José Navarro-Betancourt
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A New Pill for High Cholesterol: The First Oral PCSK9 Inhibitor

The FDA has approved Merck's enlicitide (Lipfendra), the first oral PCSK9 inhibitor. In its two phase 3 CORALreef trials, the pill lowered LDL cholesterol by 56% to 59% compared with placebo.1

Trial participants took about 97% of their assigned doses, which is encouraging given that the pill must be taken daily on an empty stomach. We do not know whether that will hold up in the real world. Adherence to statins is poor, and a daily fasting pill will not necessarily be easier to maintain than an occasional injection.2

Pricewise, Lipfendra's out-of-pocket price is about $315 for a 30-day supply, roughly a third below the list price of the injectable drugs in the same class. Repatha and Praluent list at about $490 a month. Leqvio (three doses in the first year, then twice a year) works out to around $540 a month.

Cost is still the big barrier to access. Even Lipfendra sits far above the cash price of a generic statin, which runs about $4 to $15 a month.

Here is a quick recap of why this is such an important drug class.

Nature's validation of PCSK9

PCSK9 is an enzyme made by the liver that binds LDL receptors and marks them for destruction. Those LDL receptors are the docks that pull LDL cholesterol out of the blood, so less PCSK9 means more receptors and lower LDL.

Human genetics gave us enough evidence to say that lowering LDL cholesterol by inhibiting PCSK9 was a promising approach in terms of efficacy and safety.

When PCSK9 activity is reduced from birth, the lifetime risk of cardiovascular disease is much lower than in the general population. People who carry one broken copy of the PCSK9 gene (heterozygous) have 15% to 28% lower LDL cholesterol throughout life, along with a 47% to 88% lower risk of heart attack.3

People born with two inactive copies of the gene can have extremely low LDL cholesterol and still be healthy. In one such case (a compound heterozygote carrying two different inactive variants) LDL was around 14 mg/dL, with no major health concerns. For reference, optimal LDL in a healthy adult is below 100 mg/dL, though new evidence suggests you can get too low (more on that below).4

Genetic validation also works the opposite way around. People with a gain-of-function mutation produce an overactive version of PCSK9, carry higher LDL cholesterol, and often develop cardiovascular disease at a young age. This form is dominant, so a single overactive copy is enough.5

These genetic discoveries are relatively recent: gain-of-function mutations were identified in 2003, followed by protective loss-of-function variants in 2005. Together, they sparked a race to develop drugs that inhibit PCSK9. The first was alirocumab (Praluent), approved in July 2015. Today there are five approved options, in several different kinds of treatment:

Pharma companyCommercial nameDrugModalityYear approved
Sanofi/RegeneronPraluentAlirocumabMonoclonal antibody, injection2015
AmgenRepathaEvolocumabMonoclonal antibody, injection2015
NovartisLeqvio6InclisiransiRNA, injection2021
LIB TherapeuticsLerochol7LerodalcibepFusion protein, injection2025
MerckLipfendraEnlicitideOral macrocyclic peptide2026

Oral peptides

Enlicitide is a peptide. Peptides are hard to give as pills, because enzymes in the gut digest them and their size keeps them from crossing the intestinal wall.

Enlicitide gets around this in two ways. It is a macrocycle, a peptide stitched into a ring, which makes it more stable and harder for gut enzymes to degrade. And it is co-formulated with a permeation enhancer, sodium caprate (a.k.a. sodium decanoate), a medium-chain fatty acid that briefly loosens the junctions between intestinal cells so the drug can slip through.8 This is the same principle used by oral semaglutide (Rybelsus and the Wegovy pill), which relies on a different enhancer called SNAC. Like oral semaglutide, enlicitide is taken first thing in the morning on an empty stomach, and you wait at least 30 minutes before eating.

Cholesterol vs heart attacks

Lipfendra was approved specifically to reduce LDL cholesterol in adults with high cholesterol. It is not yet labeled as reducing heart attacks, strokes, or cardiovascular death. We know that two injectable antibodies, evolocumab9 and alirocumab10, prevent those events, because their randomized cardiovascular-outcomes trials measured and reduced them directly. Lipfendra's cardiovascular outcomes trial, CORALreef Outcomes, is running now with more than 14,000 patients, but it will not report until around 2029. Inclisiran and lerodalcibep also lack completed cardiovascular-outcomes trials.

How low is too low?

In healthy adults, an optimal LDL is under about 100 mg/dL, and levels under 40 mg/dL are usually considered very low. In general, aggressive lowering is good for high-risk patients. However, there are a few debated findings worth keeping in mind.

