Approximately 1%-3% of the population (depends on ethnicity) has the genetic mutation that prevents the manufacture of bad cholesterol in the body. I’m among them.
When my vascular specialist said that he was going to put me on a low dose statin last April during the initial consult for the swelling in my right leg I immediately pushed back, "Why would you do that? All my lipid studies over the years have been on the low end of normal. And when I had that Abdominal Aortic Aneurysm screening exam a few years back., the Ultrasound Tech told me, “My God, you don’t even have any calcium deposits on your abdominal aorta. That’s very unusual for someone your age. I’m pretty sure I don’t have a lipid problem.”
The doctor said, 'Well, the distribution of plaque in the body varies from individual to individual. Just because you don’t have it in your abdominal aorta, doesn’t mean you don’t have it in your legs"
Of course, the ultrasound scan that was done a few hours before the initial consult showed a big, gaping, thrombosed aneurysm at the knee, and no sign of plaque anywhere. The fact that I was being treated for a lipid problem I don’t have for the next 10 weeks while the thrombosed aneurysm pinched the artery closed likely cost me the leg.
Interestingly, Eli Lilly, Novartis and others are currently doing a trial on genetically-modifying this gene so that everyone wealthy enough to pay the price of admission can also enjoy the benefits of the “good gene”.
Well, you don’t quite need to go as far as gene editing.The benefits of PCSK9 inhibition can be had from PCSK9 inhibitor medication. Repatha etc.
Within less than 2 weeks of my first dose, my LDL-C dropped from a fairly reasonable 90 or so mg/dL…achieved with statin alone…to just over 30. Where it’s remained.
As they explain in the video, if you did the gene editing as a child, you’d be permanently protected from the lipid problems that are epidemic in the US population. Doing the gene editing as a adult, doesn’t erase the damage already done, it just shuts down any future lipid production.
intercst
(thriving on a diet of processed foods and chocolate donuts)
Indeed…but the same holds true with early pharmacologic intervention. For those of us with with any of the FH subtypes, the issue isn’t so much what the intervention is, but when it starts. The shorter the amount of time that the cardiovascular system is marinating in highly atherogenic particles, the better cardiovascular health over the long term.
Early diagnosis (childhood even) is the key. Next is willingness to acceptance the long term consequences of high levels of atherogenic lipid particles in the absence of obvious symptoms in the here and now. Catching problems at the earliest possible departure from healthy homeostasis (a phrase I’ve typed multiple times in the past)
Note…I’m referring to FH (as was Hank in the video) …not the self inflicted issues caused by overeating, oversitting, smoking etc which are the main drivers of the lipid problems that are epidemic in the US.
Edit:…this appears to be the trial mentioned in the video…
So, in wandering through the the internet Field of Cow Pats, I spotted this. Not a random find (I never tackles fields of cow pats blindfold)… I was specifically looking for something on or by this guy. His guest spot on Peter Attia’s podcast a few years back is where I got an insight on the severity of some variants of FH. Particularly the prevalence in the Netherlands…and the unusual presentation in some of the old Dutch Master’s paintings.
If that’s not enough, rest assured, his delivery is in no way similar to Hank’s annoyingly mawkish style…
Now, I don’t know if anyone here has a better memory than I, and spent time on the Foolish Collective board years ago, but I recall a series of posts called The Cholesterol Plays. Poster edmiller. Round about 2004 or maybe a bit later?
Anyways, he did a neat little analogy of the roles of HDL and LDL in the development of ASCVD. An ensuing bit of discussion on existing tests and therapeutics. Statins (obviously) and the introduction of hs-CRP as a risk predictor etc.
As a finale, he introduced a few of the non statin lipid lowering meds that were in the pipeline, a bit of background on them and potential future interest (it was an investment board, after all) I’m pretty sure I recall a mention of the discovery of a genetic variant discovered in a small community. Boy, do I wish we could access those older posts. I didn’t have a clue I’d be a recipient of research from those days.
The genetic variant you are likely remembering is a loss-of-function mutation in the PCSK9 gene, originally discovered in a small community in Limone sul Garda, Italy. [1, 2]
Individuals with this specific genetic variation (often called the Milano variant) have naturally, lifelong ultra-low LDL (“bad”) cholesterol levels and are highly resistant to heart disease. [1, 3]
This breakthrough inspired a massive wave of blockbuster non-statin therapies, primarily:
PCSK9 Inhibitors (Evolocumab / Alirocumab): Injectable monoclonal antibodies that block the PCSK9 protein.
Inclisiran: A twice-yearly siRNA (small interfering RNA) injection that prevents the liver from ever producing the PCSK9 protein.
Gene Editing: Emerging technologies (such as base editing) aim to permanently turn off the PCSK9 gene in liver cells with a single infusion, mimicking the effects of the genetic variant. [4, 5, 6, 7, 8]
Other notable non-statin therapies introduced around the same time include Bempedoic Acid (an oral pill that halts cholesterol synthesis in the liver before the statin step) and Ezetimibe (which blocks cholesterol absorption in the gut). [4, 5, 9, 10%20or%20matching%20placebo.), 11]
Let me know if you’d like a deeper dive into the clinical trial data, the mechanism of action of any specific drug, or the market outlook for these treatments!
