New Lp(a) lowering drug

#228

Thank you for all your suggestions @relaxedmeatball, @CronosTempi and @DeStrider

I agree with everything you’ve all stated and if I knew what I know now I would never have agreed to taking 80mg Atorvastatin. My GP (or PCP) was apparently taking advice from the lipidologist at my local hospital’s Metabolic Clinic. Because my elevated triglycerides weren’t responding to 20mg Atorvastatin they advised to double it to 40mg. After three months my triglycerides had actually slightly increased so they advised to double it again to 80mg. In the meantime I had started investigating and discovered that triglycerides can respond to high dose Omega 3 so had increased my daily dose from 1g to 4g. On the next lipid panel my triglycerides had miraculously nearly halved. I told my GP that this was probably due to the increased Omega 3 but she dismissed that idea and said that my body had just needed the extra strength statins. At this stage I still trusted the NHS so accepted this explanation. Thankfully I still continued with the high dose Omega 3 though.

My trust started to wane after discovering Rapamycin News and all the amazing knowledgeable people who post on here. My CVD protocol is still evolving but this is it for now:

Atorvastatin 40mg (I shall continue to reduce this in steps, first to 20mg and finally 10mg over the next 6 months)
Ezetimibe 10mg
Fenofibrate 160mg
Nebivolol 1.25mg
Aspirin 75mg (or 81mg depending on source)
Colchicine 0.5mg
Niacin 3g
Omega 3 from algae 4g
Metformin 1g
Acarbose 50mg
Finasteride 0.5mg
Nattokinase 10000FU
Regular and Kyolic garlic
Geranylgeraniol 150mg
plus some other supplements like K2, Vitamin D, Pine Bark, etc.

On my list to add gradually over the next 6 to 12 months:

Empagliflozin
Bempedoic Acid

Since reducing the statin dose to 40mg my muscle pain has eventually subsided but it’s still there which is why want to continue to minimise the dose. I will also try alternative statins if I still get pains at 10mg. However I don’t want to abandon statins because they have done a remarkable job in lowering my LDL if nothing else. And yes my HbA1c has inched up a little since starting Atorvastatin in spite of me now taking Metformin and Acarbose.

Even though they would probably be the most helpful thing for my Lp(a) I don’t want to take the risk of importing PCSK9 inhibitors from India due to the temperature storage issues and it would appear it’s impossible for me to obtain them legally in England.

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#229

Whoever this person is, they’re an idiot and this “protocol” is at least a decade out of date. Statins barely touch triglycerides, so anybody prescribing statins for that is terribly misguided.

FYI I am a Professor, not a doctor, and I don’t see patients. But I do research cardiovascular systems and I am friends/colleagues/associates of many awesome cardiologists and top researchers. So my opinions below:

The UK NHS approach (which I’ve seen with my parents) is to give you the crappiest statin - either Atorvastatin or Simvastatin, then just escalate the dose. This is a very old-fashioned approach, which I think is based around saving money rather than good patient care. 40 or 80mg is just stupidity, and of course you’re going to have side effects, including things like insulin resistance.

The well established evidence is that you get the majority of lipid lowering from 10mg of most statins, or even as low as 5mg with a better statin like Rosuvastatin (Crestor). The real bang for buck comes from adding Ezetimibe 10mg/day. For me, 10mg Crestor and 10mg Ezetimibe brought my LDL-C from around 200 to below 80. It also cleared up some fatty liver. (I have genetic condition of abnormally high LDL-C). It’s that simple.

For triglycerides, yes the DHA (fish oil) is an option.

You have described a huge cocktail of other drugs and supplements - many of them with anti-platelet or anti-coagulant properties. I would just say be careful with all of that. Generally it’s not advised to take aspirin etc unless you have evidence of coronary plaque. There is some risk of bleeding, and you’re stacking aspirin, nattokinase, high dose fish oil etc, you can risk GI bleeds, stomach bleeds etc.

PCSK9i might reduce your Lp(a) but they’re not terrible effective. That said, if you want a PCSK9i, it should be possible to go outside of the system, such as a private prescription. Based on the packaging information, the temperature isn’t such a huge deal. Repatha is stable for at least 30 days at room temperature.

Because they are lazy and they’re often just stuck doing the same thing they’ve always done, and haven’t updated along with new evidence. I don’t think there’s any other reasonable explanation.

In the UK, the GP is the “gatekeeper” for everything. You can’t just go and see a cardiologist or lipidologist - you need to be referred by a GP first. The GP is basically dealing with all sorts of people off the street who are coming in with all sorts of ailments and complaints, from depression and anxiety, back injuries, coughs and sniffles, can’t get their wife pregnant, weird rashes, etc etc, so I imagine it’s difficult to keep up with everything. So when this “healthy” (i.e. not dying or suffering from acute disease) dude comes along asking for whatever “exotic” blood tests and some preventative medicine for heart attack and the GP is going to pay you very, very, very little attention. The laziest approach is they test your total cholesterol and LDL, maybe trigs, then give you 10, 20, 40 and 80mg statins. And that whole process of messing around will take maybe 18 months because you’re waiting 3 months for a blood test, another month for a phone call appointment with a nurse who tells you that your LDL-C is high, then another month to see the GP to change the prescription etc etc.

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#230

The standard of care for high cholesterol should be Bempedoic Acid and Ezetemibe. Or at least Statin and Ezetemibe due to the cost of Bempedoic Acid in most places. Ezetemibe is cheap enough.

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#231

But not necessarily heart attacks?

#232

I think the reason is for some because ezetimibe trial didn’t detect any decrease in all-cause or CVD mortality, while high-intensity statins did and has more cohort data.

For me it doesn’t matter so much as I prioritize apoB lowering based on genetic studies anyway, and a trial showing MACE reduction and apparent safety is good enough for me, along with the benefits of lowering via other pathways.

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#233

Atorvastatin is as good if not better than rosuvastatin. Especially in people with diabetes or at risk of it (pre-diabetes or family history). See discussions in this thread: Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial (2023)

The evidence for omega 3 is not great. And EPA is probably better than DHA for cardiovascular health in general. (Besides, DHA causes depression.).

But I agree with everything else: the NHS is shit.

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#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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