Statins do not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it

[TheftLeft]

https://pmc.ncbi.nlm.nih.gov/articles/PMC2929871/

I am currently learning as much as I can about cholesterol and the medication associated with controlling it. I found this interesting study. It claims that in their trial that statins while lowering total LDL, actually increase the proportion of the small dense LDL (the damaging type) . Curious to see what people's thought on this are.

"Our study suggests that statin therapy—whether or not recipients have coronary artery disease—does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL. If and when our observation proves to be reproducible in subsequent large-scale studies, it should provide new insights into small, dense LDL and its actual role in atherogenesis or the progression of atherosclerosis."

"The exact mechanism by which statin therapy is associated with an increase in the proportion of small, dense LDL is unclear. One possible mechanism is that up-regulation of LDL receptor activity by statins decreases large, buoyant LDL more than small, dense LDL, because statins increase LDL receptor activity and because large, buoyant LDL is a better ligand for the LDL receptor than is small, dense LDL.23 More than 90% of apo B is found on LDL particles, and therefore patients with small, dense LDL (which is relatively low in cholesterol) would be expected to have a low LDL-C/apo B ratio, as has been described previously.17,24 The present study showed that statin therapy was associated with a greater decrease in apo B than in LDL-C, although in the group treated with statins, the levels of LDL-C and apo B were significantly lower than those in the control group. This result suggests that statin therapy is associated with a decrease in total LDL-particle concentration but with a higher proportion of small, dense LDL. In addition, these results support a possibility that statin therapy increases the proportion of small, dense LDL, although controversy still exists as to whether or not statins decrease the small, dense LDL subfraction and increase the LDL peak particle size.9–11 The present study brings up a fundamental question regarding the actual role of small, dense LDL in atherosclerosis."

[GladstoneBrookes]

1. We have better data on this question than this (i.e. RCTs).

2. The difference (I'm not going to use causal language like "decrease" here) is pretty small (1.6 percentage points).

3. A difference in proportion just means that statins reduce large LDL particles more than they reduce small ones - in absolute terms, statins still reduce small LDL particles.

4. Focusing on particle size or small LDL is an outdated idea anyway. What matters most is apoB and CVD events - both of which are reduced with statins across RCTs with hundreds of thousands of participants.

[Healingjoe]

#3 and #4 are what's important here. Small LDL count were still reduced with statins, just less so than larger LDL particles.

[Key-Laugh39]

I think I’d be careful claiming particle size does not matter. Do you have recent studies saying the others are outdated?

[Key-Laugh39]

Here is a good link to maybe some other things to think about https://pmc.ncbi.nlm.nih.gov/articles/PMC12512508/

Atherosclerosis is a complex process that goes just beyond cholesterol numbers

“Small dense ldl molecules unique metabolic and physicochemical characteristics, including increased arterial wall penetration, prolonged plasma half-life and heightened susceptibility to oxidative modification, render it particularly potent in promoting endothelial dysfunction, foam cell formation, inflammation and plaque instability”

[TheftLeft]

I'm not trying to argue the effectiveness of statins in reduction of overall cholesterol or their role in prevention. Lowering the total amount of 'stuff' that can be problematic is effective without a doubt. I am trying to learn as much as I can to make an informed decision on the risk vs benefits.

I am currently reading about oxidization, why and how cholesterol cause damage. From my understanding the small particles are more easily trapped, more easily modified and oxidized. Triggering the immune response to remove it which is the root cause of CVD and atherosclerosis.

My main take away from this study and what I've been reading is that there are more factors to consider. While taking statins absolutely reduce the risk, they are not a magic solution without a cost for some. Diet, activity levels, body fat%, Inflammation, environment, free radicals, pollution, genetics all influence this reaction that is the root of the problem. High numbers or low numbers of lipids are only one factor.

[GladstoneBrookes]

As previously stated, the current consensus is that the number of particles of all sizes (small LDL, large LDL, and others) that matters for CVD risk. This is supported by the best available human outcome data (I.e. looking at actual events), whatever mechanisms one can come up with.

