A revolutionary new approach to cholesterol-lowering has just changed the game. For decades, we’ve known that LDL cholesterol plays a central role in heart disease. But recent breakthroughs have taken us far beyond statins—into the world of gene-guided therapies that can slash heart attack and stroke risk by double digits.
In this article, we’ll explore the decades of science that led to this moment, the trials that proved it works, and what this means for the future of heart disease prevention.
Table of Contents
- Key Early Discoveries
- From Target to Treatment
- From Treatment to Endpoint Impact
- From Secondary to Primary Prevention
-
Oral PCSK9 Inhibitors
- References
Key Early Discoveries
In the late 1990s, geneticist Catherine Boileau stared at the lab notebook in front of her. Its pages were covered in cholesterol readings so bizarre they made no biological sense.
Her team in Paris had been studying a French family with frighteningly high cholesterol. Heart attacks before 50. LDL-cholesterol levels that didn’t budge. It looked exactly like classic familial hypercholesterolaemia—except for one problem: the genes that usually cause the condition were normal.
There were no mutations in the LDL receptors or APOB. Nothing that could explain why cholesterol in this family behaved like a runaway train.
So the key mutation driving the problem must be somewhere else. And if she could find it, the implications were huge. There was a gene that had a powerful influence on cholesterol levels. And, so far, we had no idea what it was. But if it could be found, maybe potent treatments to help lower heart disease rates could be developed.
Finding the right gene is like looking for a needle in a haystack. The process is slow and often involves years of dead ends. But the evidence started to look like it was pointing to a location on chromosome 1. Somewhere in the region 1p32, she suspected, there was a gene no one fully understood—one that could upend what we knew about cholesterol biology.
Meanwhile, 6,000 kilometres away in Montréal, Canada, another scientist was chasing his own mystery.
Nabil Seidah had spent years cataloguing a family of enzymes called proprotein convertases. They were obscure, unglamorous proteins that snipped other proteins into active forms. His team had recently characterised one member, a gene with the clunky name NARC-1. They didn’t know what it did. They only knew where it sat in the genome. 1p32.
Across the ocean, Catherine Boileau’s French team saw this and paused. What were the odds? Boileau’s group sequenced NARC-1 in their hypercholesterolaemia family. They hit the jackpot. A single change in the gene—just one amino acid—made the enzyme overactive. And that tiny tweak caused LDL cholesterol to skyrocket.
It was the missing piece. They renamed the gene PCSK9.
But there was one more crucial discovery that filled out the picture.
While the French group was learning that too much PCSK9 caused dangerous cholesterol levels, scientists in Texas were seeing the opposite.
Helen Hobbs and Jonathan Cohen launched a simple but brilliant project in the year 2000. They collected DNA from thousands of Dallas residents and linked it to their medical records to see what patterns emerged.
In some people, they noticed astonishingly low LDL cholesterol levels. Not borderline low. Ridiculously low.
They checked the usual suspects—LDL receptor, APOB. Nothing. Then they checked PCSK9. They identified two distinct mutations in this population. This time, though, the mutations weren’t making the gene overactive. They were breaking it.
People who essentially lacked PCSK9 had cholesterol levels cardiologists could only dream of — and they were perfectly healthy.
Researchers began to put the pieces together. Overactive PCSK9 caused dangerously high LDL cholesterol levels. But turn off PCSK9, and it caused lifelong LDL reduction and extraordinary protection from heart disease.
Suddenly, the path forward snapped into focus: If we could find a way to block PCSK9, we could substantially lower LDL safely. The discoveries described above gave us one of the clearest target validations in modern drug development.
From Target to Treatment
By the mid-2000s, PCSK9 had been transformed in our understanding from an obscure protease into a biological switch that controlled LDL cholesterol. But translating that insight into a workable therapy was another battle entirely.
Drug companies had been burned before. Many “promising” cholesterol pathways turned into dead ends. And PCSK9 presented unique challenges. Often with drug targets, we can create a simple chemical that binds to a specific site on a targeted protein. Think of it like making a key that fits a particular lock.
But the PCSK9 protein is large and complex. The usual strategy doesn’t work. In this case, researchers have to create a much more complex structure to bind to and deactivate the protein. It’s more like designing a glove that exactly fits a hand. Creating this kind of treatment has traditionally been extremely expensive.
But the genetic data was too clear to ignore. People born with broken PCSK9 genes had:
- Near-ideal LDL their entire lives
- Extremely low risk of heart disease
- No developmental problems
-
And no obvious downsides
In drug development, you almost never get a biological pathway like this. PCSK9 was that rare exception. So Amgen took the gamble.
Amgen scientists designed what’s called a monoclonal antibody that could latch onto circulating PCSK9 and neutralize it. And the reason this helps is that PCSK9 naturally binds to and deactivates LDL-cholesterol receptors in the liver and elsewhere. When we can block this activity, more LDL-cholesterol gets pulled out of the blood by those receptors.
An early trial put the concept to the test. And the results were jaw-dropping. LDL cholesterol levels fell up to 81% on top of the reduction already achieved by statins [1].
In the trials (AMG 145 n = 85, placebo n = 28), hypercholesterolemic adults receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly ×6, 140 or 280 mg every 2 weeks ×3, 420 mg every 4 weeks ×2, or matching placebo. LDL-C was reduced up to 64% (p < 0.0001) after a single dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg weekly [1].
Patients who’ve struggled with statin intolerance and stubbornly high LDL cholesterol suddenly had a new tool that behaved like a biological cheat code.
From Treatment to Endpoint Impact
But while the impact on LDL cholesterol alone was exciting, that wasn’t the real test. Instead, we needed to see whether blocking PCSK9 from destroying LDL receptors would prevent heart attacks, strokes, and heart-related deaths.
