No Lower Limit? Strikingly Low LDL-C Levels Boost Cardiovascular Protection With No Added Safety Risk

#41

I think you may be missing the point of why all-cause mortality is ever looked at in the first place. Let’s say drug A lowered LDL like gangbusters but also led to a commensurate increased incidence of cancer. From a purely CVD standpoint the drug looks phenomenal, but would you want to take it?

4 Likes
#42

I get your point but I didn’t read it to mean that deaths other than CVD related had any connection to LDL-c and any meds used to lower it. Maybe I read it wrong.

#43

@Anthony_R Not wanting to add noise to a thread, trying to be terse; I think Anthony is closest to my view of statins and LDL-c.

What is missed in these trials is testing for the sex hormones, E, T, progesterone and thyroids (mainly free-T3)!!! I can’t put enough exclamation points on. LDL in ignorance of the whole body IMHO!!!

Cholesterol all of it has values in the immune system, sex hormones etc etc. All is tossed out the window by the statin pushers IMO. IMHO Triglicerides is a better predicter of health. IE above 65ish is bad.

At 72yo male good health, low BMI I’ve very frustrated that even after 100% carnivor, table spoons of ghee, butter, lambs fat added/daiily my total cholesterol is only 175. I would prefer my total would be 225ish. My CAC is zero from a whole body scan, zero everywhere so IMHO LDL-C even the LPO-A/B is ignorable. Yes possible soft plaques, but at 72yo and triglicerides at 55 there’s zero value in a soft plaque test. I’ll die of something else like a bus hitting me etc.

I’m VERY frustrated with this LDL/statin focus ignoring sex hormone needs, imunne system needs etc etc and ignoring diet, triglicerides A1C etc etc. I do agree with the mention of inflammation, hsCRP, IL-6 etc!!! Low inflammation low to no CAC, low triglicerides, low A1C who cares about LDL, IMO.

My choice of pushing my glucose and A1C even lower is via: 1000mg imeglimin, and 10mg dapagflozen (SGLT2). I used a CGM, lingo is my fav, to tune dose vs diet vs flatness of glucose / day.

Sorry, I view LDL-C and statins as mainly a drug co profit discussion and these studies are surely funding by the drug co’s to keep this debate swirling IMO.

FWIW my results on a carnivor diet is 100% affected by which source of meat. CAFO meat, seed oils would not have the same good health results in my studies. The farming conference acresusa.com had speakers on regenerative vs cafo vs cafo on distilary grains. 100:1 or more difference in omega 6 / 3 ratios!! Poison to healhy. An easy source to buy from is: piedmontese.com. The best tested meat is smaller and smaller producers all mail order from North West mid western states on calcium underlayment soils.

Best to all, curt

1 Like
#45

I’m with you about 95%, but the other 5% I’m against LOL. I don’t think we should totally ignore LDL-c and Apo-B. If we want to be prudent about disease prevention I think LDL-c and Apo-B should also be maintained at reasonably low levels or better said somewhere between 50-80 depending on one’s risk level (i.e. family history and LPa level). The rest I totally agree that Hb1ac/FG, hs-CRP, sex and other hormones are very important to look at also.

2 Likes
#46

Would love to see studies on triglycerides being a better predictor of health.

Cholesterol still finds a way to make it to sex hormones and the immune system. Lack of cholesterol is not an issue there. Amount of circulating cholesterol is small compared to the amount that makes it to all your cells, and it is this relatively tiny amount that drives CVD . Statins/psck9 lower circulating LDL, which is harmful. The other 90% or so of cholesterol that your body uses is untouched by statins because it never makes it to circulation. Your body is never running out of cholesterol, but it can be harmed by excess circulating cholesterol. That is why there is no lower limit for amount of circulating that is harmful.

3 Likes
#47

We have beaten statin use to death in various threads. No matter how much evidence there is for statin use, there are still outliers who are against statin use based on minority evidence. The vast preponderance of studies favors statins.

Once again, the Luddites are attacking statins. Millions of lives have been saved globally since their introduction, with the number continuing to grow. Statin use was estimated to have prevented approximately 37,000 to 42,000 deaths annually in England and Wales alone by the mid-2000s

Nobody is asking you to use statins. That is an individual choice for those who want to be on the wrong side of science.

Here’s a breakdown of the evidence, from direct clinical trial data to large-scale epidemiological modeling, with references. Here is the evidence presented by AI. If you want to dispute the evidence, please do so.

1. The Foundation: Evidence from Clinical Trials (Mortality Reduction)

The most robust evidence comes from randomized controlled trials (RCTs). A landmark meta-analysis by the Cholesterol Treatment Trialists’ (CTT) Collaboration is the gold standard. It pools individual patient data from over 25 large statin trials, involving more than 170,000 participants.

