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The Cholesterol War Is Over (Here's Who Won) — Transcript

by Dr Brad Stanfield · 2,546 words · 399 segments · language en · Watch on YouTube

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0:00In 2006, researchers in Dallas found a
0:02woman who broke everything that we
0:03thought we knew about cholesterol. She
0:05was 32 years old, a healthy aerobics
0:08instructor, normal liver, normal
0:09kidneys, no health problems. But then
0:11when they tested her blood, her LDL
0:13cholesterol came back at 14, not 140,
0:1714. To put that into perspective, the
0:19average LDL cholesterol in a healthy
0:21adult is around 100 to 130 mg per
0:24deciliter, and doctors generally start
0:26to get a bit concerned if the levels go
0:28above 160. Below 70 is considered
0:31excellent for high-risk patients. But
0:33this woman was at 14. So how was that
0:36possible? Well, Helen Hobbs wanted to
0:39find out, and the irony is she hadn't
0:41planned on studying cholesterol. When
0:42her mentor at UT Southwestern suggested
0:45that she joined a lipid research lab,
0:47her reaction was immediate.
0:48Lipoproteins, oh no, so boring. And she
0:51later admitted that that just tells you
0:53how little I understood about science.
0:55So she and Jonathan Cohen had been
0:57running a massive project called the
0:59Dallas Heart Study, collecting DNA from
1:01thousands of residents, linking it to
1:03their medical records to see what
1:05patterns emerged. Now in some people,
1:07they noticed astonishingly low LDL
1:09cholesterol levels. And when they
1:11checked the DNA, they found mutations in
1:13a gene called PCSK9. But these
1:16mutations, they weren't making the gene
1:18overactive, they were shutting it down.
1:20And the people who carried these
1:21mutations, they weren't getting sick,
1:23they were thriving. They had
1:24dramatically lower rates of heart
1:26disease, about an 88% reduction in
1:29coronary heart disease risk. So that
1:31aerobics instructor, she had mutations
1:33in both copies of her PCSK9 gene. So her
1:36body produced none of that protein, and
1:38she was perfectly healthy. So what Hobbs
1:40had stumbled upon was the clearest
1:42natural experiment in cardiovascular
1:44medicine. If you could block PCSK9, you
1:47could dramatically lower your LDL
1:49cholesterol safely. So now the race was
1:51on to build a drug that could mimic what
1:53this woman's DNA was naturally doing.
1:56And Hobbs later described how fast the
1:58field moved. So geneticists, they took a
2:00little while to understand this, but the
2:02pharmaceutical companies, they got it
2:03right away. So what does PCSK9 actually
2:06do? Well, in simple terms, it destroys
2:08the receptors on your liver that your
2:10liver uses to pull LDL particles out of
2:13your blood. So the more PCSK9 that you
2:15have, the fewer receptors that survive,
2:18and the higher your LDL particles in
2:20your blood climbs. So if you block
2:22PCSK9, those receptors survive and more
2:25cholesterol particles get cleared. And
2:27it was Amgen who designed a drug called
2:29evolocumab, which is a protein that
2:31latches onto circulating PCSK9 and
2:34neutralizes it before it can destroy the
2:36LDL receptors. And in early trials, LDL
2:39cholesterol, it dropped by 81% on top of
2:42statin therapy. So for patients who
2:44struggled with high cholesterol despite
2:46maximum statin doses, this was a
2:48completely new tool. But lowering a
2:50number on a blood test is not the same
2:52as preventing heart attacks. That
2:54requires a much bigger, much longer, and
2:56much more expensive study. So the
2:58FOURIER trial was that study. It
3:00involved over 27,000 patients with
3:03existing heart disease. So half of them
3:05received evolocumab, and the other half
3:07received a placebo, all on top of statin
3:09therapy. And the result is a 20%
3:12reduction in heart attacks, strokes, and
3:14cardiovascular deaths. That was a
3:16triumph, but it came with a caveat that
3:18critics were quick to point out. Every
3:20patient in the FOURIER study had already
3:23had established heart disease. So
3:24skeptics argued that aggressive LDL
3:27lowering might only help people who were
3:29already in trouble. Maybe pushing
3:30cholesterol that low in healthier
3:32patients would cause more harm than
3:34good. So the harder question was this:
3:36What if you started earlier? Could you
3:38prevent the first heart attack, not just
3:40the second or third? So in a follow-up
3:42study called the VESALIUS CV trial,
3:44researchers looked at over 12,000
3:46patients across 33 countries. None of
3:49these patients had ever had a heart
3:51attack or a stroke. All of them had
3:52pre-existing atherosclerosis, which
3:54basically just means that they had
3:55pre-existing blockages in their blood
3:57vessels, or they were high-risk
3:59diabetics with LDL cholesterol levels of
4:01at least 90 mg per deciliter. And after
4:04the 4.6-year follow-up study period,
4:07roughly twice as long as the FOURIER
4:08study, the answer came back as yes.
