Cardiovascular disease is a solved problem

(totalhealthoptimization.com)

84 points | by brandonb 2 days ago

20 comments

  • WhatsTheBigIdea 2 days ago
    This paper's core idea is based on the assumption that circulating LDL is the cause of heart disease. That assumption is false.

    Taking satins is proven to reduce heart disease rates, but there are lots of other drugs that lower LDL... many with much more efficacy than satins.

    These non-satin drugs do not reduce heart disease rates significantly.

    There something else going on here. High LDL is correlated with the development of heart disease, but it does not cause heart disease. Satins do reduce the risk of heart disease and they do reduce LDL, but their positive effect on heart disease rates is not caused by reduced LDL.

    • brandonb 2 days ago
      There are multiple independent risk factors for heart disease. The major ones are:

        - LDL / ApoB
        - Blood pressure
        - inflammation (hs-CRP)
        - Insulin resistance (HbA1c)
        - Lp(a): strongest hereditary risk factor.
        - eGFR: a measure of kidney function
      
      Non-statin drugs like PCSK9 inhibitors have been shown to reduce heart attacks, strokes, and other cardiovascular events on top of statin therapy. One randomized control trial was FOURIER in 2017: https://www.nejm.org/doi/full/10.1056/NEJMoa1615664
    • KempyKolibri 2 days ago
      Why do we see consistent dose response between LDL lowering SNPs and cardiovascular disease in Mendelian randomisation studies, then?
      • daveguy 1 day ago
        Heart disease is clearly not Mendelian. So, unless you have a specific well-designed study to cite, that is a non-argument.
        • graboy 1 day ago
          https://www.jacc.org/doi/10.1016/j.jacc.2012.09.017

          Across different genetic variants, lower lifetime LDL -> lower risk of death. Check out figure 3.

          The causality of LDL -> plaque buildup -> 55-60% [1] of heart disease related deaths is also well understood, so it seems clear to me that preventing plaque buildup in the first place prevents over half of heart disease related deaths.

          Would like to know if you disagree, "Minimize LDL at all costs" goes current mainstream medical guidance, so I'd like to disconfirm my beliefs if possible.

          [1] Number from deep research.

        • KempyKolibri 1 day ago
          Graboy has provided the citation I would have given, as well as an excellent explanation. I’m not sure what you mean by “heart disease is clearly not Mendelian”.
          • graboy 1 day ago
            What do you think of Dr. Schooling's response that the Mendellian effects might be inflated? I think they had a good defense but was not entirely convinced they hadn't sidestepped the issue that Schooling was getting at, wasn't sure either way.

            https://www.jacc.org/doi/epdf/10.1016/j.jacc.2013.01.067

            • KempyKolibri 11 hours ago
              I wasn’t aware of that critique, thanks for sharing. Before I read the response my first thought was “why such consistency across different SNPs, then?”, so I would certainly agree with that aspect of the defence.

              In general, Ference’s explanation just seems more parsimonious than Schooling’s. It’s possible that they’re right, but I think they would need to show that the specific genes in Ference’s study are affected by age in this way.

              I wouldn’t claim to be a great expert in MR, though. I can just about keep up with surface level understanding of them but once you get into the nitty gritty stats, pleitropy testing etc it’s a bit over my head tbh.

          • daveguy 1 day ago
            Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease. I thought that was basic enough that I didn't need to explain it. But here goes...

            A clinical score changing with treatment is not unconfounded by mendelian randomization. When the genetics are clearly more complex than what you are mathematically randomizing for, the control doesn't solve the confounding. eg you haven't suddenly "proven" the effects are non-genetic. We already knew heart disease is non-mendelian. But showing something is non-mendelian doesn't mean you've shown it's not genetic. I hope that clarifies, because I'm not sure I can explain it to you in simpler terms.

            • KempyKolibri 1 day ago
              > I thought that was basic enough that I didn't need to explain it. But here goes...

              This is quite the tone to take when the actual point being made has demonstrably sailed over your head, considering the reference provided to you explains it very clearly.

              Which is more likely - nigh on every lipidologist, cardiologist and nutrition researcher is wrong, or you might have made a mistake yourself?