Amgen committed to a massive cardiovascular outcomes program — the kind that costs hundreds of millions, runs for years, and has no guarantee of success.
The FOURIER trial involved 27,564 participants with heart disease who were already on statin therapy. Half were placed in the treatment group, receiving either 140 mg every 2 weeks or 420 mg monthly of evolocumab, Amgen’s PCSK9 inhibitor. The other half were given a matching placebo [2].
The trial showed that evolocumab cut major cardiovascular events by 15%. Relative to placebo, 9.8% of evolocumab patients experienced a major cardiovascular event vs. 11.3% in the placebo group (hazard ratio, 0.85; 95% CI, 0.79 to 0.92; P<0.001) [2].
Looking at a smaller subset of events that included heart attacks, strokes, and heart-related deaths, the risk reduction was an even greater 20% — 5.9% in the treatment group vs. 7.4% in the placebo group (hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001) [2].
It was a triumph, but also expected. If someone has plaque in their arteries and very high risk, lowering LDL aggressively should help.
From Secondary to Primary Prevention
But clinicians were left wondering: What if we started earlier?
In the FOURIER trial, many of the participants had already had a heart attack or stroke. Could we prevent the first event, not just the second or third?
LDL-cholesterol-lowering has a key property: the earlier you start, the more benefit you get. Which makes perfect sense. But when it comes to investigating the impact of a treatment, there are significant obstacles. Early prevention trials require far larger numbers, far longer follow-up, and far more money.
The TIMI Study Group — the same group behind many of the definitive statin trials — decided to take on the question directly. They enrolled 12,257 patients across 33 countries with atherosclerosis or high-risk diabetes in the VESALIUS-CV trial. None had ever had a heart attack or stroke. All had LDL ≥90 mg/dL despite standard therapy [3].
Participants were randomized to receive evolocumab (6129 patients) or placebo (6128). The median follow-up was 4.6 years [3].
About a year into the study, LDL-cholesterol levels had dropped an average of 55% from baseline in the treatment group [3].
The final results, published in November 2025 in the New England Journal of Medicine, were clear: evolocumab prevents first cardiovascular events in high-risk patients who have never had a heart attack or stroke.
For the composite of death from coronary heart disease, myocardial infarction, or ischemic stroke (3-point MACE), the treatment group saw a 25% reduction: 336 patients (6.2%) in the evolocumab group vs. 443 (8.0%) in the placebo group (hazard ratio, 0.75; 95% CI, 0.65 to 0.86; P<0.001) [3].
For the 4-point MACE outcome — which added ischemia-driven revascularization — the risk reduction was 19% (747 [13.4%] vs. 907 [16.2%]; hazard ratio, 0.81; 95% CI, 0.73 to 0.89; P<0.001) [3].
No evidence of increased adverse events was found [3].
VESALIUS-CV gives us confidence in high-risk primary prevention. But it raises an important question. How do we make this strategy easy enough, cheap enough, and accessible enough to use earlier in the disease course — maybe even in low-risk individuals?
Because right now, the biggest barrier to PCSK9 therapy isn’t the biology — it’s the delivery. These drugs are injections. And they’re expensive. And both of these factors keep them from being used as widely as they might otherwise be.
Oral PCSK9 Inhibitors
And that’s why another piece of the story that was published literally the next day after the VESALIUS-CV study is so important.
It concerns an entirely new class of PCSK9 inhibitor — not an injectable monoclonal antibody like evolocumab — but an oral pill called enlicitide.
Researchers tested this new approach in individuals with heterozygous familial hypercholesterolemia (HeFH) — people with a genetic mutation that makes their LDL cholesterol skyrocket, despite existing therapies.
In this phase 3 randomized clinical trial, participants aged 18+ were using lipid-lowering therapy (moderate- or high-intensity statins). Those with a history of major atherosclerotic cardiovascular disease needed an LDL-C of ≥55 mg/dL, and those without such history required LDL-C ≥70 mg/dL [4].
Participants were randomized 2:1 to 20 mg of enlicitide (n=202) or placebo (n=101) once daily for 52 weeks [4].
At week 24:
- Enlicitide group: −58.2% LDL-C
- Placebo group: +2.6%
-
Between-group difference: −59.4% (95% CI, −65.6% to −53.2%; P<.001) [4]
At week 52:
- Enlicitide group: −55.3%
- Placebo group: +8.7%
-
Between-group difference: −61.5% (95% CI, −69.4% to −53.7%; P<.001) [4]
Safety results were also promising: no difference in the incidence of adverse events, serious adverse events, or study discontinuation due to side effects between the groups [4].
This is huge. For the first time, PCSK9 inhibitors aren’t just powerful — they’re convenient. If a daily pill can deliver the same LDL-lowering as an injection, this might open the way for an effective new tool to use not just in high-risk cases, but for lower-risk patients as well.
But this was a very specific group of high-risk individuals. Future studies will need to test enlicitide in broader groups of patients, especially lower-risk ones. And ultimately, we’ll want to see not just LDL reduction, but hard outcomes — heart attacks, strokes, and deaths.
If the results mirror what we’ve seen with injectable PCSK9 inhibitors, this could represent one of the most powerful advances in cardiovascular prevention in a generation.
Final Thoughts
Even when that day comes, however, one thing remains unchanged: when it comes to improving health outcomes, we should always start with lifestyle factors. Getting exercise and diet right is a must. These are two incredibly powerful levers we can pull to modify our risks.
Some elements of our diet — like fiber — can be particularly helpful. That’s why I include psyllium husk, a source of fiber that’s been shown to have cholesterol-lowering effects, in MicroVitamin+ Powder. But just because I take a supplement, that in no way means you have to also.
