primary prevention?

Ballantyne: One of the reasons for this design is because what we've seen is the uptake in terms of primary prevention of some of the nonstatin therapies has not been as high as [in] the very high-risk patients [who] already had a heart attack or a stroke. So the inclusion of a large number of people in primary prevention was very important. One of the things that comes up is most health care providers, when it comes to cholesterol, are not used to giving an injection. So having an oral formulation might make things simpler and easier for both the health care provider and the patients in terms of initiation of a new therapy.

AJMC: As PREVENT risk increased, so did age, diabetes prevalence, and antihypertensive use, but baseline LDL-C stayed similar. What could this tell us about the patients who stay above LDL-C goals on statin therapy?

Ballantyne: Well, the trial was designed [so] you had to be over 70 [mg/dL LDL-C]. If you look at the individuals who came in with primary prevention, it's about 850. They were scattered over the various risk categories, from low risk, less than 3%, to over 10%. Now, the most obvious thing is the risk calculators put a lot of weight on age. We know that age is probably the single biggest risk factor for having events, and so as the risk goes up, you see the age goes up. What was reassuring is that in all of the risk categories, you got a very good reduction in LDL cholesterol, right around 60%, [as] seen for the overall study. Non-HDL went down; apoB went down. Those are our key parameters in terms of risk for cardiovascular events, and then the safety was also very good. It is something, though, that we need to be looking at all the risk factors. And one of the things about the PREVENT [equations] is, in the younger people, don't just look at the short-term risk, the 10-year risk. Look at the 30-year risk.

AJMC: Placebo-corrected LDL-C reductions ranged from 57% to 63% across all risk groups at week 24. How should clinicians read that consistency, and did any of the results surprise you?

Ballantyne: No, it was always very reassuring that you see consistency, and we've seen that in the CORALreef program. [It] had a study with heterozygous FH [familial hypercholesterolemia]. They had the same reductions as people who were high risk, and we've seen it with another study, the AddOn study. But basically, all the trials are showing very similar reductions in terms of LDL cholesterol, non-HDL, and apoB, along with some favorable changes in Lp(a) [lipoprotein(a)]. So it's very reassuring that whatever risk category the patient has, they're going to get very similar benefit.

AJMC: Where could an oral PCSK9 inhibitor fit for patients in primary prevention who are above LDL-C goals, especially those at borderline or intermediate risk?

Ballantyne: Well, the hope is that by making things a little simpler and easier, we will see better treatment. Most health care providers and patients are used to, for example, treating asymptomatic conditions like hypertension [and] hyperlipidemia. They're used to giving a pill. And there's only one dose, 20 mg. Call it the KISS [principle]: Keep it simple, stupid. Basically, you got one dose. You can add it to [a] statin, ezetimibe, anything else. There's no drug interactions. It's a very simple thing for the health care provider to prescribe, and then for the patient, you take it once a day. So that's also easy. Now, you should take it in the morning fasting, but [it] turns out you can take it with coffee. And taking a medication while fasting is actually quite common. One of the most commonly used medications is thyroid supplementation, and that's taken fasting every morning.

AJMC: Looking ahead, what evidence, such as cardiovascular outcomes data or real-world evidence, is still needed before enlicitide becomes part of routine primary prevention?

Ballantyne: Well, there is a very large outcomes trial in progress, and we also presented data here on a long-term extension, so the patient-years of exposure are much higher now as compared to when the drug was approved, even in July. So I think the safety issue and the efficacy issue—the major driver right now is: Are you able to successfully get your patient to lower their LDL, non-HDL, and apoB? Even in the package labeling approved by the FDA, it mentions that lowering LDL and atherogenic lipoproteins is really the central part in terms of [what] has shown benefit for reducing CV [cardiovascular] events. And this is exactly the same mechanism of action. It blocks [the] interaction of PCSK9 with the LDL receptor, as seen with the monoclonal antibodies.

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