LDL Study Q&A: kidney damage, NNT, and funding sources

You asked 349 questions about my LDL video. I'm answering the ones that matter most — including who paid for the study.

Last week I broke down the LDL cholesterol trial. The comments flooded in — and several of you asked exactly the right questions. In this follow-up, I'm going through the most important ones as a vascular surgeon who's spent years treating the consequences of bad cardiovascular advice.

In this video:
🫘 Kidney function & muscle toxicity — one commenter raised a sharp mechanistic point worth spelling out: statins can cause muscle damage → muscle damage could reduce muscle mass → less muscle mass means less creatinine production → which can look like improved kidney function on labs, even if your kidneys haven't actually improved. We walk through whether this confound holds up in the data.
📊 Number Needed to Treat (NNT) — the stat based on ABSOLUTE risk reduction that keeps drug effects in perspective
🔬 Plaque measurements vs. clinical outcomes — why these are NOT the same thing
💰 Funding sources — who sponsored the trial and how to weigh that when reading the results
✅ A genuine surprise at the end — something the authors did that I didn't expect, and that actually matters for how much we can trust this data

If you're on a statin, managing  ldl cholesterol, or trying to understand heart disease risk beyond what your doctor has five minutes to explain — this video is for you.

Watch the original video first: https://www.youtube.com/watch?v=Q2lvd9ND7rA

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___________________________
🧬 About Dr. Lily Johnston
  
Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

More comment responses this time for the Is Is Zetamib, the Secret to Preventing Dementia video that we dropped last weekend. You guys said a lot of great things in the comments, and there were a couple of really interesting questions that I hear fairly frequently in my practice. Let's go through it. If you're new here, my name is Dr. Lily Johnston. I am a board-certified vascular surgeon. I am also a specialist in cardiometabolic prevention. So hopefully you will never need me as a surgeon. So Don Cooper says, very informative. You offer your critiques with compassion. Your channel is a wonderful resource. I would quibble about not breaking out the vascular dementias. My understanding is that standalone vascular dementia, Sans Alzheimer's, is rare. This gets into the heart of how we get a diagnosis of dementia and how we decide which one is which. It turns out that's complicated. Let's go to open evidence and see what the literature says. So if we ask open evidence, the answer is yes, vascular dementia is less prevalent than Alzheimer's dementia by about a third, but it is the second leading cause of dementia worldwide. So let's go through this and we're also going to see that in fact, very rarely do people just have one cause of dementia. Often we have a mixed picture, and vascular risk factors and vascular components contribute a fair amount to the overall burden, even if the official diagnosis is Alzheimer's dementia. So open evidence tells us that vascular dementia is the second most common cause after Alzheimer's and accounts for 15 to 20% of all cases compared with Alzheimer's, which is roughly 60 to 70% of cases. However, these figures vary widely depending on the diagnostic criteria, the population studied, and whether mixed pathology is included. So the American Heart Association estimated that up to 2.7 million people in the United States were living with vascular dementia or mixed dementia with a vascular component in 2020, compared with 5.8 million with Alzheimer's disease. And Medicare claims data found that vascular dementia was 14.5% of all dementia diagnoses. Claims data are not that exciting, so I wouldn't hang my hat on that. But what I want to highlight for you is the important caveats that open evidence calls out that we just talked about, which is that the true burden of vascular contributions to dementia is likely underestimated. Pure vascular dementia is relatively uncommon, but mixed pathology, which is vascular plus Alzheimer's or plus frontotemporal dementia or some other type of dementia, is very common, especially in older adults. So in the ERIC study, which is an observational cohort, pure cerebrovascular disease, meaning plaque or stroke in the arteries in the brain or the neck going up to the brain, was found in only 2% of cases. But Alzheimer's with secondary cerebrovascular cause was present in 23%, and primary cerebrovascular disease with secondary Alzheimer's was 18%. And autopsy studies show that over 75% of dementia cases exhibit some evidence of vascular pathology, with approximately one-third showing significant vascular pathology. So stepping back, this means a third of all patients with dementia of any kind have severe contribution from their vascular disease. What this means is controlling vascular risk factors, like we talk about all day, every day on this channel, is how we help people mitigate risk for especially the vascular components of dementia. As we are going to see in the upcoming APOE4 series, the same things that will improve your cardiovascular health are also incredibly likely to lower your risk for Alzheimer's dementia independent of the vascular component, or maybe as part of it. It's unclear, but a rising tide lifts all ships. So if we go back to this worldwide estimate, the World Stroke Organization estimates approximately 8.5 million people have pure vascular dementia. An additional 9 million have mixed vascular and degenerative dementia. So this is really a mixed bag. And we want to be sure that we are using all of our tools to help delineate what is what. But as far as the study goes, it makes it difficult to distinguish, right? We just said this is a really mixed bag. Even people with a primary diagnosis of Alzheimer's have some component of vascular disease. When we look, it's, you know, 75% and a third have severe vascular disease. So maybe it's not fair to ask us to tease out vascular stuff from the Alzheimer's dementia cases. Um, that seems like maybe it's so frequently diagnosed together that it's going to be really challenging to pull apart for studies like the one on azetomide that we talked about in the last video. But thanks for that comment. Now I hope we all have a better understanding of the fact that vascular dementia is not rare. It is less common than Alzheimer's, but vascular disease is a big contributor for all cases of dementia worldwide. And William Donahue asks, how real is the risk of dementia from Iatrogenically, meaning medically lowering LDL and APOB to extremely low levels? For example, APOB of 30 in the pursuit of optimizing cardiometabolic health. So I'm going to expand and broaden this question just a little bit because I get this maybe certainly every week, maybe uh as often as once a day in my practice when we start talking about lipid lowering therapy, people want to know why this is like why we think this is safe. Because the brain is 25% of our body's cholesterol. And if we start taking cholesterol-lowering drugs, don't we like suck the brain drive all the cholesterol? Isn't this a big deal? So let's go through this. And the first thing I'll say is that some of our lipid-lowering drugs will cross the blood-brain barrier, right? This is the very specific, very rigid um fence between the circulation in the rest of the body and the circulation of the brain. And only very specific things are able to cross that blood-brain barrier and actually enter into the very protected circulation of the brain. Some of our lipid-lowering drugs will cross the blood-brain barrier, but many do not. And they may have different ability to cross the blood-brain barrier based on uh how well they dissolve in water versus fats. This is a point of, I would say, debate and contention in the