My LDL Was 192. Then I Found the First PCSK9 Pill.

Name: My LDL Was 192. Then I Found the First PCSK9 Pill.
Uploaded: 2026-08-14T14:00:05.000Z
Duration: 23 min 3 s
Channel: Hillary Lin, MD

Hillary Lin, MDAugust 14, 202623m

Topics35

Personal Story and Family History of High LDL0:00 Introduction of Oral PCSK9 Inhibitor0:31 Discovery of PCSK9 Gene1:01 French Familial Hypercholesterolemia Studies1:30 UT Southwestern Mouse Experiments2:00 LDL Receptor Function and PCSK9 Mechanism2:31 Dallas Heart Study Design3:00 Dallas Heart Study Results3:31 ARIC Study Interpretation4:30 Evolutionary Perspective on PCSK9 Variants5:00 Human with No PCSK9 Function5:32 Human Genetics Validation6:30 PCSK9 Mechanism of Action7:01 PCSK9 as Disposal Tag7:31 Drug Design Challenge with PCSK98:00 First PCSK9 Antibody Drugs8:31 Approval Timeline and Early Trials9:01 Personal Use of Repatha9:31 Inclisiran as siRNA Approach10:31 Inclisiran Dosing Advantages11:31 Merck's mRNA Display Technology12:01 MK-0616 Development13:00 Oral Formulation Challenges13:30 Clinical Efficacy of Oral PCSK9 Inhibitor14:30 Cardiovascular Outcomes Evidence Gap15:30 Practical Considerations for Daily Pill16:02 Side Effects Profile16:31 Comparison of Treatment Approaches17:30 Verve Gene Editing Approach18:00 Base Editing Studies18:31 Verve 102 Phase One Results19:31 Epigenetic Editing Alternative20:00 Final Considerations20:30 Decision Framework21:30 Conclusion22:01

In a Nutshell

The FDA has approved the first oral PCSK9 inhibitor (anacetrapib/Lipfenra), which lowers LDL 56-59 percentage points more than placebo by blocking PCSK9 from degrading LDL receptors. This breakthrough stems from human genetics showing that people born with reduced PCSK9 function have lifelong 15-40% lower LDL and 47-88% fewer heart attacks. For patients unable or unwilling to inject monoclonal antibodies like Repatha or wait for twice-yearly inclisiran, this daily pill offers a reversible, needle-free option—though long-term cardiovascular outcomes data are still pending until 2029.

AI-Generated Notes

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My LDL was 192, even though I felt completely healthy. My cousin had the same kind of shock, very fit, but also with high lipids. In my family, we see numbers like this everywhere. My father is still recovering from a heart transplant after a heart attack. My grandmother died suddenly due to cardiac arrest. On the positive side, we now have the medication to tackle tough inherited risks like mine. Today, I use evolocumab, brand name Repatha, a PCSK9 inhibitor I inject every 2 weeks. It works so well that I fully believe as a longevity physician that it's made a bigger difference for my personal longevity than any other intervention, period.

But, what if it were easy as a pill? Because now, for the first time, that pill exists. The FDA just approved Lipfenra or anacetrapib, the first oral PCSK9 inhibitor in the United States. In its pivotal trials, it lowered LDL by roughly 56 to 59 percentage points more than placebo. The pill is part of a much stranger story, a story that starts with a scientist who was not studying cholesterol at all.

At the Clinical Research Institute of Montreal, Nabil Seidah and his two colleagues were screening genes involved in neuronal apoptosis and liver regeneration when they found a new gene. It was highly expressed in the liver, but no one knew what it was doing there. They called the protein NARC1. At that point, it was a scientific curiosity from the wrong field. Then, within months, patients gave it an entirely different meaning.

In France, Marianne Abifadel, Karim Bouillo, and their colleagues were studying families whose cholesterol levels made no sense. Their disease looked like classic familial hypercholesterolemia, the inherited form of very high LDL, but the known genes couldn't explain them. So, they traced the mystery to variants in a newly described gene. NARC1 at this point had become PCSK9, and an obscure laboratory finding had become the missing clue in families with runaway LDL levels. The French variants made PCSK9 too active. Some made the protein overactive, others helped it grip the LDL receptor too tightly. Either way, LDL rose, sometimes to severe levels. Researchers still don't know exactly how.

At UT Southwestern, Jay Horton's group tried a blunt experiment. They forced mouse livers to make extra PCSK9. The LDL receptors disappeared, even though the messenger RNA used to make those receptors did not change, meaning the body is still encoding and telling the body to make these LDL receptors, but they're being taken away. Three different scientific groups reported versions of the same finding.

So, why does this all matter? It's because LDL receptors are the liver's clearance machinery for LDL. They're like little hands, they go and pull LDL particles out of the blood. Fewer working receptors means LDL accumulates. That suggested that PCSK9 was not preventing the receptor from being made, it was doing something to the finished receptor. So, Helen Hobbs and Jonathan Cohen made the reverse prediction. If extra PCSK9 removes LDL receptors and drives cholesterol up, then a broken copy of PCSK9 should produce the mirror image, more working receptors and unusually low LDL.

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My LDL Was 192. Then I Found the First PCSK9 Pill.

Personal Story and Family History of High LDL00:00

Introduction of Oral PCSK9 Inhibitor00:31

Discovery of PCSK9 Gene01:01

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