To feed the trolls a bit:
Thank you sir, you have a heart of gold.
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Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study)
https://www.ajconline.org/article/S0002-9149(22)00322-8/pdf
Bempedoic Acid
Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials
https://www.lipidjournal.com/article/S1933-2874(20)30254-3/fulltext
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This is important research not so much because of these particular results, but conceptually. Here the researchers showed that the aging heart undergoes profound changes, which might be seen as characteristic of aging. But in a remarkable conceptual shift, they realized that those changes are actually beneficial adaptations to prevent arrythmias which increase with age. So if you tried to stop those “age associated changes”, you’d be counterproductively harming protective adaptations, and be worse off. This is not an unknown concept. The very idea of cell induced senescence is a defence mechanism in the context of cancer - telomeres shorten to prevent endless proliferation characteristic of cancer. The protein p53 induces cell death, and a naive attempt to prevent cell death leads to cancer should p53 be disabled.
Recently Matt Kaeberlein had an episode interviewing a gut microbiome researcher, who discussed how with age the diversity of the gut microbiome drops. There has been a great deal of effort expended on trying to prevent this drop in diversity. But while low diversity in a young person is undesirable, the low diversity which is prevalent in an old microbiome is actually adaptive and results in superior health in the elderly, and if one introduces more diversity by for example doing a fecal transplant from a younger person, you get dramatic deterioration (opposite of the blood exchange effect).
The concept that the aging body doesn’t simply deteriorate across the board and all age related changes are undesirable and result in health impairment is extremely important for biohackers trying to extend lifespan or healthspan. In seeing any age related change as undesirable rather than a healthy adaptive defense mechanism can lead to disaster. We must be always asking ourselves which change should be opposed and which should be accomodated. This is why I have profound reservations about Michael Lustgarten’s project. Yes, some changes are associated with aging - but that does not mean we should automatically seek to counteract them and return to “youthful” values. More important is to ask which changes lead to earlier mortality or morbidity - counteract those.
So for any supplement, medication, intervention, ask yourself if you are helping or hurting your lifespan/healthspan by attempting to counter an age related change, make sure you are not counterproductively counteracting a healthy adaptation.
Age-Associated Perinexal Narrowing Masks Consequences of Sodium Channel Gain of Function in Guinea Pig Hearts
https://www.jacc.org/doi/10.1016/j.jacep.2024.12.027
Changes in the aging heart may lessen the risk of irregular heartbeats
"The discovery challenges the idea that all age-related changes in the heart are harmful.
“As we get older and cardiac cells get bigger, the body compensates by making electrical communications more robust,” said Steven Poelzing, the James and Deborah Petrine professor at the Fralin Biomedical Research Institute. “Making sure the communication between cells remains high during aging appears to occur naturally to keep cardiovascular disease in check.”
Poelzing suggests that the body compensates for an aging heart by reinforcing the structure between cells to strengthen electrical communication and support the rapid influx of sodium ions that initiate each heartbeat.
Arrhythmias occur when the heart’s electrical signals become too fast, too slow, or disorganized. They affect millions worldwide and can range from harmless to life-threatening, increasing the risk of stroke, heart failure, and sudden cardiac arrest.
The National Heart, Lung, and Blood Institute reports that atrial fibrillation is the most common arrhythmia, affecting more than 2 million adults in the United States, with numbers expected to rise significantly."
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You may find this an interesting read. It seeks to tease out the impact of statins and v.low ldl-c on haemorrhagic stroke.
It does a good job of highlighting the potential confounders in cohort studies, and seems to give a balanced view on where we have absent data, and the cautious conclusions and strategies we might adopt where there is a heightened risk of haemorrhagic stroke or other cvd
https://www.ahajournals.org/doi/10.1161/strokeaha.117.019322
Its 2017 though… so may there be a better, more recent overview
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I didn’t expect my post to restart the debate around the optimal apoB level 
There’s nothing new in this Chinese study. We know that:
- According to RCTs and Mendelian randomization studies, “lower is better”.
- According to association studies, there is a U-curve, and the optimal is around ~120 mg/dL for primary prevention and ~100 mg/dL for secondary prevention.
