Ann Marie Navar, MD, PhD, is an associate professor of cardiology at the University of Texas Southwestern Medical Center.

Ann Marie Navar, MD, PhD

Ann Marie Navar, MD, PhD | Image Credit: UT Southwestern

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.

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.

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

 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?

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?

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?

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?

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?

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?

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.

Livingston R. Enlicitide Receives FDA Approval for Hypercholesterolemia Following CORALreef Trials. 

. July 17, 2026. Accessed July 22, 2026. 

https://www.hcplive.com/view/enlicitide-receives-fda-approval-for-hypercholesterolemia-following-coralreef-trials

Merck Clinical Trials. CORALreef Outcomes. Accessed July 22, 2026. 

https://www.merckclinicaltrials.com/trial/nct06008756/

Articles

FDA approval of oral enlicitide (Lipfendra) adds a once-daily PCSK9 inhibitor that reduced LDL-C ~56–59% in hypercholesterolemia and HeFH as adjunct to diet/exercise and background therapy. Efficacy across LDL-C, non–HDL-C, ApoB, and Lp(a) appears numerically comparable to alirocumab/evolocumab, potentially improving goal attainment, especially when injections are a barrier. Real‑world–conducted trial data suggest yearlong durability with fasting morning dosing. Access and payer coverage will likely determine uptake, while CORALreef Outcomes will test longer-term adherence and MACE reduction, including high-risk primary prevention.

Ann Marie Navar, MD, PhD, highlights enlicitide’s FDA approval for hypercholesterolemia and its potential to fundamentally change therapy.

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

Enlicitide Receives FDA Approval for Hypercholesterolemia Following CORALreef Trials

 has officially approved the first-ever oral PCSK9 inhibitor, enlicitide, for the reduction of LDL-C in adult patients with 

Parent company Merck announced the approval on July 16, 2026, which followed positive data from the CORALreef Lipids and CORALreef HeFH trials. Enlicitide, approved under the name Lipfendra, substantially reduced LDL-C in both trials compared to placebo. The drug is administered in the form of 20 mg tablets as an adjunct to diet and exercise and has been approved for patients with heterozygous familial hypercholesterolemia (HeFH) in addition to hypercholesterolemia.

“This is really big,” Ann Marie Navar, MD, PhD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center, told 

 in an exclusive interview. “We now have an oral option that lowers LDL cholesterol by up to 60% on top of high-intensity statins and other background therapies. That’s huge in terms of getting more patients to goal.”

CORALreef Lipids was a multinational, double-blind, randomized, placebo-controlled trial including patients with a history of major 

atherosclerotic cardiovascular disease (ASCVD)

 events with an LDL-C level of ≥55 mg/dL or those who were at risk of a first ASCVD event with an LDL-C ≥70 mg/dL. These patients were assigned in a 2:1 ratio to receive either 20 mg enlicitide or placebo daily for 52 weeks.

The primary endpoint for CORALreef Lipids was mean percent change in LDL-C level from baseline to week 24. Secondary endpoints included mean percent LDL-C level changes at week 52 and mean percent change in non-HDL-C, apolipoprotein B (apoB), and lipoprotein(a) levels at week 24.

A total of 2904 patients were enrolled in CORALreef Lipids, of whom 1935 received enlicitide and 969 received placebo. Mean LDL-C level at baseline was 96.1 +/- 38.9 mg/dL, while mean percent change by week 24 was -57.1% (95% CI, -61.8 to -52.5) with enlicitide and 3% (95% CI, 0.9 to 5.1) with placebo. This represented an adjusted between-group difference of -55.8% (95% CI, -60.9 to -50.7; 

 <.001). The percent change in LDL-C at week 52, as well as the changes in Lp(a), non-HDL-C, and apoB at week 24, were all greater with enlicitide than placebo.

The CORALreef HeFH trial included patients ≥18 years old with HeFH who were actively using lipid-lowering therapy – either a moderate- or high-intensity statin – and who had an LDL-C level ≥55 mg/dL with a history of major ASCVD or an LDL-C level ≥70 mg/dL without a history of major ASCVD.

Participants were randomly assigned in a 2:1 ratio to receive either 20 mg of enlicitide or placebo once daily for 52 weeks. The primary outcome for CORALreef HeFH was the same as in CORALreef Lipids, while secondary endpoints included the same measurements of apoB and non-HDL-C, as well as percent change in LDL-C at week 52.

A total of 303 patients were enrolled and randomized, with 202 receiving enlicitide and 101 receiving placebo. Mean LDL-C at baseline was 119 mg/dL (standard deviation [SD], 41 mg/dL). Mean percentage change at week 24 in LDL-C was -58.2% in the enlicitide group versus 2.6% in the placebo group, with a between-group difference of -59.4% (95% CI, -65.6% to -53.2%; 

 <.001). The mean percentage change in LDL-C at week 52 was -55.3% in the enlicitide group versus 8.7% in the placebo group, with a between-group difference of -61.5% (95% CI, -69.4% to -53.7%; 

While the approval itself was based on the positive results from these 2 trials, Merck has also launched the ongoing CORALreef Outcomes study, which is examining the effects of enlicitide on cardiovascular morbidity and mortality over the long term.

“This approval is just the first step,” Navar said. “Now we actually have to get it into the hands of our clinician prescribers, and then ultimately into our patients. 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?”