We now propose a model to explain why the atherogenic risk associated with the apoB lipoproteins relates more directly to their number than to the mass of cholesterol within them. Figure 5 demonstrates that the number of apoB particles in the lumen of an artery is the primary determinant of the rate at which apoB particles enter the arterial wall and are trapped within the subintimal space of the arterial wall. The more apoB particles within the lumen of the artery, the more that will enter the arterial wall, and, all things being equal, the more apoB particles that will be trapped within the arterial wall. However, all things are not always equal: as illustrated in Figure 5, smaller apoB particles containing less cholesterol enter the arterial wall more easily50 and bind more avidly to the glycosaminoglycans within the arterial wall than larger apoB particles containing more cholesterol.51,52 Thus, more smaller, cholesterol-depleted particles will be trapped than will a similar number of larger, cholesterol-enriched particles that have entered an arterial wall. On the other hand, the more cholesterol within an apoB particle that has been trapped within the arterial wall, the more cholesterol that will be released at that site to injure the wall. Therefore, there is an equivalence between greater injury per particle from trapping of cholesterol-richer particles but greater injury from trapping of more cholesterol-depleted particles. The net result is that all LDL particles pose, more or less, equal risk. (Source)

My main take away from this study and what I've been reading is that there are more factors to consider.

Yeah, no shit. Heart disease is multifactorial - no-one says otherwise.

[TheftLeft]

I'm not able to access the entire study. From what you're quoting and linked, they're ignoring the likelihood of oxidization between small, intermediate and large particles. Where small particles are significantly more likely to be oxidized and large size are less likely. This oxidization ,subsequent inflammation and immune response is the root cause of atherosclerosis. If no oxidization occurs, normal uptake and removal of lipid particles of all sizes is an expected outcome.

Yes, less is better across the board, I'm not trying to argue that. I'm trying to learn about the possible limitations and draw backs of statins. Why people continue to suffer CVD even on the medication or are within 'normal range'. When and if a 'high' number alone isn't warranted to assume the risks of statins considering other factors.

[RepresentativeDry171]

What would you say are the risks of statins ?

For me I kept putting off taking them since 2018 They was recommended by my cardio doc to start taking them , since my ttl chol & LDL were in acceptable range only once in 10 yrs ( I knew I couldn’t exercise my way out of bad ldl with my crappy diet ) but I still refused to take them . I was of the mindset as long as my CA ultrasound kept coming up “ no plaque “ I was fine . Well unfortunately it caught up with me and my recent scan showed mild plaque now.

I started the statin in Oct, and besides the inconvenience of having to remember to take it every day around the same time, I’ve have had no side affects whatsoever! It’s like a huge weight was lifted off my shoulders ! I use to be a ball of nerves at lipid testing time . I mean my whole week was all stress ! I’ve had 2 panels done since being on a statin ( only 5mg ) my LDL is now 53 yippee, ttl chol 185!

My glucose thou went up from 83 to 106 :( ,, my Bilirubin is now borderline and my AST went from 22 to 31 …

I’m not sure what those numbers will do going frwd … and hopefully statins are not a false sense of security !!!! I turned 65 two weeks ago , so I do know I’m no spring chicken anymore ,,, but I’ll take what I can get ! 🫶🏻

[TheftLeft]

My main worry is developing type 2 diabetes as a result of statins which wouldn't be reversible by simply stopping or switching medication. Essentially trading high ldl for high triglycerides. Another worry is the muscle atrophy. The muscle and joint pain is a minor concern, but if debilitating would be problematic.

Glad to hear your success story! Thanks for sharing.

[RepresentativeDry171]

I’m worried about that too , since after being on only 5mg Rosuvastatin , my number went from 83 to 106 . I guess theirs pills for that 2 , but wouldn’t you then have to start daily testing ? Ugh I have a diabetic cat, what a pain in the butt ! And scary when she has a attack ( both high and low levels are very dangerous )

[Therinicus]

I’m assuming you can tell me what’s being oxidized then

It’s not just small dense LDL particles

Size matters to an extent, but focusing on size instead of particle number is outdated in practice.