Some studies have found a small association between very low LDL and hemorrhagic stroke, bleeding in the brain, though the randomized PCSK9 trials did not show a clear increase.11 Older studies have linked low cholesterol to depression and anxiety. That work is heavily confounded, and the PCSK9-inhibitor and statin trials have not shown mood disorders or changes in cognition.12

Lowering LDL too much during pregnancy is another theoretical concern. One complex study looked at this with genetic proxies of PCSK9 and found associations with several categories of congenital malformation. Genetic proxies are variants near the PCSK9 gene that are strongly associated with lower LDL, so they somewhat stand in for the drug's effect. These proxies do not capture what happens when a pregnant woman takes the drug, and the variants were not necessarily true loss-of-function mutations. No birth defects have been established from the drugs themselves, and pregnancy is not a formal contraindication for any PCSK9 inhibitor.13

Where the field is going

Chinese companies have developed four anti-PCSK9 antibodies that are now approved in China: tafolecimab from Innovent Biologics (2023), ebronucimab from Akeso (2024), ongericimab from Junshi Biosciences (2024), and recaticimab from Hengrui Pharmaceuticals (2025). None of these is approved in the US yet.14

AstraZeneca's AZD0780 (laroprovstat) is worth watching. It is a small molecule rather than a peptide, so it doesn't need a strict morning fast and works by a different mechanism. Instead of blocking PCSK9 from grabbing the LDL receptor, it binds a separate pocket on PCSK9 and stops the PCSK9-receptor complex from being dragged into the cell and destroyed, so the LDL receptor survives. It is in phase 3 (the AZURE trials), with readouts expected in 2027.15

Another program to watch is VERVE-102, a gene-editing therapy originally developed by Verve Therapeutics, which Lilly acquired in 2025 for about $1B upfront. VERVE-102 is designed as a single infusion that switches off PCSK9 in the liver. Early data suggest that its LDL-lowering effect can persist for at least 18 months. Whether it will last a lifetime remains unknown.16

LDL targets keep getting tighter

Guidelines keep tightening. In the early 2000s, the recommended goal for high-risk patients was below 100 mg/dL. A 2004 update introduced an optional goal below 70 mg/dL for those at very high risk. Today, for very-high-risk patients, both European guidance and the 2026 US dyslipidemia guideline set the LDL cholesterol goal to under 55 mg/dL.17

Access may be broadening too. Leqvio's US label was updated in 2025 so that it no longer has to be used alongside a statin, which may make earlier use and insurance approval easier. It would not be surprising to see more PCSK9-targeting drugs move into mainstream care.

Fun fact: why do we even have PCSK9?

If PCSK9 is so safe to remove, why do we have it at all? One speculative hypothesis is host defense. The LDL receptor is a doorway that several viruses use to enter cells, including a group of rhinoviruses and, in some studies, hepatitis C and dengue. By pulling those receptors off the cell surface, PCSK9 might once have offered some antiviral protection.18

Footnotes

  1. Merck news release, July 16, 2026. ↩

  2. Vinogradova Y, et al. "Discontinuation and restarting in patients on statin treatment." BMJ. 2016;353. PMID: 27353261. ↩

  3. Cohen JC, et al. "Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease." NEJM. 2006;354(12):1264-1272. PMID: 16554528. ↩

  4. Zhao Z, et al. "Molecular Characterization of Loss-of-Function Mutations in PCSK9 and Identification of a Compound Heterozygote." Am J Hum Genet. 2006;79(3):514-523. PMID: 16909389. ↩

  5. Abifadel M, et al. "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia." Nat Genet. 2003;34(2):154-156. PMID: 12730697. ↩

  6. Novartis media release. ↩

  7. LIB Therapeutics news release. ↩

  8. Tyagi A, et al. "An Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the LDL Receptor." Circulation. 2023. PMID: 37125593. ↩

  9. Sabatine MS, et al. "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease." NEJM. 2017;376:1713-1722. DOI: 10.1056/NEJMoa1615664. ↩

  10. Schwartz GG, et al. "Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome." NEJM. 2018;379:2097-2107. DOI: 10.1056/NEJMoa1801174. ↩

  11. Ma C, et al. "Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study." Neurology. 2019;93(5):e445-e457. PMID: 31266905. ↩

  12. Giugliano RP, et al. "Cognitive Function in a Randomized Trial of Evolocumab." NEJM. 2017;377(7):633-643. PMID: 28813214. ↩

  13. Ardissino M, et al. "Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations." Eur J Prev Cardiol. 2024;31(8):955-965. PMID: 38294056. ↩

  14. Mansfield BS, et al. "The evolving therapeutic landscape of PCSK9 inhibition." Atherosclerosis. 2026;414:120670. Full text. ↩

  15. AstraZeneca news release, March 31, 2025. ↩

  16. Lilly news release, May 2026. ↩

  17. 2026 ACC/AHA/Multisociety dyslipidemia guideline, Circulation. ↩

  18. Seidah NG, Prat A. "The Multifaceted Biology of PCSK9." Endocrine Reviews. 2022;43(3):558-582. Full text. ↩