The key finding is that statin therapy significantly reduces all-cause mortality in a broad range of patients.

Key Finding: For every 1.0 mmol/L (approximately 40 mg/dL) reduction in LDL cholesterol, statins reduce the risk of all-cause mortality by about 10% over 5 years. This effect is driven primarily by a 20% reduction in major vascular events (heart attacks, strokes, and coronary revascularizations) and a smaller, but significant, reduction in coronary and vascular death.

Reference:

  • Cholesterol Treatment Trialists’ (CTT) Collaboration. (2010). Efficacy and safety of more intensive LDL cholesterol lowering: a meta-analysis of data from 170,000 participants in 26 randomized trials. The Lancet, 376(9753), 1670-1681.
    • Specifically, this paper and its 2012 follow-up show a 10% reduction in all-cause mortality per mmol/L LDL reduction. This is the foundational evidence that makes the population-level calculations possible.

2. Calculating “Lives Saved” in Specific Populations (e.g., the UK)

To estimate lives saved, researchers apply mortality-reduction rates from clinical trials to real-world prescribing data. A highly cited study used this method for England and Wales.

Methodology: The study modeled the number of deaths prevented from 2000 to 2007 by comparing actual cardiovascular mortality rates to a projected scenario without statin use. The difference in deaths, after isolating the statin effect from other factors (like blood pressure treatment and smoking cessation), was attributed to statins.

Key Finding: Statin use was estimated to have prevented approximately 37,000 to 42,000 deaths annually in England and Wales by the mid-2000s.

Reference:

  • Unal, B., Critchley, J. A., & Capewell, S. (2004). Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation, 109(9), 1101-1107.
  • Wijeysundera, H. C., et al. (2010). Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005. JAMA, 303(18), 1841-1847. This study for Ontario, Canada, similarly partitioned the mortality decline and found substantial contributions from medical therapies, including statins.

3. The Biggest Picture: Global and Long-Term Estimates

The largest-scale estimates come from modeling the global impact and projecting future benefits.

Global Impact Model: A 2022 study for the World Heart Federation modeled statin use from 2020-2030. It is estimated that scaling up statin coverage globally could prevent 4.7 million deaths over that decade. While looking forward, this is based on the same powerful, proven mortality reductions from past trials.

Reference:

  • World Heart Federation. (2022). The Cost of Inaction: Secondary Prevention of Cardiovascular Disease. This report models that achieving 70% coverage of statins and antihypertensives in low- and middle-income countries would avert 4.7 million deaths by 2030.

The 40-Year Scandinavian Simvastatin Survival Study (4S) Follow-up: The 4S trial (1994) was the first to prove statins save lives in patients with heart disease. A registry-based follow-up of the original trial cohort, published 40 years later, provided a devastatingly clear picture.

Key Finding: Over the entire 40-year period, patients originally randomized to simvastatin had a significantly prolonged median survival by 2.9 years compared to those on placebo. This translates directly to a massive number of life-years saved, not just a delay in death.

Reference:

  • Pedersen, T. R., et al. (2024). Long-term effects of simvastatin on mortality in patients with coronary heart disease: the 40-year follow-up of the Scandinavian Simvastatin Survival Study (4S). European Heart Journal, 45(38), 3974-3983.
    • This is the most direct, long-term evidence that statins do not just postpone death but substantially extend life.

4. The Public Health Consensus

To put it in perspective, public health leaders often frame the impact in historical terms. The discovery of statins is widely considered one of the most important medical advances of the 20th century.

A landmark quote:

  • A 2016 review by former FDA Commissioner Robert Califf and colleagues stated: “The cumulative evidence from over 170,000 randomized patients establishes that for every 1 mmol/L reduction in LDL-C, there is a 10% reduction in all-cause mortality… This is a level of evidence that is rarely achieved in medicine.” This clinical trial evidence is the engine of the “lives saved” calculations.
  • Reference: Collins, R., et al. (2016). Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet, 388(10059), 2532-2561.

Conclusion: How Many Lives?

Combining these references, a reasonable, evidence-based estimate is:

  • Hundreds of thousands of lives saved in single large nations (like the US or UK) over a decade.
  • Millions of lives have been saved globally since their introduction, with the number continuing to grow.
  • The evidence suggests statins don’t just delay death by days or weeks; the 40-year 4S follow-up shows they extend life by a median of nearly 3 years in patients with established heart disease.

The precise number is a moving target based on modeling assumptions, but the order of magnitude—millions of people alive today because of this class of drugs—is supported by decades of highly consistent, large-scale evidence.