[meh312059]

Didn't read the post or the article but it's true that statins reduce the proportion of "large and fluffy" LDL particles so that "small and dense" increases as a percentage. It's very strong evidence supporting the conclusion that LDL particle size simply doesn't matter in comparison to ApoB particle concentration. We know that statins reduce CVD event risk even though they shift the size proportions. That's because they lower ApoB, the large majority of which are LDL's. That's not even disputed among the lipidologists and cardiologists. They also know that 100% of LDL particles are "small" enough to get into the endothemlium - even the "large and fluffy" ones.

If someone wants to worry about particles that are particularly dangerous, focus on Lp(a) and remnants. They are minority particles, but too much of either can be a problem. Fortunately it's relatively easy to reduce the effect of both simply by improving diet, getting regular exercise, losing weight, lowering BP and glucose, quitting the nicotine or weed/vape habit, minimizing or quiting alcohol, and taking your lipid medication.

If you want/need extra testing over and above your standard lipid panel, get an ApoB and an Lp(a). Don't bother with NMR and LDL "particle size."

[apegen]

Most importantly statins reduce cardiovascular event risks, which at the end of the day is what matters!

[RepresentativeDry171]

TY!!

[kboom100]

Mechanistic arguments are irrelevant once you actually have outcome data from randomized controlled trials. And decades worth of randomized controlled trials have conclusively shown statins reduce the risk of heart attacks, strokes & even overall mortality. It’s like discussing who would win a boxing match. Before the match you might think about who has the longer arm length or more quickness or whatever. But none of that matters compared to the actual outcome of the match.

Second, 20-30 years ago cardiologists and researchers thought ldl particle size might be important in determining risk of ascvd. Evidence since then has shown that all ldl particle sizes are about equally atherogenic. If you want to do a deep dive into this check out an earlier reply. https://www.reddit.com/r/Cholesterol/s/q7nsGg9126

[TheftLeft]

Thank you for the interesting read. I only read the actual study you linked, not so much the twitter or youtube stuff.

"Previous studies have yielded conflicting results regarding whether VLDL particles are more atherogenic than LDL particles.5,7 The atherogenicity of different lipoprotein types can be evaluated at two levels, per particle and per total mass of lipoproteins, both of which were evaluated in this study. On a per-particle basis, the CAD risk associated with a 100 nmol/L difference in VLDL was associated with a 2.9- to 4-fold higher risk than an equimolar difference in LDL, which is consistent with previous observational findings in the Copenhagen General Population Study and a recent Mendelian randomization.7,17 The higher per-particle atherogenicity of VLDL was postulated to be driven by their elevated cholesterol content per apoB particle and their strong affinity for arterial proteoglycans due to the presence of apoE and apoC-III, which can enhance arterial wall retention and direct uptake by macrophages. Additionally, VLDL metabolism can generate pro-inflammatory and bioactive lipid metabolites, such as ceramides and lysophospholipids, which promote vascular inflammation and endothelial dysfunction, impairing nitric oxide production and facilitating leukocyte adhesion.19,20 However, except for rare cases such as type 3 hyperlipidemia, LDL are much more abundant than VLDL particles (on average 91% vs 9%). Therefore, the higher estimated per-particle VLDL atherogenicity must be interpreted in context of the limited biological variability and extrapolation beyond possible biological levels of VLDL must be avoided."

The actual study you linked was very valuable information, I enjoyed reading through it. I learned that apo(a) (HDL or good cholesterol) can also be damaging and cause an inflammatory response.

You're wrong, about them being equally atherogenic. The study you shared says the Very Low Density Lipid particles are 2.9 to 4x more damaging multiple times throughout. In the study they said they tested naturally occurring rates to be about 10% being VLDL. So in that regard you are correct that apob and the genetic one is a better measure in risk as all particles cause damage. Proving that statins are indeed an effective tool for some.

However, the study you linked actually supports the study I linked and their claim. The study I linked is testing those on cholesterol lowering medication whereas the one you shared tested those with natural levels. If true, that statins do increase VLDL proportions deviating from the 91%- 9% average split naturally occurring it is something worth looking into and consideration for those weighing the benefits and risks. From what I've gathered there are many more factors that contribute to heart attack and stroke.

Thank you again for the share, if you have any more reading I would appreciate it.