              > Mendelian is characterized by effects having strong influence from a single gene. Heart disease is clearly more complex than gene -> heart disease

              This seems like a misunderstanding. A single SNP clearly can affect CVD risk, that’s precisely what the paper shows. The assumptions required for an MR study to be valid do not include “the outcome must only be affected by a single gene and no other gene”. It’s required that there’s no pleiotropy present in the exposure (I.e. the SNPs). The exposure here isn’t heart disease, it’s SNPs that affect LDL-c levels, and the outcome being measured is CVD. So your point doesn’t pose an issue for the study and the inferences it makes.

              But honestly - just read the paper. I think both that paper and the EAS consensus paper are very approachable.

            • graboy 1 day ago
              I think maybe you are saying that there may be some way that the genes affect heart disease not through LDL, and therefore MR does not apply because the "exclusion restriction" [1] fails here? Or are you talking about a different assumption?

              The cited study addresses this, which is why I pointed to figure 3. They argue that if genes were causing heart disease not through LDL in any meaningful way, you wouldn't expect such a clean dose-response consistency across different genetic variants - it would be more jagged.

              [1] https://en.wikipedia.org/wiki/Mendelian_randomization#Defini...

              • daveguy 2 hours ago
                It seems you are confusing mendelian randomization for specific alleles associated with LDL-C production and conflating that with mendelian randomization somehow controlling genetic confounding of heart disease. The control is for the LDL production, not heart disease.

                Here is a simple primer on mendelian randomization: https://www.psomagen.com/blog/what-is-mendelian-randomizatio...

                Please review the key principles and assumptions section. Using MR to control for genetic confounding of heart disease fails all assumptions. Thats why it quite directly does not follow.

                This is why the paper presented does not support the claim that LDL is the sole source of heart disease. I'd be interested to hear what the authors of that paper (which is legitimate) think about it being used to support the OP's claim because "mendelian randomization".

    • loeg 2 days ago
      > [that circulating LDL is the cause of heart disease] is false.

      I think your comment really owes the rest of us more explanation of this part.

    • thomassmith65 2 days ago
      *statins?
      • blell 2 days ago
        The fact that this word is misspelt every single time makes me want to dismiss the entirety of the comment.
        • mark-r 1 day ago
          My browser underlines the word statin to indicate a misspelling, but does not underline satin. We've been trained to believe the computer is always right when it flags an error, but unfortunately it's not 100% accurate.
    • justinator 2 days ago
      Simplifying, we are all essentially born with heart disease. It's just a game of how long it takes for it to kill us. No way around it.

      Unfortunately, our biology isn't perfect.

      • mock-possum 1 day ago
        That’s not really a helpful attitude to take when trying to prevent heat disease though
        • justinator 1 day ago
          Reality is like that.

          Before hoping for a miracle, may I suggest adding more walks into your week?

    • readthenotes1 2 days ago
      The article goes on to say it's not all LDL. Keep reading. The first part agrees with my cardiologist, at any rate
    • medstrom 2 days ago
      > High LDL is correlated with the development of heart disease, but it does not cause heart disease.

      You realize this sentence is an oxymoron?

      Unless you meant to say "it does not cause the development of heart disease". I agree correlation is not causation.

      • rowanG077 2 days ago
        I don't think it is. Something can either be correlated and causal or correlated and non-causal. It makes sense to talk about which.
      • smt88 2 days ago
        > You realize this sentence is an oxymoron?

        No it isn't.

        Think of heart disease as slow, long-term damage to the cardiovascular system, and cholesterol is what the body uses as a bandaid.

        If you have a lot of LDL cholesterol available, your body will use a lot of it, and you'll have stiffer arteries. If you don't have much available, it takes longer for the bandaids to build up.

        This is one of the reasons statins reduce the number of heart attacks, but don't always seem to reduce all-cause mortality.

        • KempyKolibri 2 days ago
          The band aid analogy doesn’t make sense when we consider the MR studies showing the lower your genetically determined LDL-c, the lower your risk of CVD. If everything was randomised except the number of band aids, why would having fewer band aids result in lower CVD risk?

          > This is one of the reasons statins reduce the number of heart attacks, but don't always seem to reduce all-cause mortality.