Briggs, A. D. M., Mizdrak, A., & Scarborough, P. (2013). A statin a day keeps the doctor away: comparative proverb assessment modelling study. BMJ, 347, f7267–f7267. https://doi.org/10.1136/bmj.f7267 Cited by: 46

Heller, D. J., Coxson, P. G., Penko, J., et al. (2017). Evaluating the Impact and Cost-Effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke. Circulation, 136, 1087–1098. https://doi.org/10.1161/circulationaha.117.027067 Cited by: 143

Nowak, M. M., Niemczyk, M., Florczyk, M., Kurzyna, M., & Pączek, L. (2022). Effect of Statins on All-Cause Mortality in Adults: A Systematic Review and Meta-Analysis of Propensity Score-Matched Studies. Journal of Clinical Medicine, 11, 5643. https://doi.org/10.3390/jcm11195643 Cited by: 55

Orkaby, A. R., Driver, J. A., Ho, Y.-L., et al. (2020). Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older. JAMA, 324, 68. https://doi.org/10.1001/jama.2020.7848 Cited by: 260

4 Likes
#49

Happy with my LDL and ApoB being lower than 20.

I’m on Ezetimibe (10mg), Pitavastatin (4mg), Bempedoic acid (180mg) and Inclisiran

3 Likes
#50

I remember when statins came out and of course my LDL was awful. My doc tried to talk me into it but full disclosure he said when he went to the conference, they said ACM for the drug was about the same as without it. When they asked why the reply was that there were increased homocide, suicide and accidents which made up the difference, everybody laughed and went home to prescribe more statins. The next year they got the same story and there were a few smiles. The next year they said the same thing and the room was silent. Early statins did increase homocide suicide and accidents. They affected the brain.

If you don’t know ACM you don’t know whether you should take it or not. And the details could be important. Side effects could be more important than the effects. You don’t know if you don’t check.

#51

Great numbers.

What was your escalation/ladder for each med?

And what were ldl/apoaB at each step?

Any side effects?

#52

I have never seen any evidence showing a link between statins and homicides and suicides. Even AI can’t find any. If you can’t provide concrete evidence, don’t post it. Anecdotal or hallucinatory evidence that is disproved by science is not helpful.

Evidence does not show that statins cause homicides or suicides. While some anecdotal reports and early studies hypothesized that lowering cholesterol might increase aggression and suicidal ideation, large-scale medical research indicates that statins do not increase the risk of suicide or violent behavior.

Studies: Large-scale population-based research published in PubMed and the National Center for Biotechnology Information found no increased risk of suicide attempts, death from suicide, or depression associated with statin use.Regulatory Stance: The U.S. Food and Drug Administration lists no general boxed warnings for suicide or violent behavior linked to statins.

Aggression and Homicide Reports Gender Differences: Research from the University of California, San Diego (published in PLOS One) noted that statin use is generally associated with lower aggression in men, but was linked to higher aggression scores in a subset of women.

Violence Links: There is no clinical or forensic evidence causally linking statins to homicides. While some early theories explored whether excessively low cholesterol could lead to behavioral changes, systematic reviews of FDA adverse event reports have not established a valid causal connection between statin therapy and therapeutic reports of violence towards others, as discussed on the National Center for Biotechnology Information.

2 Likes
#53

Amazing that we have to explicitly say that statins don’t cause suicide or homicides, when they’ve been one of the most used medications in the last 40 years. And this on a board where on average, people know more about statins and ldl.

5 Likes
#54

From Claude Fable 5:

Statins and homicide/suicide: what the evidence actually shows

The short answer, wearing both hats: there is a genuine historical scientific signal linking cholesterol lowering generallyto violent/non-illness death, but the evidence that statins specifically raise suicide or homicide risk is weak, inconsistent, and largely refuted by modern trial-level data. It’s important to separate three distinct bodies of evidence, because they are frequently conflated.

1. The original trial signal (early 1990s) — this is the real basis for the concern, but it is not statin-specific. The foundational finding is Muldoon et al., BMJ 1990, a meta-analysis of six primary-prevention cholesterol-lowering trials (24,847 men). Coronary mortality fell, but total mortality did not improve, and there was a significant excess of “non-illness” deaths — accidents, suicide, and homicide/violence — in the treated arms (roughly ~1.7-fold). Critically, those trials used diet, fibrates, resins (cholestyramine), and other agents — not primarily statins. Muldoon’s own 2001 follow-up meta-analysis (non-illness mortality, incl. later trials) found the effect attenuated and no longer statistically robust once statin trials were added.