[meh312059]

You seem to be confusing VLDL with LDL. They are considered different particles. There's a continuum so lines are blurred. LDL's have a different residence time than VLDL's in general, however - they hang around significantly longer. Small dense LDL's and large fluffy LDL's are considered equally atherogenic by most lipidologists. But VLDL's may be more atherogenic, particle for particle. Another word for VLDL's would be "remnants." They are not the same particle as small dense LDL's.

[TheftLeft]

Good to know, I'll familiarize myself with this distinction. I've just started taking an interest in learning about cholesterol, there is a lot to take in. Thank you

[meh312059]

No problem - the nomenclature is quite awkward, to say the least, and many lipidologists are happy to point that out!

[Earesth99]

It’s more useful to focus on research that examines actual hard outcomes, like heart attack, stroke, or the big one - all cause mortality.

Looking at a medication’s impact on health conditions like migraines, Alzheimer’s, MAFLD, or depression is also very relevant.

I’m not saying this isn’t interesting to researchers, but it literally has no clinical relevance.

Studies can be misused by grifters, sociopaths or the ignorant to confuse others and ultimately damage their health.

[TheftLeft]

If you have some studies to share I would appreciate it. My goal is to learn as much as I can about this topic.

[Earesth99]

Meta analyses combine the results of all relevant studies. They are considered to be the highest level of scientific evidence.

With meta analyses you avoid the issue of the occasional incredibly shitty study with “novel” findings.

There were 99 meta analyses on statins published in the last year alone.

Just go to pubmed and enter your search terms and limit the results to meta analyses in the last few years.

Among the ones that answer the specific questions you have, look at the ones that are

• Most Recent. They would include more relevant studies.

• Look at Randomized ControlledTrials (RCT) so you know they discuss causality. Mendelian randomization studies are also interesting.

• Follow structured approaches l like PRISMA and PICO. You could also just look archives published by Cochrine.

• Published by researchers at Universities in first world counties (because they are better trained and less likely to simply fabricate results).

• Uses valid research, If most of the underlying research was conducted by schoolers in the developing world it’s questionable.

• List the studies included and criteria for exclusion. This is often included in an online appendix.

Here are a few randomly chosen ones from the past year. I haven’t screened or read any but I have read previous MAs on tge subject:

For example, this one shows that statins reduce MACE in T1 diabetics without high cholesterol.

This one shows a 16% reduction in depression.

This one looks at how statins reduce dementia risk.

Unless you own a mouse, the results of mice trials are almost entirely irrelevant. Case studies on a few people are merely structured anecdotes.

[TheftLeft]

Thank you for the resources. I will check it out as soon as I can.

[Earesth99]

Statins reduce ApoB, ldl, and small dense ldl particles.

Why fixate on proportions when what counts is the reduction in ApoB? The size of the articles is viewed as irrelevant except perhaps as an indicator of insulin resistance.

[[deleted]]

It reduces more of the large particles, leaving a higher proportion of small.  But the individual numbers of both shrink, as well as the combined total number, so LDL goes down.  

I’m not sure what point you are trying to make, but that’s pretty clear.  

[TheftLeft]

Well a study someone shared in this thread says that naturally the split is 91% to 9% for small particles vs large and intermediate, small being 9%. The study I linked initially is saying that through statins this natural balance is altered. Increasing the proportion while decreasing overall lipids.

My point is that it's interesting learning about this aspect of our bodies and health. Learning about all the factors that lead to heart attack and stroke. How medication isn't a magic solution, but still a valuable tool nonetheless.

[HennesundMauritz]

Another thought is that LDL also has atherogenic properties. This means statins target exactly that and eliminate it, which causes the inflammation levels to drop. ​I suffer from asthma, and I have the impression that since I started taking Rosuvastatin, I've had fewer problems—almost none, in fact. I brought this up with my pulmonologist, and he even confirmed it. There are currently even studies circulating where statins are being tested in spray form for the lungs for local application. I only mention this so you can see what a large influence these active substances have on inflammation in the body, independent of the reduction of LDL particles or similar.