          That’s one potential explanation, but I don’t think it’s the most likely one. We tend to see non significant ACM in smaller, less powered trials, or those with lower LDL-c lowering. ACM is simply a less sensitive endpoint - if you have a treatment that reduces CVD incidence, then the “CVD incidence” endpoint will give you significant results with fewer CVD event differences between study arms compared to ACM since your power to detect differences is diluted by other fatal events that aren’t affected by statins (cancer, motor accidents etc).

      • elromulous 2 days ago
        You realize correlation does not imply causation?

        Edit: this was written before OP edited their comment

  • sghiassy 2 days ago
    I wonder how many Cardiologists would call cardiovascular disease “a solved problem”

    My bet is close to none

    • brandonb 2 days ago
      I think there's a a bit of a paradox here: cardiovascular disease is solved biomedically, yet still remains the #1 cause of death worldwide.

      From a biomedical standpoint, we have highly accurate biomarkers (e.g., ApoB, Lp(a), hs-CRP), long-term risk prediction models, knowledge of nutritional biochemstry, and next generation drugs like PCSK9 inhibitors and lepodisiran that can lower ApoB and Lp(a) by 90%. So there's no fundamental reason why cardiovascular disease has to be in even the top 10 causes of death.

      Practically speaking, providing guideline-recommended preventive care would require ~27 hours per doctor per day. And the incentives are misaligned: health systems profit when hospital beds are full, so they lack the business model to actually invest in prevention.

      So it's a clear illustration of a systematic gap between research and care delivery.

      • lm28469 2 days ago
        > I think there's a a bit of a paradox here: cardiovascular disease is solved biomedically, yet still remains the #1 cause of death worldwide.

        Because most people don't give a shit about their health, no amount of pills will save you if you eat like the average american.

        • vladgur 2 days ago
          I also think that many people don’t know - I would wager for men that a significant percentage of them do not go to see a doctor preventively unless injured or sick and not that may know their blood pressure or cholesterol trends
      • vladgur 2 days ago
        Thanks for sharing this and empowering others to improve their heart health outcomes.

        I’m not in love with the idea of sharing my biomarkers with multiple health-tech companies and really want a self-hosted solution to import biomarkers from multiple sources such as Apple Health, arbitrary csv and jsons while avoiding duplication.

        Claude Code is something that will make this dream a reality for me pretty soon.

        Do you have any tips on biomarker data design or import gotchas?

        • brandonb 1 day ago
          The thing that took the most time was normalizing biomarker names and units across labs. Even for the same lab chain (say, Quest), you'll get the same biomarker with slightly different names (e.g., Lp(a) vs Lipoprotein(a) vs Lipoprotein a) or units (e.g., cells/uL vs 10^9/L).
          • vladgur 22 hours ago
            that was my experience just comparing Apple Health export using Stanford Labs data vs say FunctionHealth.

            Im hoping to use LLMs to help with this process.

            Will try to use LOINC dataset to standardize against

      • loeg 2 days ago
        Well, and everyone knows they should exercise, and many know they should avoid dietary saturated fats, but most people neither exercise nor avoid highly fatty foods.
      • dubeye 1 day ago
        Couple of reasons why I think this is nonsense .

        the mainline guideline is more exercise and better diet which is the treatment to much more than just heart disease. that's not something 27 hours of doctors a day can provide unless you give them guns

        the treatments reduce risk, but they don't change the fact the human body is very reliant on the heart and increasingly vulnerable to cardiac death with age, even with perfect biomarkers

      • dogmatism 1 day ago
        given the entrenched attitudes and the time it takes to actually get people to do the thing as evidenced by all the contrarians in the thread...

        it would take a lot more than that. Ain't no doc got all that time to go through all this with every person who should take cholesterol lowering medicine but wants to argue their internet sourced bs

    • Aurornis 2 days ago
      “Solved problem” is too strong of language, but the cardiologists I follow are generally open about the idea that we have enough tools and knowledges to reasonably prevent and manage it the average person.

      Even without medications, we’ve had enough knowledge about diet and lifestyle factors that the average person (excluding generic abnormalities that lead to abnormally high risk) could reasonably avoid heart disease through lifestyle and diet alone. That’s easier said than done for a lot of people in the modern world, so it’s good that we have a few different medications on top of that knowledge.

