I am a Hospitalist and come from a health promotion/ disease prevention background. My blind devotion to this mindset has changed considerably with the recognition that net harm may well come as we look to intercede on a younger population, branding the well with pre-illness. John makes a cogent argument here but I would draw these conclusions with great caution. The absolute versus relative risk reduction paradox lives on.

Expand full comment

Do we just ignore the risk inherent in the drug itself?

Expand full comment

Not really. Note that I have no medical training, or even much interest in medicine, so I could well be wrong on this. But it seems to me that it is clearly implied that the article talks about *net* change in life expectancy. Aiui, a change in average life expectancy of X months, by definition, already includes any reduction in some individuals.

Now, the article is limited in that it only addresses length of life and not quality of life. But those two usually go together, and there's only so much you can cover in a short article, especially one that remains comprehensible to non-experts. Not to mention that measuring quality of life is incredibly complex, and I'd argue inherently subjective. So this should not be taken as criticism, just as a point on which a future article could expand.

Expand full comment

John, I agree with you that primary prevention needs to start earlier in life, BUT the focus should be on the more significant drivers of ASCVD, not cholesterol. The cholesterol-heart theory is a logical fallacy that has been perpetuated for decades.

If cholesterol causes heart disease, then fasting and avoiding sugar and junk food should cause heart disease because that often raises cholesterol, particularly LDL.

Statin trials inadvertently miss a major confounder, insulin resistance, due to the reliance on a glucose-centric metric. LDL....as exciting as it is, with the ability to drive it into the toilet, lacks terrain thinking.

It represents a reductionist lens with which we approach the concept of atherosclerosis causation and prevents the expansion to a more holistic approach; whereby a simultaneous interplay of hormones and the normal state of play of the human body is considered.

You see, insulin resistance is a huge driver generally of high ApoB particle numbers – so the much-lauded correlation between ApoB and poor outcomes…could be mainly due to this aspect. Tricky that. Even after decades of research, I don’t think there’s any data available that tracks ApoB outcomes – specifically when all the other metrics are great, where there is absence of disordered lipid metabolism (either genetically or acquired).

Additionally, the atherogenicity of apoB is not uniform. LP(a) IS AROUND 6-FOLD GREATER THAN THAT OF LDL ON A PER PARTICLE BASIS. Remnants are 5-10 times more atherogenic than LDL. Guess what condition raises remnants? Insulin resistance!

Here are some studies that are relevant:

Effect sizes of low HDL-C and high HDL-C in conjunction with varying levels of TG and LDL-C in the Framingham Offspring cohort showed that LDL levels were irrelevant when TG<100 and high HDL (metabolically healthy).

In the WDHR, 38.7 mg/dL higher LDL-C level was not significantly associated with ASCVD risk in those with CAC=0, whereas it was associated with an 18% increased risk in those with CAC>0. To further support that the presence of coronary atherosclerosis modifies the LDL-C–associated risk for events, a very high LDL-C level (≥193 mg/dL versus <116 mg/dL) was associated with a substantial increased risk of MI and ASCVD in those with CAC>0, whereas no association was found for those with CAC=0. This is in line with previous results from the Multi-Ethnic Study of Atherosclerosis, in which LDL-C level was not associated with future events among asymptomatic individuals with CAC=0 followed for up to 16 years. Indeed, given that atherosclerosis is a multifactorial disease with numerous known risk factors as well as genetic determinants not all patients will develop atherosclerosis despite elevated LDL-C levels. Heterogeneity in the association of LDL-C with coronary artery disease is an inconvenient problem for the "LDL causes ASCVD" crowd. This heterogeneity has also been found in the UK Biobank across the polygenetic background with no association between LDL-C level and coronary heart disease in those with low polygenic cardiovascular risk.

In CLEAR Outcomes study, "Inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC." Also, there was no evidence of an association between LDL and cardiovascular death or all-cause mortality.

