This week we talk about LDL, HDL, and cardiovascular issues.

We also discuss one-time therapies, statins, and pharmaceutical economics.

Recommended Book: Blood by Dr. Jen Gunter

Transcript

Cholesterol is the most common type of what’s called a sterol, which is a type of steroid, but also structurally technically an alcohol. But functionally, and classified by scientists, cholesterol is a lipid, which in this case is similar to a fat in all but how the body uses it. Cholesterol is the type of sterol most commonly found in animals—other types are found in plants and fungi—and its function, and this is where it varies from fats, which are used to store energy, is to basically help hold the cell membrane together, and it also serves as an intracellular messenger.

Cholesterol is especially prevalent in the brain and spinal cord of animals, but it’s found throughout their bodily tissues, as well, and again, it’s vital for holding everything together and helping things communicate, in addition to being a precursor for vitamin D, steroid hormones, and bile.

You want to have cholesterol, then, as without it you would be dead.

Too much cholesterol in the blood, however, can also make you dead, especially when it’s bound to what’s called low-density lipoprotein, or LDL, as that contributes to cardiovascular disease like heart attacks and aneurysms, which can massively impact one’s overall wellness and quality of life, and at extremes lead to the whole system shutting down as a consequence of heart attack, stroke, and the like.

A lot of things can contribute to the development of cardiovascular disease, including habits like smoking, genetic predisposition, and the enthusiastic consumption of alcohol and unhealthy foods. But high blood cholesterol, of the LDL variety, is one of the top contributors, as these low-density clusters of lipoprotein can clog the pathways that blood takes throughout our bodies. Other, denser types of lipoproteins, HDLs, can clear it, like a heavier, denser substance pushing through clogs of less-dense materials that are gumming up a pipe, but LDL is at times accumulated as a result of consuming delicious but unhealthy foods, which are hard to avoid, and for some people the only consistently available and affordable foods; and for other people LDL accumulates as a result of their genetic predispositions—two things that are devilishly difficult to change.

What I’d like to talk about today is a new type of therapy that may be very good news for people who struggle with the accumulation of LDL, and why this is being seen as very good news more broadly, at the scale of entire nations, as well.

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Pharmaceutical company Eli Lilly is testing a new, experimental drug called VERVE-102 which is a one-time infusion that is currently administered over the course of about four hours, and once completed, it turns off a gene called PCSK9, which is responsible for making a protein that regulates cholesterol levels in humans.

As I said, this drug is still being tested, so these are early results. But in a study of 35 people with high cholesterol levels, high levels of LDL or LDL-C, which is short for lipoprotein cholesterol, they found that this infusion, which again, is a one-time treatment, so get it once and then theoretically at least you never have to get anything done ever again, it reduced those LDL and LDL-C levels by as much as 62%, and that reduction was maintained a year and a half after the infusion; that’s how far out they’re retested so far, and the hope is that each retest will continue to show the same.

On the strength of those very promising results, a Phase 2 study has been planned by the end of 2026, and the US Food and Drug Administration, the FDA, previously fast-tracked this existing study, because of the promise and potential this drug already demonstrated in early studies; all of which is considered to be very significant progress and possibility.

To understand that significance, though, it’s useful to know some health stats. And I’m going to focus on the US here, as that’s where this drug is being developed, but many wealthy countries have similar stats, at least in terms of cardiovascular disease struggles.

As of 2024, which is the last year we had good, cohesive data on this in the US, it was estimated that about 11-12% of the US adult population has high cholesterol levels. This typically doesn’t come with any symptoms, but it can contribute a higher risk for all those cardiovascular diseases, including heart attack and stroke. A further 86 million US adults have borderline or elevated cholesterol levels, which can easily tip higher, but also, even in that existing, elevated state, contribute to negative cardiovascular outcomes.

There are treatments for high cholesterol, the most common of category of which are called statins, which reduce the production of LDL by inhibiting an enzyme that produces cholesterol in the body.

Unfortunately, these drugs do come with some usually minor side effects, which can cause patients to stop using them, and they have to be taken daily, ideally at the same time each day. That necessity for consistency leads to a lot of incorrect or incomplete usage, which reduces the effectiveness of these drugs. But it’s also estimated that only about 54.5% of US adults who would benefit from statins are currently taking one—so that’s people who could benefit and who have it prescribed, and then within that number are all the people who are taking this drug incorrectly or incompletely, reducing the effectiveness. So a relatively small number of people who should probably be on these things are getting the full benefit they offer because of the nature of the drug.

And that’s not great, because in the US alone, heart disease is the leading cause of death for pretty much every adult demographic; men, women, people of most racial and ethnic and economic groups, you name it, heart disease is the biggest threat to their lives.

One US citizen dies every 34 seconds of some kind of cardiovascular condition, and as of 2023, 1 in every 3 deaths in the US was caused by the same, adding up to just over 919,000 people that year.

Between 2021 and 2022, alone, the cost of services and medications related to heart disease added up to more than $168 billion; again, that’s just in that period, and just in the US.

And once more, these are ailments that are caused or heavily influenced by high levels of cholesterol, which are themselves amplified by common lifestyle choices, environmental factors that are hard for many people to avoid, and just by raw, dumb luck because of genetics.

This treatment category, then, is being seen as a pretty big deal because a one-time infusion means those who receive it don’t have to remember to take a pill every day at the same time, and won’t experience those statin-based side-effects.

It also means that people who are currently costing the medical system a bunch of money each year, because they need treatments for all the issues they suffer as a result of high cholesterol, will suddenly cost the system a lot less money, for treatments and medications. Not for nothing, their health and quality of life will likely improve as well. So in addition to having better, healthier outcomes personally, their cost to healthcare systems will drop.

Eli Lilly’s drug isn’t the only one currently working its way through clinical trials, either.

Amgen is working on a similar treatment, and Novartis and Ionis Pharmaceuticals have drugs that are even further along in the process, their medicines that cut heart attacks, strokes, and cardiovascular deaths could be approved by the FDA as soon as next year.

There are a lot of caveats worth noting here, including that the science is still out as to whether this approach, silencing proteins that lead to the creation of more LDL and a similar substance called Lp(a)—which is more dangerous because it’s stickier and thus more likely to get stuck in important blood pathways, and it’s also more likely to be caused by genetics than lifestyle—the word is still out on whether reducing these things in the body actually reduces hearth attacks and stroke.

Some people have had this particular risk variable dramatically reduced, but have still suffered from cardiovascular events, which raises the question of whether this path is the right one to take in trying to reduce this category of health issues; the correlation between LDL and heart attacks and strokes might not be a clear-cut as long assumed.

There’s also the issue of price. Drug-makers are economically incentivized to sell treatments over cures, because that means they can continue selling their product over time, potentially for the life of the patient, and a cure, in contrast, is a one-time hit that in theory should alleviate the need for future treatment.

There’s a chance, then, that the drug-makers will decide they need to make these one-hit treatments really, really expensive in order to make their R&D dollars back and to make the kinds of profits their investors expect from them. That could then reduce the potential audience for these treatments, even if they are effective, and could further slow their deployment and future research in this space.

If these trials continue to go well, though, there’s a good chance that this combination of similar but distinct treatment types will provide a more sustainable alternative to current options, and that, like the recent bogglingly rapid and widespread deployment of GLP-1 treatments for all sorts of issues, could lead to a new paradigm in this facet of the medical world.

Show Notes

https://en.wikipedia.org/wiki/Cholesterol