      • dubeye 1 day ago
        the cardiologist I pay, visit and follow, would likely advise perfect diet and excercise will only reduce risk not eliminate it.

        So it comes down to definition of 'resaonably'. diet and excercise will 'reasonably' reduce risk of most disease.

        • Aurornis 1 day ago
          > will only reduce risk not eliminate it.

          Same with medications? It’s well known that medications don’t eliminate risk.

          For the average person without genetic outlier risk, perfect diet and exercise would definitely make heart disease a non-issue in their lifetime.

          The risk your cardiologist is talking about is probably the risk that you have one of those genetic outlier conditions that require medication regardless of diet.

    • lm28469 2 days ago
      It's almost entirely a lifestyle problem. Shit diet, lack of exercise, obesity, &c. Overlap maps of obesity and cardiovascular deaths, they're virtually the same

      https://ec.europa.eu/eurostat/documents/4187653/10321616/dea...

      https://ec.europa.eu/eurostat/statistics-explained/images/th...

    • WillAdams 2 days ago
      Ages ago, I used to do the typesetting for the _Cardiosource Review Journal_ (lived my life around the publishing schedule because no one else was able to run a WordBASIC macro to do initial formatting, import that into a page layout program, process all the graphics and place them, and generate page proofs early enough that it could be proofed and corrected with a 24hr. turn-around until a postal rate increase killed it) --- cardiologists seem very big on data/analysis, moreso than most other medical fields.
    • agumonkey 2 days ago
      following a few cardiology conference i tend to agree with you, far from this sadly
    • bilsbie 2 days ago
      Ask yourself what happens to them if it’s solved.
    • noitpmeder 2 days ago
      I mean their livelihood is predicated on it not being solved for a portion of the population
      • medstrom 2 days ago
        There is plenty more for a cardiologist to do even if they solve the most pressing current problems. Hard to run out of puzzles in biology.
  • raphman 2 days ago
    Some information on the author:

    - The blog seems to be associated with this Twitter account: https://x.com/sichuan_mala. That person seems to be a good friend of Cremieux¹.

    - The article seems to have originally been published/unpublished in 2024 https://x.com/cremieuxrecueil/status/1922743591924899962

    - It was only re-uploaded in September 2025 (?). There's some discussion of the claims under a tweet by Cremieux who announced the re-upload: https://x.com/cremieuxrecueil/status/1974990143544287715

    ¹) FWIW: https://en.wikipedia.org/wiki/Jordan_Lasker

  • agumonkey 2 days ago
    archive just in case https://archive.ph/Od1VS

    anybody in the medical field able to give some report on state of the art CV research ?

    • readthenotes1 2 days ago
      My cardiologist recently told me the disease is mostly from Lipo(a) and small dense Ldl, that it took decades from being able to measure LDL and note the correlation to disease to be able to measure there more specific factors, and even more time to nail down the observations.

      Lipo(a) is genetic, apparently either you have it or not.

      Small dense ldl is caused apparently (not a biologist) from high triglycerides, one cause of which is high sugar diet.

    • brandonb 2 days ago
      I think the title is deliberately provocative, but they're not wrong.

      Heart disease is largely solvable from a biomedical standpoint: we have accurate biomarkers (e.g., ApoB, Lp(a), hs-CRP), long-term risk prediction models, precision nutrition, and highly effective next-generation drugs (PCSK9 inhibitors, lepodisiran, etc).

      But practically speaking, heart disease remains the #1 cause of death due to bottlenecks in care delivery: e.g., 46% U.S. counties have no cardiologists, providing guideline-recommended preventive care would require ~27 hours per doctor per day, and incentives are misaligned (health systems profit when hospital beds are full, not from prevention).

      • kiba 2 days ago
        But practically speaking, heart disease remains the #1 cause of death due to bottlenecks in care delivery: e.g., 46% U.S. counties have no cardiologists, providing guideline-recommended preventive care would require ~27 hours per doctor per day, and incentives are misaligned (health systems profit when hospital beds are full, not from prevention).

        Supposed that we have an incentive aligned health care system. What would that look like?