I have some comments about the studies you reference. There are some irregularities worth noting in the imaging study. There was a high prevalence of central obesity, dyslipidemia (atherogenic), which as stated above, would be consistent with insulin resistance and drive increases in LDL, yet the HOMA-IR was normal. Second, the difference between LDL in the progressors and regressors, was clinically insignificant (136 vs 129).

MR studies rely on strong (often unrealistic) assumptions. One of the many problems with MR is pleiotropy. PCSK9 for example is expressed in many cells and tissues with roles far beyond controlling LDL levels.

Even the supporters of MR have expressed the need for caution. For example, in his recent Editorial, Robert Hegele stated: "Is the assumption of no underlying pleiotropy for any MR that uses common variants ever valid? . . . (1) no scientific method is infallible; and (2) circumspection and vigilance are needed when interpreting MR data." Biology is indeed complex. But this complexity is exactly why we need a better understanding of the disease and its mechanisms, and better controlled studies (with fewer assumptions). These goals are not achieved by MR.

Lastly, a few words about FH. No LDL-C difference exists between FH individuals with and without CVD. No cholesterol-lowering trial has lowered the risk of CVD of people with FH. There are other possible causes. For example. it has been demonstrated that among FH individuals, several factors are

more closely associated with the risk of CVD than LDL-C, and they may indeed be causal.

The commonest and most completely documented are inborn or acquired errors of the

coagulation system and/or other thrombogenic factors, such as increased platelet reactivity.

Expand full comment

This is very interesting for a lay person to read. Thank you. I am 67 and I’ve been told by my internist to begin a statin but another year has passed and I have not started it. My weight is very healthy and I walk about 5 miles a day and do strength training and I know that I am possibly taking a risk but so far I just seem to avoid this pill because I guess I am worried about some kinds of side effects.

And my dad is 96 and healthy except for his mild dementia and my mother made it to almost 85.

I know that I am rambling here…

Your article makes me reconsider my reluctance. Thank you again.

Expand full comment

A good reason to look at each patient as an individual. It sounds like you have good genes and live a healthy life.

Expand full comment

A couple of immediate red flags come up here. The first is that almost all the figures are given for relative risk reduction. And extrapolating those over a prolonged period is purely speculative. The second problem is that the graph presented showing the separation between the cumulative end points over the 6 years period of the study is deceptive. The y axis shows percentage of events from zero to twelve percent. Put these lines on a graph with the y axis from zero to one hundred percent and it would be difficult to see the small degree of separation. This is a trick that was first described in the classic text How to Lie with Statistics. The caption underneath the graph says that it was from the West of Scotland Coronary Prevention Study (WOSCOPS) published in the New England Journal of Medicine in 1995. This is one of the five major studies of statin drugs that I reviewed and made a table of comparative results included in my book "The Cholesterol Delusion" written in 2010. I no longer have a copy of that article to check for the graph depicted here but the figures I reported showed a total mortality of 3.2% for those given provastatin and 4.1% for the controls for a real risk reduction of 0.9%. Cardiovascular Mortality was 1.6% for controls and 1.2% for the drug group. Nonfatal coronary events were 6.2% for controls and 4.3% for pravastatin for a whopping difference of 1.9%.

In my verbal summary of the WOSCOPS data I wrote: "The West of Scotland Coronary Prevention Study (WOSCOPS) was a primary prevention trial that enrolled more than 6000 healthy males with elevated serum cholesterol levels. The mean cholesterol level for the group was 272 mg/dl. Subjects were randomly assigned to either pravastatin or placebo. After 4.4 years there were no significant differences in total mortality or CHD mortality. There was a slight reduction in NFMI in the pravastatin group." So I don't know why the graph shows data out to six years. Perhaps a subsequent study determined these figures. But regardless of what statistical methods may show a "statistically significant difference", common sense tells us that differences of 1-2% have no practical significance.