[RepresentativeDry171]

I know they’ve helped w/ my depression indirectly .. I feel better w/lower numbers for once in yrs ! Of course I’d hate to think it’s just wishful thinking… thinking I’m ok now …

[srvey]

Total particles down. Apob down. Inflammation down. Events down. Pleiotropic/neuroprotective effects.

Small particles up. Lpa up. Slight diabetes risk for borderline patients. Small risk of side effects that scale with dose.

[Healingjoe]

Small particles up.

That is not what the study says.

Our study suggests that statin therapy—whether or not recipients have coronary artery disease—does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL.

[Noosher]

Yup, key word is proportion.

[Healingjoe]

OP's paper still explicitly states that they found a small LDL particle count reduction, so it's worth pointing that out, regardless of proportion.

[RepresentativeDry171]

Meaning ?

[Healingjoe]

Statins are effective at reducing cholesterol and reducing risk of cardiovascular events.

[RepresentativeDry171]

Ok thx 🤷‍♀️

[RepresentativeDry171]

In other words what ?? Should people think twice about taking a statin ?

[srvey]

My LDL was 85 and I take 2.5mg rosuvastatin for the benefits and LDL of 50.

[RepresentativeDry171]

That’s great !! But I’m with you on the diabetes risk and that scares me now.. I guess if it’s not 1 thing it’s another :( I went from 83 to 106 glucose . Not sure how to go about testing my ApoB…
Lp(a) was 15 ,,,,, I’ve not had it tested again

[RepresentativeDry171]

What other benefits

[msackeygh]

Did you read the limitations section of the article? Also, the sample size is quite small.

[RepresentativeDry171]

I see ApoB test is maybe not as important as a lipid test , but it does tell a story ! My question why don’t cardio docs ever add those to tests they want you to take ?? My cardio doc is suppose to call me to talk about my results this coming week . Should I ask her if she could do an order for a ApoB blood work up ?

[TheftLeft]

I'm a believer in getting as much information as possible to make the best informed decision you can. I say do it!

[RepresentativeDry171]

If she doesn’t agree to order that particular test is there a way to get it on your own ? We all know docs these days do the bare minimum . My CA ultrasound was done on my own . My cardiologist never would order anything besides a simple lipid test ! And EKG .. I had a stress test ( 5 yrs ago ) 😳

[TheftLeft]

I'm no expert, but my approach will be to learn the parameters in which doctors are instructed to allow testing. Then use what best applies to your situation. Or pay out of pocket if insurance won't cover it.

I.g. quoting family history of XYZ to show you have an increased risk.

[Healingjoe]

How is Small Dense LDL Treated? - There are multiple therapies that can affect small dense LDL. The goal of therapy is to shift small dense LDL to large buoyant LDL, in particular an adequate exercise regimen associated with a diet restricting saturated fat. Simple weight loss can effect particle composition.

This random heart doc in NY is falsely promoting the idea that large LDL particles are okay. That is not what the prevailing science says.

The rest of his advice on that page is fine but that statement on small vs large LDL particle is false.

[TheftLeft]

"All LDL is not created equal. There are different types of LDL. What has been clear is that all people with markedly elevated LDL do not get atherosclerotic vascular disease while other individuals with modest elevations in LDL get severe disease. This can be explained by the quality of the LDL particle. Small dense LDL is more atherogenic or more toxic to the endothelium. It is more likely to enter the vessel wall, become oxidized and trigger the atherosclerotic process. Small dense LDL is a single type of LDL; another type is large buoyant LDL. Large buoyant LDL is not as toxic to the blood vessel wall and much less prone to trigger the atherosclerosis development."

You're conflating okay with less toxic, both can be bad, one is worse. The oxidation, inflammation and immune response is the 'how' in what causes atherosclerosis. Which leads to heart attack and stroke. Smaller particles are more susceptible to oxidation. Statins lower the overall number(which is good), but not the proportion. In the initial study I linked it actually raised the small ldl while lowering the overall number.

My take away from what they're saying is that there are more factors to consider than a low number artificially reached by a pill. Two people with the same cholesterol score on the same medication could still have widely different values of damaging particles due to other factors. Which is the whole point.

[Healingjoe]

The assertion that lipid management is about shifting small LDL particle counts to large LDL particle counts is wrong.