        I think one outcome is that the healthcare system eventually expands due to population growth and less death. Accidents happen, rare cases become more common, even as we get good at fixing or preventing them.

      • unsupp0rted 2 days ago
        Is it naive to say:

        1. Check your ApoB, Lp(a), hs-CRP every 4 months

        2. Feed that into a current-gen LLM and ask it to tell you what drugs to take and at what dosages

        Would that solve about 90% of the issue?

        • brandonb 2 days ago
          I started a company that does exactly that (except we also have doctors who can prescribe the medications, not just LLMs). So I don't think the approach you describe is naive, but others might. :)
  • inglor_cz 2 days ago
    It is very much not a solved problem unless you can actually cure it in existing patients, e.g. reduce or remove the extant plaques from their blood vessels.

    This is not pedantry, this is a vital problem of hundreds of millions of currently living people, many of which don't even know their own status.

    I believe this can be done in the near future, there are some interesting initiatives in this direction, but it is very much not a solved problem.

  • ashleyn 2 days ago
    Obesity, junk food addiction, and chronic inactivity still remain unsolved as ever.
    • kccqzy 2 days ago
      I agree with you, but I suppose the point of the article is that we can solve cardiovascular disease without first solving obesity or chronic inactivity.
    • loeg 2 days ago
      Obesity is solved! Tirzepatide.
    • justinator 2 days ago
      GLP-1's baby.
  • bilsbie 2 days ago
    Here’s a counterpoint if anyone is interested: https://www.midwesterndoctor.com/p/why-are-statins-so-danger...

    I’m not saying either side is right but when it comes to your health why not evaluate as many opinions as possible.

    • hombre_fatal 2 days ago
      I wish the “counter points” to my claims were always as bad as that link. It has a little bit of everything, from Fauci to seed oils to a Joe Rogan video.
    • graboy 1 day ago
      Here is the chief editor of JAMA internal medicine arguing there is not enough evidence to prescribe statins for primary prevention in those 40+: https://www.natap.org/2016/HIV/ied160021.pdf
    • loeg 2 days ago
      Your article starts by comparing the harms of statins to the harms of scary COVID vaccines. I'm not sure it's very credible.
  • unsupp0rted 2 days ago
    Commenters are really piling on, without, it seems, reading the article.

    The author addresses a lot of the obvious gotcha points I see in the comments.

    Although I don't think the author realistically explores the downsides of statin use, papering over the common side-effects.

    • Modified3019 2 days ago
      Dramatic clickbait titles should expect to get responses that match.
  • Finbarr 2 days ago
    Very similar to https://myticker.com/ though a little denser.
    • vladgur 2 days ago
      Thanks for sharing this — amazing resource and resembles my experience with US health care.

      I recently asked my doctor at Stanford - a pretty expensive hospital but one of the top cardio hospitals in the country - to get me an APoB test. He said that it may not be covered by insurance.

      So instead I spend $360 or so on a year worth of biomarkers from Function Health that included ApoB and others

  • onesandofgrain 2 days ago
    It was my understanding that circulating free triglycerides and LpA were the main risk factors for CAD and not LDL. In addition to AGEs?
  • MPSimmons 2 days ago
    >Lp(a) levels are almost purely genetically determined and so elevated Lp(a) is essentially due to a poor roll of the genetic dice... For simplicity, we will devote little further attention to either of these secondary risk factors”

    As someone who rolled poorly on those genetic dice, I would like to complain. But also, disregarding a factor that impacts 20%[1] of the population seems disingenuous.

    [1] - https://familyheart.org/family-sharing-tools/high-lpa-family...

    • brandonb 2 days ago
      Lepodisiran has reduced Lp(a) by 94% in clinical trails. After it gets approved, IMO the author should re-write this section.
  • dmead 2 days ago
    Valve failure often has nothing to do with diet. This is junk.
    • OutOfHere 1 day ago
      There are other cardiac failure modes too, for example electrical and hypertrophy.
  • Ifkaluva 1 day ago
    Why was this flagged? I was under the impression that the content of the article reflects the current mainstream medical view.
  • ericd 2 days ago
    Hm, so statins for everyone? What’re the downsides?
    • brandonb 2 days ago
      The main side effects of statins are muscle pain and brain fog (from some statins -- others cross the blood-brain barrier much less).