Expand full comment

I’m curious as to why European guidelines for statin use in women have changed? It seems relevant to this discussion to bring in long term side effects of statins, especially in women.

Expand full comment

I practiced as did many of my colleagues in rural Texas. There were a few towns that start with the letter L . If you asked an 80-year-old who they live with they would say mom and dad . Their name really should be longevity. Was it the water? Genetics obviously because they're all related. An elderly man complained of new onset angina with exertion. The exertion was throwing Hay (as a New Yorker, I needed an explanation) He would throw 50 pound bales of hay from the back of his truck to the ground. He would get some chest pain after throwing 30 of them, you do the math. So you had genetics, hard work, but you could also add a sense of community, friendship, support, and even religion, perhaps. I would always chuckle at the younger docs who felt if they couldn't practice in downtown Austin they were missing out -they didn't really understand. As an aside after I was injured driving to these clinics, not a day went by when the majority of the patients would not take time out of their visit to inquire about my health. And it was not a platitude. I received a card signed, I think by most of the community, it was an amazing experience. So absolutely there are things you can do as part of your life early on that will extend your life later on.

A lot of those things are not as quantifiable as LDL reduction, but from personal experience, I might argue they are substantially significant .

Expand full comment

Sadly those with “Primary” in their doctor title aren’t doing the basics of this thinking. Drugs last, behaviors first to address the metabolic disease we see all around us. Better eating takes effort like everything else worth doing. Cardio and strength training 6 of 7 days takes effort but obviously worth doing. Do those paying the insurance bills need sticks vs carrots since the adverse outcomes associated with poor lifestyles don’t see to be enough of a deterrent.

Expand full comment

Better eating AND vitamin D3 supplementation, since there is very little vitamin D3 in food, fortified or not, or multivitamin tablets. Please see my comment above and the research articles cited and discussed at: https://vitamindstopscovid.info/00-evi/ .

With white skin, which will become suntanned, it is generally possible to attain the 50 ng/mL 125 nmol/L circulating 25-hydroxyvitamin D the immune system needs with ultraviolet B skin exposure. However, except near the equator, if there was no monsoon, this is not naturally available all year round, so you would need a special UV-B lamp and protective eyeglasses. All such UV-B (ca. 297 nanometres is needed to convert 7-dehydrocholesterol to vitamin D3 cholecalciferol) also damages DNA and so raises the risk of skin cancer.

So this is not a practical, or safe, way to attain 50 ng/mL 25(OH)D all year round.

Those with black or brown skin would need even more UV-B - equivalent to staying out in the African sun most of the day without much in the way of clothing, housing or vehicles. Almost no-one does this any more, for good reason. So, virtually everyone in the world needs vitamin D3 supplementation, from birth (except for infants breast fed from vitamin D3 replete mothers) in order to run their immune systems properly. Food can only contribute a small fraction of what is needed.

Food can help attain the 20 ng/mL 50 nmol/L 25(OH)D needed by the kidneys to hormonally (with a very low level of circulating 1,25-dihydroxyvitamin D calcitriol) regulate calcium-phosphate-bone metabolism. So food to some extent or fortification of food can help with this, but fortified food can never attain the 50 ng/mL the immune system needs.

Expand full comment

Guess I don't see your change in thinking as very consequential. From the patient's point of view it doesn't matter whether the old or the young get the greater benefit from an intervention, it only matters how much benefit he/she gets. And regardless of how you process and present the data, from a patient's point of view it is still the lottery choice: a small chance of a large benefit for the small price of taking a lot of pills. Even what the experts consider a high risk of 5%, let's say, of a primary outcome over 10 years implies a 95% chance of absence of the primary outcome, which might very reasonably be accepted by a sensible individual.

It is supportive to the proposition that the intervention is valuable that the effect persists and appears to increase with time, but to be rigorous we can't forget that many such observations have not stood up to longer periods of observation.

