New Lp(a) lowering drug

#234

It’s so interesting and timely that you posted this. It confirms everything I learned yesterday, and it explained my entire life with doctors.

I was telling someone ‘in the know’ about how after seeing 5 cardiologists and countless doctors, no doc ever gave me a solid protocol for baby aspirin until this week (after deep diving on the topic in another thread here). This is also the case for my family members and their docs. They had to specifically ask to get a recommendation. In this same conversation I also said I might not even continue seeing a cardiologist because I had to bring him my ideas of colchicine, ezetimibe and bempedoic acid, which he thought were excellent ideas, but he never told me himself. I felt why am I paying him.

It was explained to me that the overwhelming majority of doctors will never be the ones to bring up anything that is not proven and not in the standard protocol, even if they know it will work better, because they can’t get sued if they give you suboptimal ideas as long as they are the standard acceptable suboptimal ideas.

I understood and respected this was the case for not recommending something edgy like rapamycin, but I was shocked to learn it’s the case for even something as simple as aspirin or other cholesterol lowering meds.

I’ve always scratched my head that even my favorite docs only give me great advice on things after I asked. I could never understand why I had to be the one to bring things up, but now it’s all so crystal clear. If I look back, all the pieces of the puzzle seem to fit.

If any of the US docs have a different view of why this happens, my mind is open @KarlT

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#235

I certainly can’t speak for all physicians, and I don’t see scheduled patients in an office. (I’m an ER doc)
My guesses as to what happens:
Most physicians have become employees, and don’t control their schedule. They are expected to see 4-6 patients an hour including the time it takes to document everything. So they have to be fast and go with quick easy answers.
Quality has taken a backseat to speed, quantity, and google reviews.
They can’t possibly keep, up with new information because there is too much of it. About 5000 new papers come out every day.
And realize that although physicians are generally well paid, physicians pay is almost unchanged over the past 20 years. Well below inflation. Few are going to do work they’re not getting paid for. And few physicians will go into the lowest paying specialty of primary care.
And yes, there is some concern about malpractice suits.

Put that all together and you’ll get a short visit in which the physician is direct and goes with the easiest, quickest standard fix to your problem. If you want better than that, you need to be well educated about what you have and want. Or you could seek out concierge medical care.

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#236

Totally agree. Though it does seem that statins have other benefits (like reducing inflammation, and some effects on plaque stabilization). But for preventative medicine in otherwise healthy people, I weight ApoB much more heavily. (Especially in my case with heterozygous familiar hypercholesterolemia)

Ezetimibe, as mentioned by Tom Dayspring many times, is a really great drug but it’s just not that powerful as a monotherapy. And the trail where it was assessed wasn’t the best, so doctors (especially ignorant GPs) have a bad impression of it. For me, it was an absolute game-changer.

That’s a really interesting thread, thanks for sharing. I think my statement of “crappiest” statin was probably unfair and I retract it. That said, those are two different trials with different populations, not a head-to-head, so I don’t think we can conclusively say that one is better. But you’re right that Atorvastatin doesn’t seem objectively worse.

However, of course Rosu is definitely stronger on a mg for mg basis. I just can’t wrap my head around the approach of going up to 80 damn mg of Atorvastatin before adding another drug, when the doctor is looking at a patient with persistently high LDL-C. IMO that’s more about the NHS being stingy than about doing what’s best for the patient.

For example, my mother has LDL-C of around 230mg/dl. (Familiar hypercholesterolemia. I was diagnosed by getting the hell out of the NHS, and now I have LDL-C of less than 40 mg/dl. I’ve also already established that statin monotherapy is totally ineffective for me, so we’d assume the same for her). But in the UK, the doctor prescribed her 10mg Simvastatin. Obviously that did absolutely nothing, which should be a surprise to nobody. Then he increased it to 20 mg. That also did nothing. Then he upped it to 40mg. Then she started to get the muscle aches and her liver enzymes start to go up. And that whole process has taken more than 1 year messing around with appointments, results etc.

A doctor with a functioning brain would look at her, realise she’s not obese, doesn’t have metabolic dysfunction, and this is simply a genetic case, especially given her family history and the fact that her son (and grandchild now) also have sky high LDL-C. Plus, my mother explained that her son is on a very effective combination of drugs. So why not just go with that? It’s basically snobbery where the GP thinks they know best and they can only follow their protocol of dose escalation. So frustrating!

Yeah, omega 3 evidence isn’t great. If he’s taking fish oil rather than one of the pharma products, then presumably he’s getting both DHA and EPA. My point was more about being careful with “thinning” the blood too much, since he’s got high dose fish oil, aspirin, nattokinase etc.

