N=1 big time, I noticed it right away, then later did read it in studies and the reason why eludes me now. My recollection is that they just stated it and didn’t explain.
I still have a couple boxes of empag in the drawer. I can’t make it through the night and stop all the time to pee in the day. Not worth it. Dapag I don’t even notice.
Full paper:
Very-High-Prevalence-of-Nonoptimally-Controlled-Traditional-Risk-Factors-at-the-Onset-of.pdf (461.3 KB)
Note the risk factors they used, and how they all include people receiving treatment for those risk factors:
Why? 3 reasons, according to AI:
I don’t think there is any doubt that there are issues with high BP, high ApoB and/or high glucose. The question is what happens without those.
Sorry, I was not looking to answer your question, just my own curiosity about study parameters.
As for your question: all the paper says is that an analysis of those with 0 risk factors that still had a CVD event revealed that they either had multiple risk factors that were “high-normal” or “subthreshold” range, had genetic factors not accounted for, or non-traditional factors not accounted for (high inflammation, physical inactivity).
Physionic: Can we reverse Atherosclerosis?
Video and Summary/analysis here: Physionic Podcast Videos and Summaries / Transcripts - #120 by RapAdmin
I switched to it myself from Rosuvastatin three months ago and my A1C seemed to drop from 5.4 to 5.2 and working out at the gym has been more painless (probably was having myalgia without realizing it until I stopped Rosuvastatin)
Good data point. Thank you
I think if you look at the graph Rapadmin posted, it’s very clear that there are diminishing returns from increasing doses of any of the statins.
So Pitavastatin 1mg gets you a 32% reduction. Doubling dose to 2mg gets you an extra 4%, and doubling again to 4mg gets you 43%. 4x more drug to get an extra 11% reduction isn’t a good trade-off IMO.
My cardiologist told me (and I agree) that you’re almost always better off using smaller doses of different drugs. So the 1mg Pitavastatin, plus 5mg Ezetimibe is going to perform WAY better than 6mg Pitavastatin.
I know I’m late to the reply, but unfortunately, without the scan it’s just total guesswork. You could be extremely lucky and have none, or you could have tons. There’s no way of knowing.
And Rapadmin correctly pointed you to the PESA study which quantified exactly what you’re talking about. At age 50, around half of people have measurable coronary plaque. Some people are unlucky. Autopsies of soldiers who die in wars in their 20s have found early atherosclerosis. Children of parents with familial hypercholesterolemia can develop atherosclerosis before the age of 10.
For what it’s worth, I’ve talked with the lead author(s) of the PESA study series, and all of them told me that targeting below 50 mg/dl is better than following guidelines of 100 or even 70. Lower and earlier is better, and we haven’t identified a single reason why doing this would be a problem.
I am really curious about this. What’s the logic here?
As for the rapid increase in CAC, it sounds alarming but you can consider it as a good thing because it means the soft plaque you already had is stabilising. Generally, soft plaque is more dangerous because it likes to rupture, and calcified plaque is more stable.
As for the HBA1C% I am sceptical that 20mg Rosuvastatin would raise it to 6.3-6.7%. Statins can definitely cause a bit of insulin resistance, but I don’t think it’s common that it would affect it as much as your numbers.
Do you exercise? In my experience, resistance training (lifting weights) is the single biggest thing to keep my blood glucose and HBA1C% down.
I’m sitting at 58 ApoB, and I’d really like to drop 6 to 52. I also take Bempedoiic acid and Ezetemibe as well. So going to 4 mg of Pitavastatin is the best course for me.
Sad news. I just found out a ex-colleague of mine died of a heart attack this month. He was 39 yo and leaves a widow and 3 yo daughter. He was moving house and complaining about a lot of stress. I guess he had a lot of plaque he didn’t know about. But, man, 39 and having a life-ending coronary just seems so wrong…
While the average age for a first heart attack is roughly 65.5 years for men and 72 years for women, heart attacks are increasingly occurring in younger adults, with about 1 in 5 now happening in people under 40. Rates are rising in those under 55, particularly among Black women.
Wow - so sorry to hear about this. I’ve never heard of a heart attach happening at such a young age. I wonder if it might have been something congenital.
True, I used to think sub 80 is ok, but now I’m fully onboard with the sub 50 idea. I’m currently working towards that goal, and so far, so good (from 124 to 72 in 6-7 months on 2mg Pita, and 10mg EZe) still ways to go. Will check my markers in 6 months again and adjust accordingly.
Err… maybe? Or more combatively: nah. This is common conventional wisdom, which has its place, certainly, and in many contexts. That’s the thinking behind “several low dose classes of agents for BP control, instead of high dose one class” and other conditions. But it’s easy to fall into just repeating well worn cliches that may not obtain in all contexts. I think it’s worth pushing back against in this case for the sake of general awareness.