4:11There was a 25% reduction in heart
4:13attacks, strokes, and cardiovascular
4:15disease. So it had taken 20 years, but
4:18what Helen Hobbs had found in that
4:19aerobics instructor's blood had been
4:21validated in the largest scale
4:23imaginable. Ultra-low LDL was not
4:26dangerous, it was protective. And now we
4:29had proof that deliberately lowering it
4:31before a heart attack ever happens could
4:33prevent that heart attack from ever
4:34occurring. But the VESALIUS CV study, it
4:36included a mix of patients. So some of
4:39them had existing atherosclerosis again,
4:41plaque buildup in their blood vessels,
4:43but some other patients had just
4:44diabetes with no visible disease. So the
4:47question was whether the benefit held up
4:49in that second group. So the ones
4:51further back in the disease process that
4:53hadn't yet developed plaque in their
4:54blood vessels, the ones that most
4:56doctors wouldn't think to treat
4:57aggressively. Well, the question was
4:59answered on March 28th, 2026 at the
5:02American College of Cardiology
5:03conference. So researchers, they
5:05presented a pre-specified analysis of
5:07just the diabetic patients in the
5:09VESALIUS CV study. So this was a group
5:11of just over 3,000 people with diabetes,
5:14but again they'd never had a heart
5:16attack, they'd never had a stroke, and
5:17they had no significant atherosclerosis.
5:20So half of them received evolocumab, and
5:22the other half received a placebo. And
5:24again, they were followed up for about
5:254.8 years. And at the 48-week mark, the
5:28LDL cholesterol in the treatment group,
5:31it dropped to 52 mg per deciliter
5:34compared to 110 mg per deciliter in the
5:37placebo group. And by the 98-week mark,
5:39the median was down to 44 mg per
5:42deciliter. And the clinical impact was
5:44striking. The combination of heart
5:46attacks, strokes, and cardiovascular
5:48death was reduced by, and get this, 31%.
5:525% in the evolocumab group versus 7.1%
5:56in the placebo group. So a hazard ratio
5:58of 0.69. And then there were the
6:01exploratory findings that stopped me in
6:03my tracks. A signal for reduced
6:05all-cause mortality. There was a 24%
6:08lower risk of dying from any cause. Now
6:11this is a subgroup analysis, and
6:12mortality was not as pre-specified
6:14outcome, so we can't make definitive
6:16claims here. But a hazard ratio of 0.76
6:19for all-cause mortality in a primary
6:21prevention population is a signal that
6:23you do need to take seriously. And one
6:26detail that matters here, the benefit
6:27emerged after the first year. And this
6:30makes sense. By stopping plaque from
6:32developing in the first place, it's
6:33going to be a slow, steady accumulation
6:36of protection. Dr. Nicholas Masston, who
6:38is one of the study authors, put it
6:39directly, "I think the study changes the
6:41paradigm. We don't have to wait until
6:43someone has atherosclerosis to treat
6:45them intensively. It challenges the way
6:47that most doctors think about
6:49cholesterol treatment, waiting for the
6:51disease to declare itself before getting
6:53too aggressive. The starter suggests
6:55that waiting costs lives." But here's
6:58the problem. Evolocumab is an injection.
7:00It costs thousands of dollars per year.