lipid community, but people talk about this fairly frequently. Some of our statin drugs, for example, are what we call lipophilic, meaning they preferentially uh are in fat-soluble forms. Others are hydrophilic, meaning they uh preferentially dissolve in water and are less likely, maybe, to cross the blood-brain barrier. Studies have shown that even the lowest intensity statins, when taken for long enough, we can find some evidence of them in the cerebral circulation. What impact that has on the cholesterol transport and synthesis in the brain is much less clear. We are going to go look at the accumulation of all of the evidence that has been collected on this question to get a better look. And I want to do this using a new tool that I'm playing with, and it's called consensus. It is a way to, I would say, broadly query the scientific literature and try to get as balanced and comprehensive a view of what's been published as possible, because I can find you a study that shows you whatever I want it to show. If I want you to say that, you know, lipid lowering causes dementia, I'll pull up the case report where people have had brain fog and I'll tell you why this was on the FDA warning label for these medications for a while. If I want to tell you that statins are the best thing since sliced bread and they will prevent dementia, I'll find you a paper that says that they prevent dementia. But what I think is a more honest approach to this is looking really broadly. What does the, you know, uh plurality of the evidence say when we take it all together? So let's hop over to consensus and I will show you what that tool thinks the answer to this question is. So I asked Consensus to do a deep dive. And the question I asked was, what is the relationship between lipid lowering therapy and dementia? I tried really hard not to sway that question one direction or another. And I'm going to scroll up a little bit just so you can see the breadth of the search that happened here. So here's the question that we asked. This is a deep search through consensus. So it actually ran 21 parallel searches and it came across 22 million records and eventually narrowed this down to 50 citations. We'll show you that whole process a little bit later, but we're going to go step by step through the report that Consensus brought us. And the introduction says the relationship between lipid lowering therapy and dementia risk has been a subject of intense research and debate. While cholesterol, especially in midlife, is associated with increased dementia risk. We're going to talk about this in an upcoming video. The impact of lowering lipids on cognitive outcomes remains unclear. Large-scale meta-analyses and randomized controlled trials generally show that lipid lowering therapy does not increase the risk of cognitive impairment or dementia. And some observational studies suggest a potential protective effect, particularly for statins against all-cause dementia. So that's really setting the stage. Let's keep scrolling here. And what I love about this tool is that it's going to show you an overall summary of all the papers and their conclusions. So in uh these papers, it says, N of 34, they actually had 50 that they totally collated for the whole report, but 34 had this answer. 35% said yes, it will lower the risk of dementia. 35% said possibly. Mixed results in 9%, and seven studies or 21% said no. So let's go through all these details. All right. So recency looks at methods, tier one studies, the quality of the journals, and the number of citations. This is all available to you through consensus. And so this is in an effort to help you appreciate not only are there studies, but what is the quality of the literature that is speaking to this question. So you're gonna go through here and just take a look at what talks about yes, no, and maybe. And now it's gonna tell you what the methods were. How did it get to this answer? So a comprehensive search was conducted, over 170 million research papers. And here's the search strategy: 88.3 million were retrieved, 1.6,000 were eligible, meeting relevance and quality criteria, and the top 50 papers were included in the final analysis. So evidence from meta-analyses and randomized trials. So this would be considered our highest level of evidence, meaning the least likely to be confounded by the indications. Randomized controlled trials are sometimes shorter in follow-up and are often done in higher risk populations. So we may see that the medications are administered later in life. This would be done to increase the chances of seeing events or reducing events. So all of that is important, but generally these will be the least confounded trials. In this school of studies, lipid lowering therapy does not significantly reduce the incidence of dementia or cognitive impairment compared to controls. But they also don't find that it increases the problems either. And back to the original comment, we're now asking about extreme lipid lowering. So down to an APOB of 30 was the original comment. The PCSK9 inhibitor trials are really the ones that speak to this the best because in those trials, we actually have larger cohorts of patients who achieve LDLC less than 20 milligrams per deciliter, which is quite low. And uh they actually did formal cognitive testing for some of those folks. And we don't see any increase in either subjective cognitive complaints or in objective cognitive testing measures in cohorts of patients who had exceptionally low circulating LDL levels. Now, this is interesting, though, because the PCSK9 inhibitors, the monoclonal antibodies, are too large to cross the blood-brain barrier. So we don't think that those levels are necessarily replicated in the cerebral circulation. And this is part and parcel of why piecing this out is tricky. But right now in 2026, if you're gonna get your APOB that low, most likely you're using a PCS-K9 inhibitor to do it. It's possible that there are folks who are on statin and azetomib who are getting their LDLs down that low plus very stringent nutritional components. But most often, if you're that low, it's because you're on a PCS-K9 inhibitor. And those, to the best of our knowledge, and chlycerin's a little unclear to me, which is a small interfering RNA. But for