Can I ask where you get “DHA causes depression” from? I know about potential atrial fibrillation at high doses, but I’ve never heard the depression thing before. Thanks.

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#237

I totally understand the situation. And I feel the “gatekeeper” system in the UK where the GP deals with literally everything is kinda crazy. They can’t be an expert on mental health, rashes, infectious diseases, diabetes and everything that.

That said, I do disagree with your statement here. Even if you are educated, I have found that a lot of doctors dismiss your suggestions or experiences. I am a white, relatively wealthy, PhD-educated dude with good social status who isn’t afraid to speak up and it took my years to get my cholesterol issues taken seriously. UK GPs just say “you’re young so don’t worry about this stuff”. It must be awful if you are from a less “powerful” social group and you have doctors just brushing off your questions.

I totally get that Beth. For baby aspirin, I think a big problem is that the evidence is kinda messy. There was a point where it seemed like it should be added to drinking water, and then the tide turned where almost nobody should be taking it. Now, it seems to be much more subjective - basically, if you have existing cardiovascular disease such as plaque, then the rewards might outweigh the risks (bleeding, mostly). But for the average person, probably they should not be using aspirin.

As for doctors, I think they tend to be conservative by nature. I actually blame the Hippocratic oath of “first do no harm”. It feels to me that they’d rather let 100 patients hurt of something due to inaction rather have 1 patient hurt because of action. It’s a very backwards approach in 2025 where we should be focusing on avoiding those chronic diseases in the first place. For LDL-C, we know that there is risk reduction all the way down to 20 mg/dl. But if you’re an otherwise healthy person with LDL-C of 90mg/dl, pretty much no doctor will help you bring it down to 20. However, in 30 years when you have horrible chest pains and can’t climb stairs, then they’ll throw a cocktail of drugs, bypass surgeries etc at you.

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#238

Study should’ve randomized to either rosuva or atorva, etc, it was a secondary analysis though:

Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial 2023

#239

In the atorvastatin vs rosuvastatin we discussed different studies. Not just one.

The mg to mg comparison is irrelevant.

What matters is: take the lowest statin dose possible + ezetimibe. Actually given that statins can mess up with glycemic control I would argue to start with ezetimibe and if not enough add the lowest dose of ator (if diabetes or at risk of) or rosu (if not). Ezetimibe divided my ApoB by 2. I’m a hyperabsorber I guess.

Surprisingly it’s well proven in RCT but no one knows about it. See this thread: Omega 3 makes me depressed: why?

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#240

Interestingly it was when i combined low dose atorvastatin(10mg) everyother day and 5mg Rosuvastatin on the alternate day that my LDL went to 1.2 . (from 5.5) Solo therapy of 40mg Atorvastatin only lowered LDL to 3.5 (from 5.5.) Solo therapy 20mg of Rosuvastatin was the same 3.3 .

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#241

I tried the 6m pcsk9i Leqvio and was extremely unimpressed. As a solo therapy it only lowered LDL to 2.6 and my side effects-chronic cough , lethargy, brain fog(like early onset dementia!) were unpleasant. I would not sign up for a more permanent gene therapy-pcsk9i treatment.

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#242

unless you are concerned about alzheimers… Atorvastatin in lipophilic and rosuvastatin is hydrophylic. The prevailing thought is that you don’t want to inhibit cholesterol synthesis in the brain so I’d choose rosuvastain over atorvastatin any day. Better yet Bempedoic acid if it gets your lipids where they need to be without the additional punch of a statin.

Probably the best case (maybe even only case) for daily 81 mg aprin is if you have high Lp(a).

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#243

Yes I see the other study now. That’s interesting and I retract my statement about Atorvastatin being shitty. Thanks for the correction.

For me personally, Ezetimibe monotherapy was also reasonably effective. Actually more effective than statin monotherapy. So I think I’m with you in the hyper-absorber category, though mine is HeFH (heterozygous familiar hypercholesterolemia).

I’ll just use LDL-C in mg/dl as the illustrative examples. Here are my results:

No treatment: 180
Ezetimibe only (10mg/day): 140 (22% reduction)
Rosuvastatin only (10mg/day): 180 (i.e. zero effect) (0% reduction)
Ezetimibe and Rosuvastatin (10mg/day of both): 73 (60% reduction)

So as you can see, there is a synergistic effect from taking both, which I can’t really explain.

Then adding Repatha at 140mg 1x per month: 25 to 45 mg/dl depending on when I measure (86 to 75 % reduction)

My HBA1C never moved.