Editors’ Note: Navar reports disclosures with Esperion Therapeutics, Bristol Myers Squibb, Amgen, Janssen Pharmaceuticals, Eli Lilly, Novo Nordisk, and others.

Merck. Merck’s LIPFENDRA (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the US FDA to Reduce LDL-C in Adults with Hypercholesterolemia. July 16, 2026. July 17, 2026. 

https://www.merck.com/news/mercks-lipfendra-enlicitide-is-the-first-and-only-once-daily-oral-pcsk9-inhibitor-approved-by-the-u-s-fda-to-reduce-ldl-c-in-adults-with-hypercholesterolemia/

Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. 

Ballantyne CM, Gellis L, Tardif J-C, et al. Efficacy and safety of oral PCSK9 inhibitor enlicitide in adults with heterozygous familial hypercholesterolemia. 

Videos

Ann Marie Navar, MD, PhD, discusses the groundbreaking approval of the first oral PCSK9 inhibitor and what it means for patients managing their LDL-C levels.

Closing Thoughts on ASCVD Management

In the final episode, 'Closing Thoughts on ASCVD Management,' the panelists explore what meaningful, systemic change would look like in cardiovascular prevention, opening with the observation that early and consistent attention to lifestyle, blood pressure, and cholesterol management could reduce cardiovascular disease mortality by as much as 75%. The discussion identifies several interconnected levers for closing the treatment gap, including the integration of automated risk assessment tools within electronic medical records in primary care settings, structured wellness touchpoints that remove the burden of prevention from overstretched practitioners, and algorithmic treatment pathways that allow clinicians to anticipate the combination therapy intensity needed to reach a patient's LDL goal from the outset rather than waiting through sequential adjustments. One panelist notes that with currently available tools and a streamlined approach, it is theoretically possible to get virtually all patients to their LDL goal within approximately three months using eight clearly defined steps. The panel also reflects on the misalignment between healthcare reimbursement structures and preventive care, with one panelist noting that procedural and diagnostic services continue to be rewarded far more generously than prevention-focused practice, representing a fundamental systemic barrier to implementation.

The episode closes with final thoughts from each panelist, converging on a shared message of urgency and optimism. The panel emphasizes that the tools to achieve guideline-recommended LDL targets already exist, and that the primary remaining challenges are consistent measurement, diligent follow-up, and sustained patient engagement. Panelists stress the importance of establishing a baseline lipid panel before initiating therapy and repeating testing regularly to confirm both efficacy and adherence, proactively inviting patients to share concerns that might otherwise lead to silent discontinuation. The series concludes with a call to action grounded in the principles of personalized medicine, reminding clinicians that assessing individual risk, setting clear LDL targets, combining lifestyle and pharmacotherapy appropriately, and maintaining an ongoing partnership with each patient are the cornerstones of meaningful ASCVD prevention and treatment.

Thank you for watching this Peer Exchange series on ASCVD. Please subscribe to our newsletter for information on upcoming video series.

Experts reveal how risk assessment, LDL-C targets, and smarter follow-up boost adherence—turning guidelines into real cardiovascular prevention.

Navigating Access, Shared Decision-Making, and Long-Term Adherence in ASCVD

In 'Navigating Access, Shared Decision-Making, and Long-Term Adherence in ASCVD,' our experts delve into the practical realities of accessing advanced lipid-lowering therapies in the United States, where insurance coverage for PCSK9 inhibitors varies considerably across commercial plans, Medicaid, and Medicare. The panel distinguishes between Medicare Part B and Part D coverage structures, noting that inclisiran tends to fare better under Part B while monoclonal antibodies such as evolocumab and alirocumab are subject to the more variable Part D formulary landscape, often requiring prior authorization and generating significant administrative burden for clinical practices. One panelist describes training a dedicated staff member to manage insurance denials and appeals, reflecting the reality that securing guideline-directed therapy for high-risk patients frequently demands substantial practice resources. The panel also highlights an emerging third pathway for access, noting that some manufacturers are beginning to offer direct-to-patient programs at reduced prices, with monoclonal antibody costs dropping to approximately half of retail price in some cases, though even these reduced costs remain out of reach for many patients.

The conversation then shifts to shared decision-making as a cornerstone of long-term adherence, with the panel referencing survey data from studies of 5,000 and 10,000 statin-prescribed patients showing that a key predictor of self-reported adherence was whether patients felt genuinely consulted and included in the treatment decision by their prescriber. The panelists acknowledge that time constraints in clinical practice can make thorough shared decision-making difficult, but argue that the investment pays dividends in long-term patient buy-in and persistence with therapy. The episode closes with a candid discussion about the challenge of health misinformation, with the panel encouraging clinicians to proactively acknowledge that much of what patients encounter online about medications is unreliable, and to position themselves as trusted partners in the patient's health journey, emphasizing that the personal connection between prescriber and patient remains one of the most powerful tools available in supporting adherence and achieving lasting ASCVD risk reduction.

Our last episode, 'Closing Thoughts on ASCVD Management,' further explores ASCVD, highlighting the critical steps needed to bridge the persistent gap between guideline-recommended LDL goals and real-world clinical outcomes, with panelists offering forward-looking recommendations spanning healthcare system reform, risk assessment tools, treatment algorithms, patient engagement, and the foundational importance of long-term follow-up and adherence.

Learn how clinicians reach ultra-low LDL targets in high-risk patients using ezetimibe, PCSK9s, and smarter insurance documentation.