- Mechanistically, 70 mg/dL seems to be enough to see plaque regression: Cardiovascular Health - #1053 by adssx . See also the Miami Heart Study: Cardiovascular Health - #1209 by adssx
Is there a significant benefit in going even below 70 mg/dL? We don’t know yet, but there are many ongoing RCTs aiming to answer this question: Rapamycin and risk of cardiovascular disease - #2972 by adssx
My concern with LDL lowering is the increased risk of viral infections: Low LDL cholesterol and risk of bacterial and viral infections: observational and Mendelian randomization studies 2025
This might partially explain the U-curves. However, if people get all their vaccines up to date, is the risk of low LDL annulled?
Strokes don’t seem to be a problem:
- Causal relationship between statins and hemorrhagic stroke: A drug-target Mendelian randomization analysis 2025: “These findings support the protective effect of statins on intracerebral hemorrhage.”
- LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study 2024: “This study provides supporting evidence of a potentially protective effect of LDL-c lowering through NPC1L1 inhibition on perivascular space and SVS risk, highlighting novel therapeutic targets for SVS.” (NPC1L1 inhibition = ezetimibe)
- Associations of lipids and lipid-lowering drugs with risk of stroke: a Mendelian randomization study 2023: “We cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.”
High LDL also seems to be detrimental for the various subtypes of dementia (AD, VaD, LBD, FTD):
- Elevated serum LDL-C increases the risk of Lewy body dementia: a two-sample mendelian randomization study 2024: “Elevated serum LDL-C increases the risk of LBD, while HDL-C and TG have no significant causal effects on LBD.”
- Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease 2024: “In addition, we provide preliminary evidence that APOB increases risk for Alzheimer’s disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB.”
- Associations of Lipids and Lipid-Lowering Drugs with Risk of Vascular Dementia: A Mendelian Randomization Study 2023: “Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.”
- Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study 2024: “Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759–0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387–0.874, pFDR = 0.0362).”
- A multivariable Mendelian randomisation study of serum lipids and dementia risk within the UK Biobank 2024: “In the univariable MR analyses, we observed no association between genetically determined serum lipids and risk of dementia. However, in a multivariable MR model containing LDL-C, triglycerides, and ApoB, ApoB was associated with a higher risk of dementia (OR per 1 SD higher ApoB 1.63, 95% CI 1.12, 2.37). Multivariable findings were consistent across IVWMR and MR-Egger, but not weighted median MR or MR-Lasso. HDL-C and ApoA1 were not associated with dementia in univariable or multivariable MR.”
On the other hand, LDL-lowering seems to increase the risk of PD.
There’s a very interesting trial in France: Statins In The Elderly (SITE), NCT02547883. They stop statins in people above 75yo and look at the results three years later. The principal investigator told me in February 2024 that the results were due to be published in the Summer of 2024. One year later: nothing published, and he doesn’t answer my emails anymore. So my guess is that the trial failed and showed no benefits (or even harm?) in stopping statins in the elderly?!
There’s also the question of confounding with Lp(a): “Our analysis (Figure) also suggests that the relationship of LDL-C to MACE tends to flatten below ≈90 mg/dL, the range encompassing most patients in the triglyceride-lowering trials, although the wide CIs at the lower range of LDL-C do not exclude a monotonic relationship across the full LDL-C range. The canonical view that “lower LDL-C is better” without limit may be in part confounded because measured LDL-C includes cholesterol contained in lipoprotein(a); therefore, patients with low LDL-C are more likely to have low lipoprotein(a). In the current analysis, the LDL-C relationships to events were adjusted for lipoprotein(a).” (Relation of Low-Density Lipoprotein Cholesterol, High-Sensitivity C-Reactive Protein, and Lipoprotein(a) Each to Future Cardiovascular Events and Death After Acute Coronary Syndrome on High-Intensity Statin Therapy: An Analysis of the Placebo Arm of ODYSSEY OUTCOMES 2025)
See also: Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis 2024
So my guess:
- If you have high Lp(a): slash apoB, the lower the better, and get vaccinated
- If you have normal Lp(a): I don’t know
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But is there any evidence of increased risk of infection and death by infections in the elderly in statin and/or PCSK9i trials depending on the LDL-C level? It could just be more mechanistic speculation and 10mg/dL is all you need to fight off pathogens.
Of note: this MR study concluded that “a 1 mmol/L lower LDL cholesterol resulted in 35–40% lower risk of ischaemic heart disease and 26–35% lower risk of all-cause mortality.” That’s massive. 1 mmol/L = 39 mg/dL.