Thanks for the links. I’d never heard of that. As you pointed out in your first post, most things I read have people saying it made them less depressed. I can’t say I’ve ever felt anything from zero fish oil to 4g per day. But it’s always mixed DHA and EPA. I’ve never tried using only one of them.

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#244

Yes that’s why the best is probably ezetimibe + BA. And one day obicetrapib?

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#245

My experience too. Ator most effective between 10mg and 40mg. U shaped curve for me as 80mg added no value. But adding Ez was synergistic, bringing TC, LDL and ApoB in line

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#246

I’m curious how much evidence there is regarding this? From what I’ve heard (not an expert on the brain at all), Alzheimers is also related to vascular dysfunction, and statins are generally protective of vasculature. From a quick search, I find papers showing reductions in Alzheimers use. Whether that’s from peripheral circulating cholesterol reductions, or brain-specific production I am not sure.

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#247

High cholesterol is a modifiable risk factor for dementia. However, evidence is weak in favor of statins for dementia prevention. Still, lipophilic might be worse indeed: Statins and cognitive decline in patients with Alzheimer’s and mixed dementia: a longitudinal registry-based cohort study 2023

Lipophilic statin users compared to hydrophilic statin users
We did not find significant differences in MMSE decline in lipophilic statin users (simvastatin, atorvastatin, fluvastatin users) (Table 4) or when considering imputed values of missing MMSE, compared to hydrophilic statins users (rosuvastatin, pravastatin users). However, it was faster in incident users of lipophilic statins (1.32 less MMSE points per year, 95% CI: -2.46; -0.18), and 3.84 less points after 3 years, 95% CI: -7.28; -0.41), compared to hydrophilic statins (Supplementary table 6). These analyses were not statistically significant in sub-analysis of age groups and sex (Supplementary table 3).

So for dementia prevention:

  • Lower cholesterol with non-statin therapies first (I’d start with ezetimibe based on Ezetimibe Reduces Alzheimer's Disease Risk (study) )
  • If you need to add a statin, add the lowest possible effective dose of rosuvastatin (even 2.5 mg might be enough). If you don’t tolerate it or if you’re diabetes, you might prefer low-dose atorvastatin.
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#248

The difference in passing the BBB between different statins not much apparently.
For passing the BBB and reducing brain cholesterol levels, thus correlated with serum desmosterol, pretty much one association paper linking serum desmosterol on MCI and AD (see this: Does low cholesterol cause cognitive impairment? Part II - Peter Attia).

Meanwhile all RCT’s as secondary endpoints are either neutral or positive and it’s investigated for dementia and healthspan in PREVENTABLE and STAREE.

I’d say on net statins probably reduce risk of total dementia, depends how much you weigh that desmosterol connection. I’d probably not be on statins now with E4 allele if it was easy and inexpensive to get apoB optimal without it or if I could test my desmosterol levels, but I’m unsure. I’d probably be on same stack as Peter Attia (bempedoic acid + ezetimibe + PCSK9i) until further evidence or new drugs.

Ezetimibe isn’t going to have enough of a lipid lowering effect on its own for most people, it lowers by 10-20%, so is going to need multiple meds.

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#249

Yes, that’s why I wrote “I’d start with ezetimibe […] If you need to add a statin, add”. This means: “You START with ezetimibe then you test your apoB and if it’s still above your target you add another drug (bempedoic acid? low-dose statin? etc.).”

That being said, for hyperabsorbers, ezetimibe will most likely do the job. E4 carriers tend to be hyperabsorbers (source, I didn’t fact-check). So ezetimibe works for those who are the most at risk of AD.

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#250

I didn’t miss that; just were setting expectations for people initiating ezetimibe monotherapy.

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#251

I believe the “evidence” for reducing cholesterol synthesis in the brain = bad for Alzheimers comes from theories based on APOE alleles. APOE4 results in poor distribution of Cholesterol to neurons so it makes sense that you wouldn’t want to reduce Cholesterol concentrations in the brain. I’m not sure that’s “evidence”, circumstantial at best. That why I described it as “the prevailing thought”.

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#252

Lp(a) reducing drug lepodisiran successful in phase 2 trials, phase 3 is ongoing.

https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart

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#253

Long duration it seems

  • Participants who received 400 mg of lepodisiran at both baseline and day 180 experienced a 94.8% reduction in average Lp(a) levels over the day 30 to 360 period, which remained 91.0% below baseline at day 360 (~1 year) and 74.2% below baseline at day 540 (~1.5 years)
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