Specifically regarding statins, it’s true that as you go up in dose, you see diminishing returns in LDL-C lowering while increasing side effects. But does that mean lower doses of statins should be taken all other things being equal? Far from it, because of a fundamental reason - statins do far more than lower LDL-C (or ApoB in general). Throw the phrase “pleiotropic effects of statins” into PubMed, and look at scads of studies. You’ll pull up tons of interesting studies vs other CV effects (unrelated to ApoB), where statins are beneficial, vs cancer, vs rheumatoid arthritis and so on, too long to list. On the whole, statins are remarkable drugs with a very, very wide effect profile. And because of that, you may actually want a higher dose. It’s similar to the case of BP meds - yes, if your sole aim is to control BP, it’s a good approach to take low doses of several meds of different classes: ARB/ACEi, diuretic, CCB etc. But you may be roughly within the upper range of normal BP and take a BP med for other reasons than lowering BP - as is my case. I take a single med telmisartan, not because I simply want to lower my BP from my normally SBP 120-130 DBP 70-80 to 100-110/60-70, which I do want, but I’d take it anyway even if my BP was already in that range (as long as I don’t end up hypotensive!), because ARBs such as telmisartan (and prospectively olmesartan), have pleiotropic benefits. And those benefits happen to show up in the higher dose range: in this case the highest dose 80mg - which is what I take daily. And it’s the same as with statins - your biggest BP drop is from 20-40mg, and only marginal decrease going to 80mg and nothing at 160mg. But precisely because the pleiotropic benefits show up prominently (and for some just) only at higher doses, you may end up with a single med and at a higher dose.
I have often said, that even if my lipids were within range, I’d still elect to take a statin exactly for all those pleiotropic benefits - it’s that good.
Of course you have to look at your total situation. Are there going to be side effects? Based on my personal medical profile, I picked pitavastatin because the side effects profile is very favorable for me (no glucose disregulation, no elevation of Lp(a), no suppression of coQ10 etc.) while the other benefits are very prominent. And I do want the highest dose marketed 4mg.
Bottom line: I disagree that the lowest dose of statin is the most bang for the buck - that’s only true of one narrow aspect (LDL-C lowering), with possible side effects elevation. A careful choice of which statin to take and at which dose might lead you to a particular statin at a particular dose based on your individual medical profile, goals and risk tolerance. YMMV.
I hope so. Been taking it for 5+ years, despite thousands of dollars in cost. Even only strength train once a week due to a study I thought I saw that the antioxidant properties of ginger counteract endogenous antioxidant production of strength train
A good new cardiovascular measurement company… recommended by a doctor here at Vitalist Bay. Its available already in Europe, but not yet in the USA.
Maybe, but I also need to respond with a “nah”, haha. The LDL-C lowering aspect is very well proven to reduce cardiac events. It’s probably the strongest drug trial evidence that we have in the whole cardiovascular or longevity fields, period. So I agree that most people should take a statin, since CVD is the number one killer by far. However, any supposed pleiotropic effects are much less well demonstrated. Most of the claims have arisen from observational studies, correlations etc.
I did do some searching, and found some mixed results, which are mostly negative. And the better quality the study, the more likely it is to be negative.
Emerging views of statin pleiotropy and cholesterol lowering - PMC - nice review article here which takes a sceptical tone.
Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression-Brief Report - PubMed - this study points out that cardiovascular benefits seem to be derived entirely from LDL-C lowering:
For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71-0.84) with an intercept that was indistinguishable from zero (intercept, -0.0032; [95% confidence interval, -0.090 to 0.084]; P =0.94), indicating no pleiotropy."
However, there is definitely some statin benefit on venous thromboembolism (Rosuvastatin for the prevention of venous thromboembolism: a pooled analysis of the HOPE-3 and JUPITER randomized controlled trials - PubMed), but I don’t know whether we’d strictly call it “pleiotropic” since it’s probably related to lipoprotein lowering.
For cancer, If you look purely at observational results, they are very, very sexy and appealing:
Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank | eLife - this mendelian randomisation study found a strong link between HMGCR variants and cancer incidence, but not between other lipid-modulating genes:
Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65–0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9 , LDLR , NPC1L1 , APOC3 , LPL ) were not.)
That’s fascinating, and there’s at least some plausible mechanism there.
Observational data are also outrageously sexy: (Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals - PubMed)
A meta-analysis of 55 articles showed that statin use was significantly associated with decreased risk of all-cause mortality (HR 0.70, 95% Cl 0.66 to 0.74) compared with nonusers. The observed pooled estimates were retained for cancer-specific mortality (HR 0.60, 95% Cl 0.47 to 0.77), progression-free survival (HR 0.67, 95% Cl 0.56 to 0.81), recurrence-free survial (HR 0.74, 95% Cl 0.65 to 0.83) and disease-free survival (HR 0.53, 95% Cl 0.40 to 0.72).
