Yes there is, but it isn’t as strong as the other evidence. There are a lot of observational studies on clinical trial data showing a benefit from going lower on event risk and plaque progression.
I would bet that a trial lowering from 50 mg/dl to 30 mg/dl would show benefit without any safety issues. Lowering to 30 is what Tom and Dan suggested to Simon as he has plaque and is relatively young.
Looking closer at the bempedoic acid pathway. Similar MACE outcomes as statins per every unit of lowered LDL, and no cancer signal. This is MR, so can’t say anything about off target effects of BA therapy.
Mendelian Randomization Study of ACLY and Cardiovascular Disease
The question not answered, or at least not fully answered, is:
Is the very low LDL a result of intervention, statins, etc., or is it caused by some other factor?
Does this make a difference in future ACM or CVD, etc.?
It’s hard not to flip-flop on whether the lower is better or there is a sweet spot in a U- or J-shaped curve. I tend to be influenced by the newest papers that I read. I don’t have the background that Physionic has to comprehensively analyze the papers.
@CronosTempi has put a compelling case for pitavastatin in several replies to this thread with little response. Does anyone else have experience with pitavastatin? IIRC atorvostatin was most commonly used/recommended here, however @CronosTempi analysis seems to indicate pitavastatin may be a superior option. I’m curious if anyone else has any thoughts on this.
Personally I’ve tried two statins (IIRC rovustatin and atorvostatin) and experienced muscle pain within a week of starting them. As a result, I had given up on statins. @CronosTempi’s glowing review of pitavastatin makes me reconsider.
Pitavastatin caused no muscle issues that rosuvastatin and atorvastatin did for me. The downside was that it shot up my liver enzyme levels. Since I do have a bit of a fatty liver problem, I researched statins according to their impact on liver, kidney, blood sugar and myalga rates and eventually ended up taking pravastatin, starting at 10mg taken at night (currently in the process of increasing to 20mg). Due to its short half life, it’s more tolerable for my liver and muscle pain is not even noticable most of the time and even the rare times it is it is very mild. Then again, I am also on creatine HCL which could be a factor.
As a general rule of thumb, if you’re prone to myalga from statins, use 1-2mg pitavastatin but if you’re worried about your liver health, use pravastatin 10-20mg. Add ezetimibe 5-10mg and a GLP1 on top of that if you still need more LDL-C reduction. Bempedoic acid could also be an option but it combination with a statin it might raise liver enzymes too high. PCSK9i are currently too expensive.
Thanks @Virilius for your perspective.
Your post reminded me that rovustatin also raised my liver enzymes. I currently take Repatha, Bempedoic Acid and Ezetimibe and my ApoB is ~45. I’ve probably mentioned this elsewhere but my risk is very high, Dad had a 5-way bypass at 47, his brother died of a heart attack around that age, high Lp(a), etc etc. So for me lower is almost certainly better despite what some of these association studies might indicate about a U-shaped curve.
Interestingly, Bempedoic Acid had no impact on my liver enzymes, or it was counteracted by the GLP-1. Currently sitting at an ALT of 15 and AST of 18.
It’s important to note, that some pitavastatin users still report muscle pain, just that the numbers are drastically lower compared to atorvastatin, rosuvastatin etc. - this includes I believe some members of this site - whether that was dose dependent I don’t know. Pitavastatin is usually given to people who have side effects from other statins just because the numbers on pita are much lower, but it’s just a fact, that some people do not tolerate statins - period. There are apparently genetic reasons, so if you happen to be very statin intolerant, pitavastatin may still not work for you. In the end, pitavastatin is still a statin. Here’s a review that compares similarities and differences between pitavastatin and other statins in general, but regarding adverse events
Quote:
“The most frequent adverse events (AEs) induced by statins are related to myopathy (in rare cases rhabdomyolysis) and liver injury. Numerous studies have shown that pitavastatin is associated with a very low rate of AEs, also with high doses and during prolonged treatment20. Even if the rate of AEs differs across trials, overall 10.4% of patients have reported AEs in the LIVES study, performed in approximately 20000 patients, treated with pitavastatin (1-4 mg/day) for 2 years57. The most common, mild in severity, AEs were myalgia, muscle spams or weakness, experienced by 1.08%, 0.18% of patients respectively. Overall, no clinically significant changes in laboratory parameters have been observed during the study. A mild increase of creatinine phosphokinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (γ-GTP), incidence was found in 2,7%, 1.8%, 1.5% and 1.0% of subjects respectively. Furthermore concomitant administration of pitavastatin with agents that, rising statins plasma levels, lead to AEs, was not associated with significant incidence of AEs8.”