7:03And even for patients with established
7:05heart disease, insurance companies, they
7:06often reject the majority of
7:08prescriptions. And for diabetic patients
7:10with no prior events, good luck trying
7:12to get an approval. So the VESALIUS CV
7:15subgroup analysis, it gives us the
7:17science, but for most patients, if they
7:19want to achieve these aggressive LDL
7:21targets, it means that we should opt for
7:23using cheap, off-patent drugs that are
7:25readily available. So statins and
7:27ezetimibe, for instance. And until very
7:29recently, no one had actually tested
7:31whether aiming for specific lower
7:33numbers made a difference. But consider
7:35this case. A 53-year-old woman, total
7:37cholesterol of 141, LDL of 67,
7:41non-smoker, no family history, normal
7:44blood pressure. By every guideline, she
7:46was at target. But she had four blocked
7:49arteries and needed open-heart surgery.
7:51Her friend's reaction afterwards said,
7:53"I thought you could only get heart
7:54disease if you had high cholesterol."
7:56Her case likely involved other risk
7:57factors beyond LDL. But the point here
8:00stands. An LDL of 67 gave her and her
8:03doctor false reassurance. And she's not
8:06an isolated case. A study of nearly
8:08137,000
8:09heart attack hospitalizations found that
8:12almost 75% of patients had cholesterol
8:14levels within the recommended targets.
8:16Nearly one in five had an LDL of below
8:2070, that supposed goal. So the question
8:22becomes, if the target of 70 isn't low
8:25enough, what should it be? And that
8:27brings us to the second study that was
8:29published at the American College of
8:30Cardiology conference in 2026. So in
8:33some ways, it might be even more
8:35important than that VESALIUS CV study
8:37that we looked at earlier. So the new
8:39trial that we're going to look at is
8:40called the ISCEV study, and it's the
8:42first randomized clinical trial to
8:44directly compare two specific LDL
8:47cholesterol targets head-to-head. So one
8:49group aimed for below 55 mg per
8:52deciliter versus the standard 70 mg per
8:55deciliter. The study enrolled 3,048
8:58patients with established cardiovascular
9:00disease across 17 centers in South
9:03Korea, and they were followed up for 3
9:05years. In the intensive group, the
9:07median LDL achieved was 56 mg per
9:10deciliter, and in the standard group, it
9:12was 66 mg per deciliter. But the results
9:15were clear. The primary outcome of the
9:17study, which was a combination of
9:19cardiovascular deaths, heart attacks,
9:21strokes, revascularization, or
9:23hospitalization for unstable angina,
9:25occurred in 6.6% in the intensive group
9:29versus 9.7% in the standard group.
9:32That's a 33% relative risk reduction.
9:35The difference between an LDL of 56
9:37compared to an LDL of 66 is just 10 mg
9:41per deciliter, but that translated to a
9:43third fewer major events. The individual
9:46outcomes were even more striking.
9:48Non-fatal heart attacks were more than
9:50halved with a hazard ratio of 0.46. Any
9:53revascularization, the hazard ratio was
9:560.63. So what about safety? Well, there
9:59were no signals of harm. There was no
10:01excess diabetes, no myopathy, no liver
10:04toxicity. Dr. Christopher Cannon, who
10:06commented on the trial, he put it
10:08simply, "55 is our new goal, and we need
10:10to really embrace that and work hard to
10:12get patients to that new goal." All of
10:15this aligns with the low target that
10:16I've personally aimed for over the past
10:18few years, and I base that on a study
10:21called the PESA study. It imaged the
10:23arteries of 4,184 apparently healthy
10:26middle-aged adults with no
10:28cardiovascular disease. What they found
10:30in a subgroup analysis of those with no
10:32conventional cardiovascular risk
10:33factors, so no high blood pressure, no
10:35obesity, no insulin resistance, etc.,
10:38was striking. Nearly half had already
10:40developed plaque in their blood vessels,
10:42and when they looked at the relationship
10:44between LDL cholesterol levels and
10:46plaque burden, the data showed a clear
10:48linear pattern, and the chart from the
10:50study is worth seeing. So, the plaque
10:52built up even if LDL cholesterol was at
10:5560, and it climbed to 64% in those with
10:58LDL of between 150 to 160. And
11:02critically, the authors note that plaque
11:04buildup appears to only develop at an
11:06LDL threshold of approximately 50 to 60
11:09mg per deciliter, the very range that
11:12the new high-risk guidelines are now
11:14targeting. And the free health roadmap
11:16tool that I've created takes into
11:18account this PESA data, and you can find
11:20a link in the pinned comment to try it
11:21out. Now, I should note some important
11:23limitations. The ESPRIT study that
11:26compared the older target of 70 with the
11:28more aggressive target of 55 was
11:30conducted entirely in South Korea. So,
11:32ideally, we'd want to see this
11:33replicated in other populations, and
11:36only 60.8% of patients in the intensive
11:38arm actually achieved the target of
11:41below 55 at the 3-year mark. But the
11:43implication here is still powerful.