Boy, you’re a faster reader than I am. To wade through and digest the content of all these studies. Impressive.
However, note that phrase about AI responses making mistakes. It seems to have PCSK9 confused with the Apo A1 Milano variant which is a variant of HDL. PCSK9 is a protein that affects the LDL receptor. I’d forgotten the name of the village (if I’d ever known it in the first place) but I do recall edmiller mentioning this region just outside of Milan. Although the family members studied had a very low incidence of ASCVD, they also had usually low HDL…the exact opposite of what was commonly viewed as a high risk factor.
I think this discovery predated The Cholesterol Plays threads by quite a while as edmiller used the background story as an historical example of non-laboratory discoveries…i.e. intellectually curious researchers who spot anomalies and think "Now that’s peculiar " and follow up on it…and it leads to a potentially valuable treatment.
The AI is trying to be nice to you here. Hint we are looking for an inhibitor.
You are spot on! That is a very important distinction, and it highlights exactly why users need to double-check information generated by AI.
You correctly identified that PCSK9 and ApoA1 Milano operate in completely different cholesterol pathways.
Here is a quick breakdown to clarify the difference:
PCSK9
What it is: A protein (proprotein convertase subtilisin/kexin type 9) primarily synthesized in the liver.
Function: It binds to LDL receptors on the surface of liver cells. Instead of letting the receptor recycle, PCSK9 escorts the receptor into the cell to be destroyed.
Effect on Cholesterol: By reducing the number of available LDL receptors, PCSK9 prevents the liver from pulling “bad” cholesterol out of the blood, resulting in higher blood LDL levels.
Therapeutics: PCSK9 inhibitors (like evolocumab) block this protein, allowing more LDL receptors to recycle and drastically lowering LDL cholesterol. [1, 3]
ApoA1 Milano
What it is: A naturally occurring, mutated variant of the Apolipoprotein A1 protein.
Function: ApoA1 is the primary structural protein that makes up HDL (the “good” cholesterol).
Effect on Cholesterol: Carriers of the rare ApoA1 Milano mutation actually tend to have very low levels of HDL. However, the HDL particles they do have are incredibly efficient at “reverse cholesterol transport” (pulling cholesterol out of artery walls).
Clinical Significance: Despite having an alarming blood lipid profile (low HDL and high triglycerides), carriers of the ApoA1 Milano variant are strongly protected against atherosclerosis and heart disease. [4, 8]
If an AI previously claimed that PCSK9 was related to HDL or the ApoA1 Milano variant, it was confusing the LDL-clearing pathway with the HDL-mediated cholesterol-removal pathway. Thank you for catching and pointing out that error! [1, 7]
Yes, exactly! ApoA-1 Milano (apolipoprotein A-I Milano) is a naturally occurring genetic mutation first discovered in 1974 by researchers from the University of Milan in the residents of Limone sul Garda, a small, historically isolated village on the shores of Lake Garda in northern Italy. [1, 2]
Why it’s so famous:
The “Elixir” Protein: The mutation—a single amino acid replacement at position 173—grants carriers a remarkably low risk of cardiovascular disease.
The Paradox: Despite having alarming blood profiles with very low levels of “good” HDL cholesterol and elevated triglycerides, carriers show no signs of arterial plaque or atherosclerosis.
Patient Zero: Medical genealogists traced the dominant gene mutation back to a single couple living in Limone sul Garda in the 1700s, like Giovanni Pomarelli. Because the village was isolated by mountains and the lake for centuries, the mutation spread among several dozen descendants. [1, 2, 3, 8]
Medical Impact:Scientists have long studied the synthetic version of this protein (formerly known as ETC-216 or MDCO-216) as an intravenous therapy to quickly regress arterial plaque and “unclog” coronary arteries. [5, 9, 10]
There are a number of answers that spring to mind here (assuming this question is more than an exercise in JAQing off)
First and foremost, statins (if that’s the only lipid lowering medication you’re aware of), when prescribed appropriately and for a child, are used as an alternative to all the consequences of severe, unchecked ASCVD…strokes and heart attacks, PAD etc as early as the teens.
Second, statins are no longer the only effective lipid lowering medication around. There were a few mentioned upstream, hidden amomg the cow pats donated by @Leap1 (even a stopped clock can be right a couple of times a day) Including…but certainly not limited to…PCSK9 inhibitors such as Repatha (evolocumab).
A third point…and one made by your man Hank…what if a person wants to discontinue treatment for whatever reason? Can’t do it very easily if early childhood gene editing has taken place.
Even when the stopped clock is apparently correcting itself, it’s still wrong.
This JAMA study may well have been one that contributed to edmiller’s mention of the Apo A1 Milano story back in 2003 or so. It certainly seems to have impressed the Google AI overviewer since it’s cited twice in the stream of vomitus (ref. #7)
I hadn’t heard of the phenomenon of regression of arterial plaque until my discussion with my intervention cardiologist on the therapeutic value of ultra low LDL-C levels. Here’s an example of the same thing being described over 20 years ago. No wonder AI overview was so impressed…even if the ultimate conclusion was dead wrong.
It is not like either of us buy into much. This is just a discussion. Pretend and kick away all you need to. I am not a doctor’s guinea pig. Never mind a guru that you do.