Review Article: Pitavastatin: Similarities and Differences Compared With Other Statins
I was on Pitavastatin for nearly 5 years both 2 and 4 mgs. LDL was in the 50s throughout. APO B in the 60/70 range. No issues with liver enzymes or muscle pain.
I switched to Atorvastatin 20 mgs because I wanted to lower LDL and APO B. I take atorvastatin 20 mg along with 1/2 tablet of Brillo EZ. Since I am diabetic my triglycerides are always high so I took 45 mgs of fenofibrate. I achieved my target - LDL below 20 and APO B 37. This was my target because 8 years ago when I did my Ca Scoring I was at 185 with OM2 at 99% (YES) blocked. I continued on. No stent nothing invasive just diet and pharma. No inducible ischemia with dubutamine stress test last year. I will retest later this year!
Sadly, pitavastatin and rosuvastatin caused a worsening of a severely sensitive chronic pain condition I have. Atorvastatin I can tolerate, though.
@Mantheunknown Why do you only take half of the Brillo EZ? I’m on the same Atorva and Brillo.
With a 99% blockage, I would seriously consider a stent. That’s just too advanced IMHO.
I prefer to go with the smallest effective dose.
I am not sure that it is 99%, even though that is what the report said. I have trekked the himalayas 10K+ feet with no discomfort. My carotid arteries are clean. I have been on Nattokinase, lumbrokinase, serrapeptase for nearly two years. Will find out later this year. Will avoid invasive procedures as much as possible.
Just remember that you can’t ‘feel’ cardiovascular disease. The first symptom of CVD is usually sudden death like what happened to my friend a couple months ago. Everything was fine until he suddenly died due to a heart attack.
just curious if the CAC was able to give you the OM2 score? Or did you do something else at the same time?
CT coronary angiogram and Ca score was provided along with that.
I’m particularly interested in this Mendelian randomization paper, thank you drawing my attention to it.
if anybody has access to a full access link i’d be grateful. Curious to see what the effect size of lower ldl-C on haemorrhagic stroke risk is.
This paper that @adssx found is a mendelian randomization study which suggests the haemorrhagic stroke risk is directly due to the low ldl-C not a side effect of interventions/statins used to lower it.
https://www.sciencedirect.com/science/article/abs/pii/S0014299925001979 1
Severe muscle pain on Rosuv and Ator (no matter how low the dose)as well as the statin ‘cough” that most of my family seems to get. No pain and no cough on pitavastatin. (1mg for the last 2m) on top of Brillo EZ .(brillo ez only brought my LDL to 2.6 trying to achieve 1.8 or 1.5 hopefully)
Horrible reaaction to Repatha- weak and cough non stop- the tried the 6 month Inclisiran pcsk9i -even worse. I would be so cautious about permanent pcsk9i gene therapy unless someone had zero symptoms with repatha and inclisiran.
The paper studies intracerebral hemorrhage (ICH), which is the most common subtype of hemorrhagic stroke (HS), itself a subtype of all strokes. ICH = ~28% of all strokes. For SVS (small vessel stroke, 14%) and LAS (large artery stroke, 15%), other Mendelian randomization studies show a reduction in risk: Cardiovascular Health - #2250 by adssx
Even for ICH, not all MR studies agree: * 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.”
Overall, LDL lowering might be neutral for all strokes, with some variations by stroke subtype and medication. The devil is in the details.
Yes, I agree there’s not a clear signal for optimum LDL-c levels when considering the risk of all types of stroke. I was responding to @desertshores who i think is focussed on the risk of ICH due to family history.
That 2nd MR study is v interesting thank you. I’m not sure it informs the “lower the better” debate which is a shame (for me the debate is about whether to pursue ldl-c below 50). It concludes:
“Our findings confirm that statins targeting HMGCR do not increase the risk of ICH and may serve as a potential intervention for prevention or treatment. This conclusion is further supported by a 9-year prospective study involving 96,043 participants, which shows that maintaining LDL-C levels between 70 to 99 mg/dL can strike a balance between cardiovascular protection and bleeding risk.[25]”
Personally, I suspect an optimal LDL-C could be anywhere in the 30 to 80 range but I’ve no idea exactly where. And it could easily vary materially with individual risk factors. certainly side effect risks of various interventions will vary by person, so if you’re in that range the decision as to whether to intervene because “lower the better” isn’t clearly supported by the evidence. So it seems right that there’s plenty of debate and uncertainty.