#41

They have not run the trial on people with high Lp(a) and you are just talking about a western world trial where most of the participants probably did not have high Lp(a) - and hence the trial was almost certainly not powered to answer the question if it helps in individuals with high Lp(a)?

I agree with you that niacin may not be net positive for people wanting to address Apo B without having high Lp(a)

Though I think it’s that the inflammatory aspects of niacin might not over power the Apo B lowering effects - not that the Apo B lowering effects are not helpful due to lack of mechanism.

For someone with high Lp(a) where it crushed their Lp(a) by 50% or so the trade off might be different as Lp(a) is even more negative than Apo B and that person gets both Lp(a) and Apo B down.

See for example:

You have to click on the first because it’s images of tweets by arguably the world’s top Lp(a) physician, but the images are not shown in the summary within this post linking to that post

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#42

I appreciate the perspective and agree that the clinical trials on Niacin haven’t shown a clear MACE benefit when added to statins. However, I think there’s some nuance worth considering before dismissing it entirely.

  1. Trial Context Matters – The AIM-HIGH and HPS2-THRIVE trials tested Niacin on top of statins, where ApoB was already well-controlled. In that setting, it’s not surprising that adding another lipid-lowering agent didn’t provide additional MACE reduction. However, that doesn’t necessarily mean Niacin is ineffective—just that it didn’t provide additional benefit beyond aggressive LDL/ApoB lowering in those specific trial populations.
  2. Lp(a) is a Different Target – Unlike LDL, we don’t yet have a definitive trial proving that lowering Lp(a) reduces MACE risk. However, Mendelian randomization studies strongly suggest Lp(a) is causal for atherosclerosis, so it makes sense to target it in high-risk individuals. Niacin remains one of the few currently available options that significantly lowers Lp(a).
  3. Practicality vs. Theoretical Risk – While high-dose Niacin has been associated with liver issues in some patients, those concerns are mostly tied to extended-release formulations. Immediate-release Niacin, at appropriate doses, has a much better safety profile, and liver toxicity is rare when properly monitored.
  4. PCSK9 Inhibitors Are Likely a Better Option—If Available – I would absolutely add a PCSK9 inhibitor to my protocol and recommend others consider them. The data on PCSK9 inhibitors shows clear reductions in both ApoB and Lp(a), with strong evidence of MACE reduction. Unfortunately, in my case, I’m based in New Zealand, where they are unavailable, so they aren’t an option for me. Given the refrigeration requirement, importing them isn’t practical either.
  5. Personalized Approach – If someone is already on maximally tolerated lipid-lowering therapy (statins, ezetimibe, PCSK9 inhibitors, etc.), then yes, adding Niacin may not be necessary. But for those with high Lp(a) and limited alternatives, the risk-benefit calculation may be different.

I’m not saying Niacin is a magic bullet, but for those of us actively monitoring biomarkers and seeking additional reductions in Lp(a), it remains a reasonable tool—at least until more targeted therapies (e.g., siRNA, antisense oligonucleotides) become widely available.

Would love to hear your thoughts on how you’re personally addressing Lp(a), given the limited options we currently have.

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#43

Sorry, but I am completely unimpressed by this motivated reasoning. First of all, elevated Lp(a) is not exactly rare. Somewhere between 20-30% of people have elevated Lp(a):

Lipoprotein(a): What to know about elevated levels | NHLBI, NIH.

Therefore in all those NA trials that failed miserably in lowering MACE/CVD, you can assume between 20-30% had elevated Lp(a), which NA presumably crushed just as it crushed LDL and elevated HDL. But even though it crushed the Lp(a) in up to a third of the cohort it did didly squat for MACE/CVD. There was not signal, and statistically there should have been if NA truly affected the disease process. The fact that Lp(a) is much worse than LDL in the atherosclerotic disease makes this all the worse. NA crushed the worst fraction in a third of the people and still didn’t do a thing to even generate a signal is just testimony to how giant a fail it has been. And what reason is there to suspect that since NA lowering of LDL didn’t do anything for MACE/CVD it therefore might do something for the lowered Lp(a)? It can fail just as well there. Which, btw., it has, because there is no signal.

Now we can argue till the cows come home that somhow there is this possibility that if you squint real hard NA will be a beautiful agent against the effects of Lp(a), but here’s the reality: the FDA, or for that matter any clinician has to prove the effectiveness of a drug in a trial. NA has not been cleared as a Lp(a) lowering agent with effectiveness against CVD. That’s a fact. There are is no such proof in the case of NA, which leaves us where? The OP said that NA brought his Lp(a) numbers down. I responded that that’s fine and dandy and great and all, but that people should be aware that NA has a very particular history with lipid lowering and MACE/CVD - a controversial one (I think I was pretty diplomatic there!). I don’t take a single thing back. I personally would never take NA for CVD, in my opinion that’s a horrible idea, but that’s up to the individual - there is no proof it’s effective, but hey, we all do speculative things.