For me the needle hasn't moved. Young or old you are faced with very close to the same choice. Of course it is right that it is your choice to make.

Do you ever think about how, just like the phenomenon that the house always wins at the blackjack table or the lottery wheel, the payers (and the manufacturers} always win when the risk-reducing intervention is applied? The small individual benefit magnifies to millions of dollars in cost savings for payers. I worry that patients' autonomy might be threatened by this at some point.

Expand full comment

Vitamin D3 and potassium supplementation are important non-drug preventives for CVD. More details follow.

Mendelian randomization is a very dodgy research technique. Those with the data like to do it, but what does it really mean in physical reality? If the signal is really strong and the assumptions valid, it might be OK.

Statins are controversial. This is a huge debate which I have not tried to properly evaluate, but here is a starter: https://doctoraseem.com/the-great-statins-divide/ .

Cutting out smoking is a no-brainer.

Drugs to lower blood pressure have all sorts of problems. It would be better to reduce sodium intake somewhat and to increase potassium intake, though this needs to be done gradually over the day. Time release potassium gluconate tablets are one approach. I use potassium gluconate in water, four times a day, 600 mg in each drink. This probably doubles my potassium to sodium ratio, however this is not a recognised treatment and there is a risk of raising potassium levels excessively with such drinks, and so upsetting the heart. I mention this out of interest, but I don't know any doctor who recommends it.

The purpose of supplemental potassium is to increase the potassium to sodium intake ratio without eating large quantities of the typically starchy vegetables and fruit which have the most potassium - with resultant much higher calorie intake.

The reason for boosting the potassium / sodium intake ratio, without drastically reducing sodium intake (very difficult and probably unsafe, as best I can tell) is that this is proven beyond doubt to lower the risk of hypertension and, independent of hypertension, to lower the risk of stroke. Please see the research articles cited at the start of these very preliminary notes on sodium and potassium: https://aminotheory.com/cv19/kna/ .

One of these is https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1106080 ". . . a higher sodium-potassium ratio is associated with significantly increased risk of CVD and all-cause mortality, and higher sodium intake is associated with increased total mortality in the general US population.".

Another is: https://journals.lww.com/jhypertension/Abstract/2015/08000/Daily_potassium_intake_and_sodium_to_potassium.3.aspx https://sci-hub.se/10.1097/HJH.0000000000000611 "Patients with elevated blood pressure may benefit from increased potassium intake along with controlled or decreased sodium intake."

Most doctors and almost all immunologists are unaware that the immune system needs at least 50 ng/mL 125 nmol/L circulating 25-hydroxyvitamin D in order to function properly. This is 2 to 10 times the level of most people, far from the equator, who do not supplement vitamin D properly (or only in the minuscule amounts recommended by governments) and who have not had recent extensive ultraviolet B exposure on ideally white skin.

Neither vitamin D3 nor 25(OH)D (produced in the liver from vitamin D3 cholecalciferol) are hormones. Good supplies of 25(OH)D are required by many types of immune cell to run their intracrine (inside each cell) and paracrine (to nearby cells) signaling systems, which play a crucial role in each cell's ability to respond to its changing circumstances.

This means that the great majority of the population have their immune responses which are weaker and less well regulated (in the case of potentially deadly cell-destroying inflammatory responses) than they would have if they supplemented vitamin D3 properly, such as, for 70 kg body weight without obesity, about 0.125 mg vitamin D3 a day (5000 IU) on average. Please see the very extensive research on vitamin D and the immune system cited and discussed at: https://vitamindstopscovid.info/00-evi/ . This includes the above recommendation for vitamin D3 supplemental intake, as a ratio of body weight, with higher ratios for those suffering from obesity, from New Jersey based Emeritus Professor of Medicine, Sunil Wimalawansa: Nutrients, 2022: https://www.mdpi.com/2072-6643/14/14/2997 .