The association between low LDL and viral infections also disappeared when using a polygenic LDL cholesterol score: “In genetic analyses using a polygenic LDL cholesterol score, a 1 mmol/L lower LDL cholesterol did not have a causal effect on risk of viral infections”
So even this study concludes that lower is better?
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“* If you have high Lp(a): slash apoB, the lower the better, and get vaccinated”
Since Lp(a) is such a negative, perhaps it might make a difference in how you slash ApoB. It is known that PCSK9i slashes ApoB without raising Lp(a), and possibly even slashing Lp(a) levels by as much as 20% (which to be clear may not be anywhere near sufficient for those with high/very high Lp(a) levels).
However, for those at high risk of CVD who need the biggest slashing of ApoB, use of PCSK9i by itself is not enough and combination therapy is used with the addition of statin, ezetemibe (and even bempedoic acid).
Unfortunately, when recommending the most serious slashing of ApoB because of high levels of Lp(a), you may need to resort to this multiagent therapy to achieve those low ApoB numbers. And that multiagent therapy includes a statin, and statins tend to raise Lp(a) levels (modestly around 10% or so, but possibly up to 20%).
So how to avoid this paradox? Well, here again the choice of which statin becomes crucial. Pitavastatin somewhat uniquely among statins does not raise Lp(a) levels at all, and may even possibly slightly lower those levels. From the study I posted:
“Pitavastatin – effect on Lp(a)
Elevated serum Lp(a) concentration is an ASCVD risk factor independent of serum LDL-C concentration [68]. The EAS consensus indicates that the cut-off value for serum Lp(a) concentration should be 50 mg/dl (−125 nmol/l) [46]. However, there are data indicating that already at serum Lp(a) concentrations above 30 mg/dl (−75 nmol/l), CV risk increases [1, 68]. There are also indications of a preference for tests that determine the number of Lp(a) molecules in nmol/l rather than the mass in mg/dl [1].
The use of statins is associated with an increase in serum Lp(a) concentrations, although this is not clinically relevant [69, 70]. On average, the increase in serum Lp(a) concentration is 6–10% [1]. The increase in serum Lp(a) levels in patients treated with statins is part of the residual CV risk that remains, despite good control of serum LDL-C levels [69, 71].
In the context of its effect on Lp(a) concentration, pitavastatin also appears to be different from other statins (no class effect), as it does not affect, or may even slightly reduce its serum concentration. The VISION randomised clinical trial evaluated the effect of pitavastatin 2 mg/day vs. atorvastatin 10 mg/day for 12 weeks on serum Lp(a) concentrations in 42 patients with hypercholesterolaemia. It was concluded that pitavastatin showed a tendency to slightly reduce serum Lp(a) concentrations, although this effect did not reach statistical significance. No such effect was shown for atorvastatin [72]. These findings were confirmed in a meta-analysis of 20 RCTs conducted by Wang et al. involving 23,605 participants. In this meta-analysis, it was found that, of all statins, pitavastatin had the most beneficial effect on serum Lp(a) concentrations, which was manifested by a tendency to reduce these concentrations [73].
Expert recommendation
Pitavastatin, unlike other statins, appears to have a neutral effect on serum Lp(a) concentrations, and may even reduce these concentrations to a small extent. Pitavastatin may be considered for use in patients with elevated Lp(a) concentrations (IIb). Further studies are needed to confirm this relationship, as well as to assess the effect of pitavastatin on the size of apolipoprotein(a) isoforms.”
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That article isn’t a study or meta analysis. It is basically just an opinion piece rehashing cherry-picked studies. I also note that there are ads for cholesterol-lowering medications.
Don’t you think that hosting advertisements for cholesterol-lowering medications could influence the Journal of Clinical Lipidology to favor content aligned with the interests of those advertisers?
All in all, not a very compelling article.
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Children have naturally low cholesterol for the first 12 years of their lives and nothing bad happens. I think the same will hold true throughout your life. Low cholesterol in the aged leading to higher mortality is probably a symptom of a life threatening disease instead of a symptom of low cholesterol.
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i must admit, i wasn’t particularly impressed with that paper either. It claimed more than the underlying referenced studies did in some instances, which is always suspicious.