      The benefit of statins is to not only lower LDL cholesterol, but also inflammation, which is now actually a stronger risk factor for cardiovascular disease than cholesterol: https://www.empirical.health/blog/inflammation-and-heart-hea...

      Layering PCSK9 inhibitors, ezetimibe, and statins can lower ApoB/LDL cholesterol by 85–90%, which would have been unheard of until recently.

      On the horizon, drugs in clinical trials lower Lp(a) (the strongest hereditary risk factor for heart disease) by 94%. Currently, there are four RNA-based drugs in trials that effectively silence the gene that makes Lp(a) in liver cells: lepodisiran, olpasiran, pelacarsen, and zerlasiran.

      • ericd 1 day ago
        Thanks! I've been looking into this a little recently, so thanks for the very timely article and advice.

        Do you have any info on good ways to nail down personal sources of inflammation relevant to cardio health, or do you think that just general anti-inflammatory diet/habits is the best we can do right now? We were hunting down a source of mold in our house recently due to some blood markers recently, which got me thinking about inflammation sources and cardio health (we found a big patch of mold between our floors and removed it, blood markers immediately improved).

      • CalChris 2 days ago
        I had the brain fog. I switched from atorvastatin (dizziness) to pravachol (no dizziness), and then again to higher effective dosage of rosuvastatin (still no dizziness). I went from LDL 152 to LDL 83.

        But I have high Lp(a) and so I'm prescribed a baby aspirin every other day. This counteracts the Lp(a) clotting effect but doesn't fix its genetic cause.

        It's a journey.

        • tresdots 1 day ago
          I was recently prescribed rosuvastatin (my first time taking any statin), and I had some very intense brain fog. How would you describe the feeling of what you experienced? The best way I could describe it to my friends and family was that I felt like I lost a quarter of my IQ and slept only 5 hours every night(I was getting great sleep, it just felt that way).

          It was such a strange feeling. It's a weird feeling to know you're brain just isn't working as it has always worked.

      • gabrielsroka 2 days ago
        > About 10% of people develop muscle aches

        > Concerns about statin effects on the brain, such as cognitive impairment or dementia, are unfounded

        https://www.health.harvard.edu/heart-health/what-are-the-ris...

    • yojo 2 days ago
      I’m old enough that my parents/spouse’s parents are all on statins. They all report side-effects, mostly digestive issues.

      I’ll eat a healthy diet, exercise, and live a life without persistent diarrhea. I’ll take statins if/when they are medically necessary, and no sooner.

    • Aurornis 2 days ago
      If you’re unlucky enough to have one of the genetic factors that predisposes you to atherosclerosis then it’s going to be statins and maybe PCSK9 inhibitors.

      For the average person, diet and lifestyle choices could be enough, but adherence can be difficult. Monitoring LDL as an imperfect but useful marker and then introducing low-dose statins on a sliding scale proportions to severity is a good idea.

      Statins are not completely side effect free (no medication really is) but they’re generally well tolerated. Statin side effects are an interesting area of research because they have a very high nocebo effect rate: People hear so much about statins and their side effects from popular media that when they’re prescribed a statin in older age they start thinking everything is a side effect of the statin. There are some actual known side effects of statins which scale with dose and some of which can be maybe offset by supplements like CoQ10, but the side effects are generally mild. I’d take the side effects over heart disease after watching some older family members struggle and then die due to heart problems.

    • amanaplanacanal 2 days ago
      Possible side effects include muscle damage, liver damage, and type 2 diabetes.
    • tresdots 2 days ago
      My experience with them was a brain fog so bad I could hardly do my engineering job effectively. Quite unfortunate as I've read that side effect isn't very common.
  • daveguy 2 days ago
    Well, that's certainly a ... hypothesis.

    And an N of 1 "experiment" on whoever wrote this.

  • paxys 2 days ago
    "Hunger is a solved problem. We just need to give enough food to everyone!"
  • skywhopper 2 days ago
    This is dangerous nonsense and should be removed from the HN front page.
  • rubing 2 days ago
    [dead]
  • AllegedAlec 2 days ago
    [flagged]