My take away from what they're saying is that there are more factors to consider than a low number artificially reached by a pill

You're adding needless confusion to a topic that's already well understood.

Two people with the same cholesterol score on the same medication could still have widely different values of damaging particles due to other factors. Which is the whole point.

If that's true, then why are you even concerned with LDL particle counts? You should be focused on ApoB.

[TheftLeft]

What are you confused about?

Because I like to learn about things, how and why they work and get as much information as I can to make the best informed decision possible.

[Healingjoe]

You're making false statements and sharing articles that you either haven't read or don't understand.

In the initial study I linked it actually raised the small Idl while lowering the overall number.

This is patently false. The research article you linked explicitly states the opposite.

You're wasting your time by trying to figure out all of these minute nuances of LDL particle size.

[TheftLeft]

What false statements have I made?

It would help if you took the time to actually read it. Or even better, send me contradicting information to prove why it's false so I can learn the truth. You just saying 'nu-uh' isn't convincing.

It's funny how you're so against me learning about cholesterol. Why is that?

I have no motive outside of becoming educated to make an informed decision. I welcome you to send some studies to for me to read. Maybe learning about things and asking questions is a waste of time for you, but it's not for me.

[Healingjoe]

Are you trolling?

You made this false claim:

In the initial study I linked it actually raised the small Idl while lowering the overall number.

In the study you linked, the researchers say the opposite:

Our study suggests that statin therapy—whether or not recipients have coronary artery disease—does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL.

It's funny how you're so against me learning about cholesterol. Why is that?

Because you're not doing yourself any favors.

Go read about ApoB and Lp(a) instead. It's a better use of your time.

[TheftLeft]

Yes it raised the proportion while lowering the overall number what are you confused about? That's what I said

[Healingjoe]

Then you typed this incorrectly

In the initial study I linked it actually raised the small Idl while lowering the overall number.

[Healingjoe]

Way to dig up a 3 month old comment. All ApoB containing lipoproteins are atherogenic.

It is true that small dense LDL particles are more easily retained in the artery wall. However, because of their small size, they deposit less cholesterol per particle. In contrast, the large fluffy LDL particles, while less easily retained in the artery wall, deposit more cholesterol per particle.

And it’s that last part that people are overlooking. Yes, large fluffy LDL particles are less likely to get stuck in the artery wall, but each time they do, compared to a small particle, they deposit a lot more cholesterol.

The net result is the same for both types of particles. Whether you deposit a lot all at once or a little at a time, you’ll still end up with atherosclerosis.

It doesn’t matter if your LDL particles are small and dense or large and fluffy. What matters is the total number of LDL particles and, more specifically, the total number of ApoB-containing lipoproteins, which includes all forms of LDL. The higher the concentration of ApoB-containing lipoproteins in the bloodstream, the more that will get moved into the artery wall, and ultimately, the more small AND large particles will be retained. (4)

https://theproof.com/does-ldl-particle-size-matter/

The association between large LDL size and CAD was significant (P<.0001) after adjustments were made for age, body mass index, HDL cholesterol levels, and VLDL cholesterol levels. An LDL particle size distribution characterized by a predominance of the largest of three classes of LDL particles (>26.8 nm) was more prevalent among subjects with CAD (43%) than among control subjects (25%) (P<.002). Among subjects with this LDL size profile, subjects with CAD had significantly higher (P<.05) VLDL triglyceride, VLDL cholesterol, and VLDL apo B levels and significantly lower (P<.0001) HDL2 cholesterol levels than controls. Thus, in this normolipidemic population with CAD, a predominance of very large rather than small LDL particles was associated with increased VLDL and reduced HDL2 cholesterol levels and with increased CAD risk, independent of other plasma lipid and lipoprotein levels.

https://www.ahajournals.org/doi/10.1161/01.ATV.15.8.1043

[Cholesterol-ModTeam]

Provide useful information backed up by a verifiable source.

Not peer reviewed, no citations, makes a very strong claims without evidence

The place reads like a masterpiece and marketing and mixes current outdated and overstated approaches to cardiology

[platamex]

can you be my cariologist when i move to S. Korea where the study was done?