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#44

I think I fall into this bucket. Genetically high ApoB and Lp(a). Now the ApoB is well under control (20-40mg/dl) with statin, ezetimibe and PCSK9i, but the Lp(a) is still bad (65 mg/dl).

For me, being fairly young (38) I would choose not go with high dose niacin. I think I have the luxury of being able to wait for proper trial data from the drugs which are already in the pipeline. They should be out within the next few years and those drugs are specifically going after Lp(a) production. I would also like to see the data about MACE reductions. I much prefer those hard outcome data, rather than just chasing after biomarker numbers. As somebody said earlier, chasing improvements in HDL-C as “cardioprotective” showed the futility of that approach.

It’s a very interesting framework to consider which is more harmful: Lp(a) or a high dose of niacin though. I would guess probably the Lp(a) is worse, but (maybe irrationally) I still feel that taking a ridiculous dose of a vitamin and getting the flushing etc doesn’t seem sensible. For now, my approach is lower ApoB and every other risk factor (blood pressure, weight, not smoking etc).

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#45

I think there is a bit of a misunderstanding here. You posted that NA lowered your Lp(a) number, but didn’t qualify that at all in any way. All I did is bring the - in my opinion - necessary context of how the NA lowering Lp(a) number might not be quite the boon it may seem if we are not aware of the history of NA and lipid lowering therapy for MACE/CVD. Nothing more, nothing less.

As to what I do personally. I happen to have sky-high Lp(a). I’m doing what seems to be the consensus at this point as articulated by Tom Dayspring - since we don’t have a dedicated drug to crush Lp(a) specifically (apart from the marginal 20% or so effect of PCSK9i), what you need to do is absolutely annihilate ApoB - get it as low as you can and drown it in the bathtub :laughing:. How - by any means necessary. I appreciate that PCSK9i is not an option for everyone for a variety of reasons. That leaves statins, BA and EZ. Statins actually raise Lp(a), so why would you use them to lower ApoB while elevating Lp(a)? As Tom Dayspring explains: while a very destructive molecule, Lp(a) is relatively a tiny number of particles in comparison to the rest of ApoB. Therefore if you use statins to absolutely CRUSH, obliterate ApoB, you come out ahead clinically even at the cost of slightly raised Lp(a) - the lowering effect swamps the negative of the Lp(a).

Therefore that’s my approach - obliterate ApoB. And ignore Lp(a), until one day a drug might come along to address this particle, and if not, I’m good anyway. YMMV.

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#46

Thanks for clarifying - I completely agree that crushing ApoB should be the top priority, and I’ve already brought mine below 0.5 g/L (most recent was 0.39) with a low-dose statin, ezetimibe, and bempedoic acid.

Where we may differ is how much to prioritize Lp(a) alongside ApoB. While Lp(a) makes up a small fraction of total ApoB, its pro-thrombotic and inflammatory properties make it disproportionately dangerous. If I can lower mine by 50% with a well-tolerated therapy, that seems like a meaningful win - especially given the lack of other options.

I understand the skepticism about Niacin, but since Lp(a) is a causal factor in CVD and there’s no FDA-approved treatment for lowering it, I don’t see a strong reason to dismiss a tool that significantly reduces it. PCSK9 inhibitors aren’t FDA-approved for Lp(a) lowering either, yet they’re widely used off-label because they reduce it by about 20%. If they were available to me, I’d take one - unfortunately, they aren’t an option where I live.

If a dedicated Lp(a)-lowering therapy were available, I’d use it. But in the meantime, I’ll work with what’s accessible.

Appreciate the discussion - it’s great to exchange thoughts with others who are serious about managing these risk factors.

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#47

Did you use ChatGPT etc for this? I don’t think they’re good enough yet and it depends on prompt and amount of tokens used.

I’d take a look at the failed niacin trial(s) and see what the risks are, then consider the benefits of lowering Lp(a). I just skimmed one now and the trend towards increase in all-cause death of 1.09 was bad, before that non-sig small improvement in major vascular events wasn’t that bad but list of different side effects detected:

Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients 2014

But it’s a different population most likely than those with higher Lp(a).

#48

No. And the study you quoted is irrelevant—no one here is suggesting extended-release Niacin with Laropiprant. Immediate-release Niacin has a different safety profile, and that’s what’s being discussed.

#49

relaxedmeatball - “I would also like to see the data about MACE reductions. I much prefer those hard outcome data, rather than just chasing after biomarker numbers. As somebody said earlier, chasing improvements in HDL-C as “cardioprotective” showed the futility of that approach.”

Lp(a) isn’t just a biomarker—it’s a causal driver of cardiovascular disease. Reducing it reduces risk. Period. We don’t yet have outcome trials proving that lowering Lp(a) reduces MACE, but that’s because those trials take time, not because the causal link is in doubt. I agree that waiting for new therapies makes sense if you’re comfortable with your current risk, but for those with very high Lp(a) and few options, it’s reasonable to act now.