a patha or evolacumab and praluint, alarocumab are not going to cross the blood-brain barrier. Those are the injectables that you get every two weeks. Okay, back to our regularly scheduled consensus programming. So the observational trials, potential protective effects. So these studies often report an association between particularly statin use and reduced risk of all-cause dementia, including Alzheimer's dementia and vascular dementia. You can see those hazard ratios here. And the subgroup analyses suggest stronger effects with longer duration, with higher potency lipid lowering, younger age and initiation, Asian populations, patients with type 2 diabetes, which is always a question in this community as well, because again, sometimes the statins will worsen insulin resistance. And we know that some component of dementia is actually an insulin resistance in the brain problem. So would statins make that worse? The data at the population level say no. And ApoE4 carriers. We'll get into this more in an upcoming video. So when we talk about lipid levels, variability, and dementia risk, high midlife cholesterol is associated with increased later life dementia risk. However, lower LDLC levels achieved through therapy do not appear to increase cognitive risk, and there is greater variability in total cholesterol or LDLC over time, and that can be linked to higher dementia risk independent of the average levels. So all of this to say we don't think it hurts. Maybe it helps, but the quality of that evidence is a little lower. Drug class differences and mechanistic insights. So statins are the most studied, right? We have the longest uh trial data for the statins, the longest cohort studies of the statins. Non-statin agents like fibrates show little evidence for benefit or harm. Nobody really uses fibrates much anymore. PCSK9 inhibitors may warrant caution due to genetic signals suggesting possible increased Alzheimer's dementia risk. So these are from some of the Mendelian randomization studies. And I think apropos of the video that we're discussing, Nick has actually talked about this in uh his newsletter and in his videos previously, that there's actually a Mendelian randomization signal for possible increase in Alzheimer's dementia for people who are genetically uh suppressed for PCS-K9. Now, again, our monoclonal PCS-K9 antibodies probably not crossing the blood-brain barrier. They're too big. What's going to happen when we start using the small molecule, like they're enlicitide, is the small molecule oral PCS-K9 inhibitor that just finished its phase three trials and is probably coming to market soon. What will happen with that? Don't know yet. Time will tell, but this is uh gonna be an important story moving forward. And again, mechanistically benefits may relate to vascular protection, anti-inflammatory effects, or something rather than the direct modulation of amyloid proteins. Okay, so there's a timeline here of the citations, and I think I will um go down here to the claims in the evidence table. So let's go one at a time through the claims, the evidence strength. And if you want to replicate this for yourself, uh all of these papers can, at least the abstracts, can be found through consensus and they will give you access to the abstracts. So the first claim: statin use is not associated with increased risk of cognitive decline or dementia. Very strong evidence for that based on multiple large randomized control trials, meta-analyses, and they show no harm across populations. Second claim, statin use may reduce the incidence of all-cause dementia, Alzheimer's dementia, vascular dementia. Moderately strong evidence that might support this. Now, this is from observational studies and meta-analyses. And exactly whether that's causal or not, we don't know yet. Again, because we didn't see it in trial, we're we're less confident in this. Claim number three: non-statin lipid lowering agents have little to no effect on cognition. Again, moderate evidence for that. Cohort and prospective studies are showing neutral results. The randomized controlled trials for the PCS K9 inhibitors did not show any impairment in cognition at very low levels of APOB, but they didn't show any protection either. Next claim: high midlife cholesterol increases later life dementia risk. There is now strong epidemiological evidence for this at a population level. This is now in the Lancet Commission on the 14 modifiable risk factors for dementia prevention. We're gonna talk about this. PCS Canine inhibitors may increase Alzheimer's disease risk. Um, they're gonna say that this is moderate. I don't actually think that this is quite correct. So there is a Mendelian randomization association with increased Alzheimer's disease, but the PCS canine inhibitors themselves, the drugs that have been tested, have not shown this association. So I want to be very clear about what's getting through the blood-brain barrier, what you're genetically susceptible to versus the molecules that we're using to lower it. So they're gonna call that moderate. I would quibble with this just a little bit based on just the language, but to be clear, yes, there is an association with Mendelian randomization and perhaps an increased risk for Alzheimer's dementia in patients, people who uh naturally have low levels of PCSK9. The last claim dyslipidemia in late life may be linked to lower dementia risk. Um, some cohort data suggest paradoxical associations. This is also sort of what we see when we start getting into conversations about people who are the oldest have you know higher cholesterol levels. There's a lot of reverse causation in here, and we have to be very careful about how we interpret those data, but um that's the weakest of the evidence here. So, in conclusion, what I would say um is that there is no evidence at a big level that it will be harmful, and there's some evidence, moderate, that it might even be helpful. And particularly if you are in a certain subpopulation, a la ApoE4 carriers, you may find that use of these lipid lowering therapies is something you want to consider to improve your risk for dementia going forward. Okay, clear as mud, right? Let me know what I missed. Drop it down in the comments below. Until next time, guys, take really good care.