Cancer-specific mortality of HR 0.6 in cancer patients is insane. However, when we see a result like that our first thought should be that it’s way too good to be true.
If we look at actual interventional trials, the results are much less positive, unfortunately. The association of statin therapy and cancer: a meta-analysis - PMC
“This meta-analysis comprised thirty-five randomized controlled studies. Twenty-eight included studies reported cancer incidence, and eighteen reported cancer mortality. The pooled results indicated no reduction in cancer incidence with statins compared to placebo [OR = 0.99, 95% CI (0.95, 1.03)]. In addition, statins did not decrease cancer mortality [OR = 0.99, 95% CI (0.91, 1.07)]. This study also performed a number of subgroup analyses, which showed no effect of statins on cancer subtypes such as genitourinary and breast cancer. Neither the type of statin nor long-term treatment with statins had an effect on cancer incidence and mortality.”
I think if there was an effect, it should be detectable in this sort of study.
There also a meta-analysis here of studies which used statins alongside conventional treatments for cancer, and found no significant effects: Statin therapy in the treatment of active cancer: A systematic review and meta-analysis of randomized controlled trials - PMC
The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07).
So statins don’t seem to be useful as a treatment for cancer, at least.
For prevention, maybe there some signal, but it’s only weak, circumstantial evidence. Obviously there isn’t any sort of RCT where people are given statins solely for cancer prevention, but Claude (LLM) tells me that for all the major statin trials in CVD, they did actually use cancer as a secondary outcome, and all of them failed to show an association (either positive or negative). If you pool the data, that’s around 170,000 participants, across 27 full RCTs, and no association:
Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy - results are as negative as results can ever be:
Cancer incidence RR was 1.00 (95% CI 0.96–1.05) and cancer mortality RR 1.00 (95% CI 0.93–1.08); in the trials of more versus less statin, cancer incidence RR 1.00 (95% CI 0.93–1.07) and cancer mortality RR 0.93 (95% CI 0.82–1.06).
In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).
That analysis was 2012, and we haven’t done many statin trails since then, since giving people placebos is unethical nowadays after statins were proven so effective.
However, one newer trial (HOPE-3, Rosu 10mg vs placebo) came out in 2016, looking at younger (well, 55+) people without CVD. i.e. representing many people on this forum, I think. The trial showed a HR of 0.76 (95% CL = 0.64 to 0.91; P=0.002) for cardiovascular outcomes, which was statistically significant and no huge surprise. They also tracked cancer as a secondary outcome. If we use the numbers from the study and approximate the relative risks (which the authors didn’t do since this was only a secondary outcome), we get:
Cancer: Event rates: rosuvastatin 267/6,361 = 0.04197 (4.20%); placebo 286/6,344 = 0.04508 (4.51%). RR = RR ≈ 0.93 (95% CI 0.79–1.10)
So that’s a small reduction in the Rosu group, but negative overall. We can also look at total deaths:
Total deaths: rosuvastatin 334/6,361 = 0.05251 (5.25%); placebo 357/6,344 = 0.05627 (5.63%). RR ≈ 0.93 (95% CI 0.81–1.08)
Obviously in this younger-ish population the number of cancers and deaths is relatively small. But there’s still no clear cancer-preventing effect here. For CVD outcomes, there were 650 total events, and a big advantage to the Rosuvastatin group (281 + 369). But for cancer incidence there were 553 total events and no advantage to Rosu (267 vs 286). That looks like a very strong sign that there is no prevention benefit, at least in the time frame of this sort of study.
If we really want wiggle room, we could claim that 5.6 years is too short to see an anti-cancer effect, and that’s possible, but it’s clutching at straws IMO.
If there’s some strong evidence out there which I’ve missed, please do share and I’m happy to change my mind.
For rheumatoid arthritis, I assume you meant this study: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)16449-0/abstract
These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.
But it’s a small study, only 116 people, for 6 months. They saw changes in some biomarkers and disease scores, not the actual disease progression. And those numbers pale in comparison to actual treatments for RA.
A later study using a health insurance claim database (Is there an anti-inflammatory effect of statins in rheumatoid arthritis? Analysis of a large routinely collected claims database - PubMed) did not find anything in ~40,000 RA patients and statin users:
These data do not show any beneficial effect of statins in reducing disease inflammation in RA patients.