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#50

Sorry if I upset you

First - I am not saying that niacin does help people with high Lp(a). I am just saying that you can not confidently say that it does not (without putting forward other arguments that you did).

The statistics do not work the way you are trial to use the non Lp(a) focused CVD trials

  • as you know I said it’s very likely that there is a net negative outcome for people who are not high Lp(a) of taking niacin (and it seems like you believe that is what the data says also)
  • but the only way your reasoning works for inferring that there is not a net positive effect on high Lp(a) people from niacin is to know that the effect on the low Lp(a) people is not that negative.

Because if that effect of niacin is even half as negative on the low Lp(a) participants (that are more than twice as many in the trial) as the effect of niacin is positive for the high Lp(a) participants then trial results will be consistent with a net negative result.

So it sounds like the correct answer based on the information in your posts and those trials is that we still don’t know

…and not that one should confidently rule out taking it

I personally do not take niacin even if I don’t have ideal Lp(a)

  • but it seems like a quite close call too me and not something where the answer is that it was as clear “bust”
#51

So look at the niacin trials without laropiprant or delayed release, it doesn’t change my point to look at the trials.

#52

Wondering what about natural PCSK9 inhibitors? No one talking on that? Melatonin, fistein, berbarine and bergamot together (my GP suggested that) etc etc.

#54

I’d take the same line I always do; that I would much prefer a drug to a supplement, where the choice exists.

Drugs have big clinical trials, control groups, an independent 3rd party to monitor safety and efficacy. Then they get FDA approval, and safety data is still collected (post market surveillance).

Supplements rarely have good quality studies, and they’re usually small and short-term, sponsored by the people selling the supplement etc.

However, my biggest issue is that we no real idea about quality control, purity, truthfulness etc. Time and time again, we see supplements where the dose is nowhere near what’s on the bottle. Sometimes the supplement in question is completely absent. And I’d be nervous about any of those plant extracts because you have no idea the original source quality (laden with pesticides etc) what sort of contaminants (solvent etc) are left behind from the processing. And the manufacturers in general are factories in China, and I don’t trust them that the bag of tea leaves for the bergamot hasn’t been sitting around the warehouse for ages, accumulating rat and cockroach droppings.

So if my idea is to target PCSK9i, I’d choose one of the two monoclonal antibodies, or the siRNA drug, which are much better understood and the quality control is good.

It’s not to say I don’t take supplements at all. But if the choice exists, it’s a pharma product every time.

2 Likes
#55

And what are your thoughts on Co Q10? Cardiovascular Health and Lipoprotein(a): How to Address a Genetic Issue and Support Cardiovascular Health Naturally - TOCOTRIENOL Tocotrienol.org ‘Coenzyme Q10, commonly known as CoQ10, is an antioxidant well known for its cardiovascular health supporting benefits. CoQ10 significantly reduces serum levels of lipoprotein(a), with reductions of 31% compared to 8.2% with placebo in one randomized double-blind placebo controlled trial.[xi] CoQ10 has been shown in meta-analysis to improve endothelial function,[xii] and in other studies to reduce LDL oxidation,[xiii] as well as systolic and diastolic blood pressure in patients with diabetes.[xiv] With the use of statin medications, which inhibit an enzyme known as HMG-CoA reductase, it is very important to include CoQ10 as a supplemental therapy as this enzyme is also necessary for production of CoQ10.’

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#56

I read this re niacin today - I think genotypes make a difference: Lipoprotein a: Genes and Lp(a)

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#57

Thanks. Yes, we discuss that a bit here and in some of the downstream posts:

@CronosTempi this might be another reason the general trials do not pick up the signal

Not only is high Lp(a) just a minority of people in those trials, but it’s then quite likely it’s mostly (or only) a subset of those with high Lp(a) that have those specific genetics that super respond and/or net benefit. Or what do you think of that part?

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#58

The link mentioned genotype → Lp(a) :arrow_double_up: → ASCVD risk :arrow_double_up:

Why not just measure Lp(a)?

#59

Hi @KiwiGuy Yes I think you’re right. It’s difficult to imagine where Lp(a) is successfully lowered but it doesn’t translate to better clinical outcomes.

Luckily quite a lot of drugs are on the way. There are three drugs in phase 3:

OCEAN(a) trial - Olpasiran, siRNA with injection every 12 weeks, 70-100% lowering
HORIZON trial - Pelacarsen, anti-sense oligo with injection every 1-4 weeks, 70-100% lowering
ACCLAIM-Lp(a) trial - Lepodisirin, siRNA with injection every 6 months. Reduced Lp(a) 97%

And two more drugs in phase 2:

KRAKEN trial - Muvalapin, a small molecule, once daily oral administration, 86% reduction
SLN360, siRNA, injection every 4-6 months, 85.6% reduction

So very soon we should have more than one option

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#60

Any sense when the first one will file with the FDA?

#61

No, sorry. But my cardiologist said he “should be able to prescribe something within 2025”, so presumably not very long.

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