11:45Every point of LDL cholesterol matters,
11:48and the old target of 70 can leave
11:50significant benefits on the table, and
11:52the PESA study tells us the same thing.
11:54And here's the part of the story that
11:56really frustrates me as a doctor. So,
11:58the drug that the ESPRIT study used to
12:00help patients get from 66 mg per
12:02deciliter down to 56 mg per deciliter,
12:05it wasn't some cutting-edge injectable
12:08that costs thousands of dollars a year.
12:10Instead, the drug is called ezetimibe,
12:12and ezetimibe is cheap, it's off-patent,
12:14and it works by basically telling your
12:15gut to not absorb as much cholesterol.
12:18It's generic, it costs almost nothing,
12:20and as of the most recent data, only 6%
12:23of patients with established
12:24cardiovascular disease are taking it.
12:266%. Karen Aspry, who's a cardiologist at
12:29Brown University, called the ESPRIT
12:32study a real-world approach for how
12:34clinicians should be titrating to a
12:36lower target using ezetimibe, which many
12:38are not doing. 2/3 of heart disease
12:41patients aren't at the LDL cholesterol
12:43target despite using statins. So,
12:45there's a cheap generic pill that could
12:47help most of them get there, but almost
12:49nobody is prescribing it. So, for my
12:51patients, we have an open discussion
12:53about aiming for the more aggressive 55
12:56target rather than 70. And personally, I
12:58take a statin as well as ezetimibe. And
13:01for the group of patients who can't
13:02reach their target levels despite using
13:04statins and ezetimibe, PCSK9 inhibitors,
13:07they do remain an option, though at the
13:09moment, cost is still a barrier. But
13:11there's reason for optimism here, too. A
13:13new oral PCSK9 inhibitor recently showed
13:16a 58% LDL reduction in a phase 3 trial.
13:19So, when it's approved, it could remove
13:21the injection barrier entirely. And the
13:23earlier you start lowering your LDL
13:25cholesterol levels, the more benefit
13:27you'll get. Now, there are some other
13:28dietary components that do have
13:30effectiveness in lowering LDL
13:32cholesterol. So, soluble fiber is one of
13:34them, and that's why I included psyllium
13:36husk, a well-studied source of soluble
13:38fiber with cholesterol-lowering effects
13:40in multivitamin plus powder. But just
13:42because I take a supplement does not in
13:44any way mean that you should as well.
13:46Now, coming back to that woman in
13:47Dallas, the aerobics instructor with an
13:49LDL of 14, and Helen Hobbs who looked at
13:52her blood and saw something that most
13:54scientists would have dismissed, it
13:55launched a 20-year chain of discoveries.
13:58The gene, the drug, the trials, and now
14:00for the first time, head-to-head
14:01evidence for that exact number to aim
14:03for. The science is clear, lower is
14:05better, the earlier the better, and the
14:07target that your doctor was likely
14:09trained on is probably too high. The
14:11only question left is whether we should
14:13act on it. And something that
14:14unfortunately has muddied the waters
14:16here is a controversy over whether
14:18there's an important link between our
14:20cholesterol levels and saturated fat in
14:22our diet. So, we'll have a look at
14:24what's driving that controversy and what
14:25the data actually says in this next
14:27video here.

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