And there were other RCTs of statins for non-LDL-lowering indications:
Aortic stenosis: SALTIRE (atorvastatin), SEAS (simvastatin/ezetimibe), and ASTRONOMER (rosuvastatin) - all failed to show effects
Atrial fibrillation and post-surgery: STICS 20mg Rosuvastatin) - failed to show effect
COPD: STATCOPE trial (simvastatin) - failed to show effect
So overall, I totally agree that statins are good drugs (I take 10mg Rosuvastatin per day), but we also have to consider that in this thread alone we’ve also had many people saying that they have myopathy, and several members can’t or won’t take them at all.
So, if there’s a choice between taking a low dose or taking none, people should generally prefer the lower dose IMO. And if you’ve got people with LDL-C sitting at 80, I still think it’s generally better to add a second low-dose medication to get that down to 50, rather than doubling up their statin at the risk of adverse effects which make them stop entirely and lose all benefits. I definitely can’t see a strong motivation for taking statins for cancer prevention or anything else, based on the evidence above.
Hey, relaxedmeatball, fantastic post and a real pleasure to dig into a topic with knowledgable posters! That’s one of the the best parts of the site 
!
You rounded up a whole bunch of papers, and I want to do it justice by reading them carefully (though some of them I’m already familiar with) rather than responding off the cuff. That’ll take me some time to digest and then give my perspective in response.
Just as a preview/heads up, my approach to statin pleiotropy is from a different direction: ACM - All Cause Mortality. When talking about drug pleiotropy in general, people want to hear concrete effects on known killers, CVD, cancer, neurodegenerative diseases etc., stuff that’s of immediate identification. And that’s usually what I also throw out when asked: cancer, rheumatoid arthritis etc. - it’s what people expect.
The problem is that this is not how most pleiotropic effects work - the effects might be minor in some contexts, like cancer, or say NDDs, and so on, and can only be identified in trials with enough power and duration, which is one reason why you have endless controversies and back and forth studies on whether statins help with cancer, dementia and so on, or in fact hurt. That’s quite natural - any drug has a primary indication where the effects are going to be stronger, and everything else is going to be minor, when that doesn’t happen, the indication can change altogether to what is the strongest effect actually observed, never mind the original indication as in the example of viagra.
Therefore instead of trying to nail very specific morbidities, my thought was to look at ACM - because ACM might capture the global effect of a drug (here statin) at a much lower power and therefore potentially more trials might be eligible. If statins are good for, say, 20 conditions, then bunching them altogether in the ACM number is easier to see than looking at each of the 20 separately - your cohorts can be smaller and so more trials can be used.
Furthermore, many pleiotropic effects are not easily resolved by concrete morbidities. As an obvious example, if the rapamycin slows down the aging rate, then all you will see is not necessarily lower numbers of specific morbidities, but simply a postponement of when they occur and therefore delay age = delay disease, not “eliminate” or “cure”. But that’s still very beneficial - except how do you capture that? Best seems to me, is through ACM (imperfect as it may be).
Ultimately, we are looking for help with healthspan and lifespan - hence ACM, who cares is statins help with CVD if they cause earlier death through cancer. What matters for total healthspan and lifespan is - does the drug affect ACM. And many benefits/harms might occur at some cellular level not easily captured by a defined pathology - we see that in the recent thread on bone resorption drugs where the ACM is lowered by 28%, but nobody can nail down which concrete pathologies are affected (speculation is all over the place, including atherosclerosis). So in order to capture all those other effects which might fall outside of the well defined pathologies of cancer, RA or NDDs, it seems like ACM is a useful metric.
So that was always my approach with statin pleiotropy - ACM.
That doesn’t mean I don’t pay attention to specific diseases, but - and here I freely admit to bias - unfortunately in my reading I focus on areas that are of relevance to me, and therefore might be a very thin slice of the pie. If I see a study “in African American women” - I skip right over it. I’m not an African American woman. I don’t do this simply out of selfishness, but because time is limited and I must focus on that which might yield me the best returns. So, as an example, when it comes to cancer, I’m going to look at statins and prostate cancer, but ignore endometrial cancer or PCOS etc. That’s a limitation of my perspective - I therefore cannot claim any comprehensive scope, but rather a pretty limited one.
Anyhow, I’m going to dive into the studies you posted and respond in time. Thank you for your comprehensive answer!
So sorry to hear that. The problem is that young men don’t pay enough attention to their health problems and don’t seek help. My son is in that age category and it takes some effort and patience to push him to do at least an annual physical. He had some labs done but his PCP somehow skipped some important tests. They were eventually scheduled after some exchange of emails. Guess what? It showed very low Hemoglobin and other markers outside normal range. Then they measured Ferritin and it was 9! It was the answer to my son’s low energy and fatigue. He thought that it’s just work, kids, life, etc. and dismissed symptoms he’s been having for some time.