2. Observational epidemiology — a consistent cross-sectional association, but confounded and directionally ambiguous. Many cohort and case-control studies show that people with naturally low serum cholesterol have higher rates of completed suicide, suicide attempts of greater lethality, impulsivity, and violent death (e.g., Paris Prospective Study I; multiple psychiatric-inpatient series). This is an association with low cholesterol as a trait, not with statin exposure. Reverse causation and confounding are major problems: depression, substance use, low-grade inflammation, cancer, and poor nutrition all lower cholesterol and independently raise suicide risk. The Annals review by Golomb (1998) is the classic critical appraisal of this literature.

3. A biologically plausible mechanism exists — the cholesterol–serotonin hypothesis. Nonhuman primate experiments (monkeys randomized to low-fat/low-cholesterol diets showed more aggression) and membrane studies suggest low membrane cholesterol reduces serotonin (5-HT) receptor density/function and central serotonergic tone, which could increase impulsivity/aggression. This gives the association a mechanistic footing — but it concerns low cholesterol as the exposure, and whether pharmacologic (especially lipophilic) statin-induced lowering reproduces the same CNS effect is unresolved.

What the modern statin-specific evidence shows — the crucial part for clinical practice:

  • Cholesterol Treatment Trialists’ (CTT) Collaboration — individual-patient meta-analyses of ~30 statin RCTs (~200,000 people) — find statins reduce major vascular events with no increase in non-vascular mortality, including no excess of accidental/violent or suicide deaths. Documented harms are myopathy, incident diabetes, and probably a small hemorrhagic-stroke signal — not violence.
  • Large pharmacoepidemiologic and self-controlled case-series studies (e.g., population-based analyses examining suicide attempt, depression, anxiety) find no increased risk of suicide attempt with statins; several actually report lower depression risk, and RCT-level data and recent meta-analyses show no association between statins and depression.
  • Mendelian randomization work using HMGCR variants (the statin target) has been applied to many outcomes but has not established a causal statin→suicide link; the suicide association tracks with the low-cholesterol trait, not clearly with the drug target.

Bottom line for the two roles:

As an epidemiologist: there is a reproducible association between low cholesterol and violent/suicidal death, plus a plausible serotonergic mechanism, but the statin-attributable component fails Bradford Hill on consistency and experiment — the strongest (randomized, confounding-free) evidence shows no effect. The old trial signal is best explained by chance, the heterogeneous non-statin interventions used, and small event numbers.

As a cardiologist: current guidance is that statins do not meaningfully increase suicide or homicide risk, and this concern should not deter appropriate prescribing. It is reasonable to remain attentive to mood in patients with pre-existing depression, but the net mortality and safety data are firmly favorable.

No credible body of evidence links statins to homicide specifically; “homicide/violence” appears only as a composite “non-illness death” endpoint in the early meta-analyses, driven by very few events.

Sources:

5 Likes
#55

I posted that because @Kelman didn’t seem to be paying proper attention to ACM. And he specifically said a car accident can have nothing to do with a medication. It certainly can. There are all kinds of drugs that can cause a car accident, and one of them could be a statin. I’m not saying it is the case currently for any statin, though they suck for me. From what I’ve read they suck for you too. Leqvio has no side effects that I can notice, but there is no ACM study coming out till later this year. I’ll decide whether to continue when it comes out. I was just making the point that biology is a complex system and we have no idea what effects a drug may have until it’s tested.

I loved that doc, he’s gone now. He was an old jewish man and great at telling stories and had a joke every time I saw him. Must have had a book he memorized a new one for each day. He loved this story and told it really well. Even though the point of the story was that statins could mess me up, he wanted me to take the statins.

1 Like
#56

Yes, but my point was we can’t blame all accident and suicide deaths on statins, otherwise half of us in these boards (that takes statins by the lb LOL) would have been dead by now. can it have a detrimental effect on some people absolutely, but when factoring deaths from causes other than CVD I can’t find a plausible connection between these deaths (non-CVD related) and one’s LDL-c level. Thus, my opinion that only CVD related deaths are a better measure if we wanted to establish a risk factor based on LDL-c level. I’m still of that opinion but we obviously don’t have/need to agree on it.

1 Like
#57

Lower is better for ACM, CVD, and stroke prevention. END OF STORY

5 Likes
#58

We agree that we don’t need to agree. I don’t agree with many of the people in my family and we’re happy.

Let’s say you’re trying to decide whether you should use a herbicide again. You look at the field and see how well it kills the weeds. It killed all the weeds. You decide to use it again for sure. Because you didn’t notice that it also hurt the crop. Your yield went down by 30%. The effect was the kill (100%), the side effect was the harm and it was very expensive. You have to look at both.

1 Like