One paper it references I’ve looked at in some detail previously. It does seem to be decent, and concludes:
“In this meta-analysis, for statins and nonstatins, the risk of major vascular events was significantly reduced by 21% for each 1-mmol/L (38.7-mg/dL) reduction in LDL-C”
So to answer the original question above, if I had LdL-C of 90, reducing it to about 50 would tempting for that 22% risk reduction. But as has been said, the haemorrhagic and PD risk may outweigh that.
From memory, eating 2 portions of oily fish a week had a similar to 22% impact on all cause mortality (mainly from CVD). So maybe I’d eat more fish while deciding whether to take a statin or not…
My baseline apob is in the 60s and I now take the odd ezetimibe (5mg maybe 12 times a year with rich meals) and rosuvastatin 5mg a similar amount. I haven’t tested since starting this bizarre regimen, and I doubt it has much impact!
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I don’t see any ads: https://www.lipidjournal.com/article/S1933-2874(25)00317-4/fulltext
The journal is still a reference. And the question was not whether this article is convincing or not but whether the guidance has changed or not. Most guidelines and papers are converging towards “Lower for longer is better”. It might be that all these authors are wrong (it would not be the first time that the mainstream consensus is wrong in science!) but as of today that’s where the science points. Then each of us has to make a decision for their own health based on the available information that is never 100% clear.
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For PD yes the risk is increased. But the PD risk is 1% so way less than the heart attack risk.
For hemorrhagic stroke, what’s your source for this risk? Mendelian randomization studies show that lower LDL is better for strokes: Cardiovascular Health - #2250 by adssx
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The consensus, most supported by RCTs, is that lower is better. Only recently has this view been challenged. Papers and studies supporting a U- or J-shaped curve are not long-term RCTs.
This is somewhat of a quandary, especially for older people.
I now typically use multiple AIs, some of which are paid “pro” versions, to obtain a consensus.
Here is the gist from multiple AIs:
“Centenarians tend to have lower or moderate LDL-C levels but with distinctive lipid particle characteristics, and in this age group, very low LDL may not always be beneficial.”
“Typical LDL levels in centenarians are commonly reported to be 70–110 mg/dL.”
“Studies investigating lipid profiles in centenarians from various geographical regions have yielded inconsistent results, showing that plasma levels of total cholesterol, LDL-C, HDL-C, and triglycerides can be normal, lower, or not significantly different compared to elderly controls.”
““Cholesterol Paradox” in Nonagenarians: Some studies on nonagenarians (individuals in their 90s) have observed a “cholesterol paradox,” where moderate hypercholesterolemia (LDL-C ≥130 mg/dL) was associated with longer survival compared to lower levels. This suggests that the conventional wisdom that “lower is always better” for cholesterol may not universally apply to the very oldest populations, potentially due to cholesterol’s role in immune function and cellular repair in aging.”
Bottom line:
“Centenarians generally have LDL cholesterol levels in the low to moderate range, but not extremely low, and the relationship between LDL-C and health outcomes in this group is complex.”
Everyone has to take into account their own personal and family history.
If there is any CVD involved, I would opt for the “lower is better” because there is some evidence that plaque can be reversed with very low LDL levels. (Not supported by any significant studies that I could find.)
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Hoiw many old people naturally have low levels of LDL-C without disease?
This is where I landed by clicking on your original citation.
But, I reiterate, it is not a compelling argument. This is not to say that they are wrong.
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The argument of nature is not a strong one. Blood pressure and blood sugar levels also tend to increase with age and yet there’s no debate for those.
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There is an argument that the values that adult human being have in their 20s are probably reasonably good values to have.
Obviously we have evolved to die at a point and there needs to be some proximate cause for this.
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Nature doesn’t want for anything, death being a thing simply evolved by accident and turned out to be a good thing for a species as a whole but bad for the individual.
If you care about the species, don’t do anything and simply accept death.
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That is a good question.
“In the ASPREE trial, which included 12,334 healthy older adults (mean age 75.2 years) not taking lipid-lowering medications, the mean LDL-C levels were 3.2 mmol/L (~124 mg/dL) for men and 3.4 mmol/L (~131 mg/dL) for women1. This suggests that naturally low LDL-C (<70 mg/dL or <1.8 mmol/L) is uncommon in this group without disease.”
While very low LDL-C (<40 mg/dL) is rare in healthy older adults, studies like NHANES found that such levels were associated with higher mortality, possibly due to undiagnosed conditions (e.g., cancer, infections)
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