Enlicitide’s FDA Approval for LDL-C Reduction and the CORALreef Outcomes Trial

On July 16, 2026, enlicitide (Lipfendra) received approval from the US Food and Drug Administration (FDA) to lower LDL-C in patients with hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). The 20 mg tablet, administered once daily as an adjunct to diet and exercise, substantially reduced LDL-C in the CORALreef Lipids and CORALreef HeFH trials compared to placebo.1

Now, with the drug expected to be accessible in a few weeks, parent company Merck will continue to investigate the drug’s safety and efficacy in lowering the risk of major adverse cardiovascular events through LDL-C lowering.2

Ann Marie Navar, MD, PhD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center and a lead investigator throughout enlicitide’s investigational pathway, spoke with HCPLive to discuss the drug’s potential impact on this condition, which affects a disproportionate percentage of the US population.

Q&A: Enlicitide’s FDA Approval for LDL-C Reduction and the CORALreef Outcomes Trial

How significant is this approval for preventive cardiology? Can it meaningfully change clinical practice?

Ann Marie Navar, MD, PhD: I think this is really big. We now have an oral option that lowers LDL cholesterol by ≤60% on top of high intensity statins and other background therapies. That's huge in terms of getting more patients to goal. The approval, though, is just the first step. Now we actually have to get it into the hands of our clinician prescribers, and then ultimately into our patients. So, it's going to come down to: are people going to use it, and are we going to be able to get payers and insurers to cover it for the patients that need it?

What barriers did the field encounter with injectable PCSK9 inhibitors, and how might an oral version overcome them?

Ann Marie Navar, MD, PhD: Well, some of the early barriers to uptake were the high sticker price, which led to really high copays and high rates of insurance company refusals, so we just couldn't get patients approved for the drug. That's actually gotten a lot better. The sticker price has come way down. The directed patient price for Repatha is <$250 a month, and a lot of PBMs have actually even dropped a prior authorization. So, approval rates are really high. The challenge is that not all of my colleagues are using them. We looked a couple of years ago, and 40% of cardiologists had never prescribed an injectable PCSK9. Over 90% of primary care doctors hadn't prescribed one. So, these drugs just haven't made it into the armamentarium of all of the clinicians that are seeing the patients who need further cholesterol lowering. This is where I'm hopeful for Lipfendra, enlicitide’s new brand name, that we'll be able to have more clinicians actually using this as an add-on after statins if people are not at LDL goal, and while the injections are really well tolerated and they work really well, I think it just takes a little bit more time to prescribe it in clinic than it does to prescribe a pill. And I think for some patients, it just sort of psychologically feels like a much bigger deal to add on a shot versus adding on a pill. I'm really hopeful that the availability of an oral PCSK9 actually broadens the number of people who are using these therapies. Maybe even use more injectables as well.

How do you interpret the 56-59% LDL-C reduction from CORALreef in the context of currently available lipid-lowering therapies?

Ann Marie Navar, MD, PhD: Well, if you look at the LDL lowering, the non-HDL lowering, the ApoB, and the Lp(a) lowering, the efficacy of enlicitide looked almost identical numerically to what we saw with alirocumab and evolocumab. Now, all three of them have a little bit greater relative reductions in atherogenic lipoproteins than in glycerin, though even in glycerin is getting you well over 50%, so we know that inhibiting PCSK9 is a really powerful way to lower LDL cholesterol. This is just basically evolocumab or Repatha in a pill.

Which patients do you expect to benefit most from enlicitide initially?

Ann Marie Navar, MD, PhD: Well, I would anticipate that probably the payers are going to make it easiest for us to get this drug for people with established ASCVD. That's certainly been the experience with the injectable PCSK9s, and that's also where we have cardiovascular outcomes data for at least the injectable class. So probably those with established ASCVD who are not reaching LDL goals, there's certainly a subgroup of patients, including those with FeFH, who just really do not want an injection and are waiting for more oral options, or on statin ezetimibe, and they're not at goal. I think this is going to be a great option for them now if they can get access to it to be able to increase their therapy and get to that goal of <55.

How do you weigh the convenience of oral medications against the adherence advantages of therapies administered every few months, like injectables?

Ann Marie Navar, MD, PhD: Well, the CORALreef Lipids trial was a clinical trial, but it also was conducted in the real world. The participants in the trial lived their normal lives for a year, and we saw that the durability of the efficacy of enlicitide was sustained for the entire year that patients were on therapy. So, we've seen in thousands of patients that people are able to get on drug and stay on it. The administration requirements for Lipfendra are that you have to take it first thing in the morning on an empty stomach, but you can take it with your other medicines. So, you could take your statin and ezetimibe at the same time. I actually think for those patients, it was actually helpful to give them very explicit instructions on when to take it because we were able to make a habit out of it. People woke up, took their meds in the morning, and they continued on. And it really just is not that big of a deal. We also have had some data since then that a cup of black coffee or black tea does not affect the exposure to drug, so you can't eat food with it because that impacts the absorption. But if you're like me and don't want to talk to anybody without a cup of coffee, you can have a cup of black coffee before that 30 minute window is up.

What further questions are you hoping that the ongoing CORALreef Outcomes trial will answer?

Ann Marie Navar, MD, PhD: Well, that trial is going to be really important to show us, you know, adherence data and LDL data for longer than a year. It will be also important to add to the continued body of evidence that lowers better not only in secondary prevention, but high-risk primary prevention. We saw data from the Vesalius trial recently that in high-risk individuals who have not had a prior cardiovascular event, PCSK9 inhibition, lowering LDL cholesterol well below 55, reduced cardiovascular events, and that was in people with high-risk diabetes or coronary calcium scores >100. CORALreef Outcomes is also including a high-risk primary prevention group, and so that's a group I'm really excited to continue to have more data on because I think the more evidence we have that lower is better in primary prevention, we'll be able to make even more aggressive recommendations to try to prevent the heart attacks before they happen, instead of waiting until they've already had an event to try to drive the cholesterol down.

Editors’ Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Livingston R. Enlicitide Receives FDA Approval for Hypercholesterolemia Following CORALreef Trials. HCPLive. July 17, 2026. Accessed July 22, 2026. https://www.hcplive.com/view/enlicitide-receives-fda-approval-for-hypercholesterolemia-following-coralreef-trials

2. Merck Clinical Trials. CORALreef Outcomes. Accessed July 22, 2026. https://www.merckclinicaltrials.com/trial/nct06008756/