Not mentioned at the 00-evi page, yet, is this 2021 article: Dai et al. "Association of Serum 25-Hydroxyvitamin D Concentrations With All-Cause and Cause-Specific Mortality Among Adult Patients With Existing Cardiovascular Disease". "Among patients with existing CVD, increasing levels in serum 25(OH)D were independently associated with a decreased risk of all-cause and cause-specific mortality. These findings suggest that elevated serum 25(OH)D concentration benefits CVD patients with vitamin D deficiency.".

The four ranges of 25(OH)D level were all low compared to the 50 ng/mL 125 nmol/L the immune system needs: less than 10 ng/mL, 10 to 20 ng/mL, 20 to 30 ng/mL and greater than 30 ng/mL.

There are a plethora of reasons for attaining at least 50 ng/mL 25(OH)D. It is easy, inexpensive and safe to do so. Reduced cardiovascular disease is one of dozens of reasons for attaining this.

So why would the first line of prevention be a bunch of drugs? Ignorance of these nutritional problems and the fact that drugs are more profitable, better promoted, and overly favored by too many doctors and patients.

Expand full comment

As always, very insightful post. But the subject is still tricky.

I put it this way to patients:

It’s a lottery. The prize is get out of jail card. You buy a ticket a day. The more tickets you buy, the more chances of winning. You still have 90% chances you don’t win anything but if you do, you get a few extra years of life. The kicker is: you will never know if you won or not. You choose.

The concept of disutility, also explored by Prof. Francis and colleagues, is useful to consider here too.

Expand full comment

Thank you for that. You help exemplify the notion that thoughtful MDs care too about getting people pills early. Because linear time somehow makes the complex adaptive being, the same as all others so simple measures can be shown in linear way.

American care is about the tangible drug. More drugs are better because the MD can assume a person has symptoms in a lottery of illness. And that lottery is equated to life on a normal curve.

Cool story. The logical fallacies in this are wonderful fuel for another book. And questions that need to be held open without answers, for the whole series.

Where are the data on consequential harms? .Why are there studies showing that statins effects disappear in healthfully adaptive beings? Where do MDs monitor the person as they self-regulate to compensate for drugs’ bio altering effects given chronic dosing and related nutritional depletion over time?

Not enough time for a good MD to do that: So in the lottery, someone calls bingo as there’s justification for referral to another expert to turn the bad effects of one drug into a case of poly pharmacy. Great. Now we can blame the patient for Kate life comorbidity. They’re not called persons in those mass casualty patient studies. Like death is the only real game rule in this win-lose lottery.

Where are the studies showing how the person varies by time of day and situations that differ one location and person to another?

Statins will always be best from birth for as long as can be if you flip assumptions about healthy biology to presume people are walking diseases (symptom and diagnostic sets) rather than understand cause and effect for the different components of symptom or end point measures?

Similar thinking on any other study built on disease data can justify preventive treatment for everything from birth assuming researchers are effective in care, blind to the person and thinking they experience the same generic lottery of life. Forget quality of life or health span!

But it’s not just the product of expert habit called standard practice. Expert media is controlled by groupthink. Call it Leet review if not censorship.

It’s the same for C19 countermeasures. Because we can’t see - we don’t know where to look to see - the presentstion of global whole population data showing excess mortality and early death is statistically significant on a dose dependent basis that is exponentially rising with age. But the significance holds across borders and differences in income. You see some preventive numbers bias towards equitable use of ‘preventive’ treatment in lower income or less educated populations who feel they win the lottery by taking it at or before birth.

But in the America’s and Britain.., studies are just not seen or allowed to be published despite peer review and acceptance for publication. Because professionals wielding the same numbers don’t want to be proven wrong on ill-presuming more is always better.

Can we tell jokes about give a boy a hammer and he can always count new need for hammering nails?

Happy Thanksgiving. Thank you for caring about the person defined as patient who is always sick and immune responses are described too as if the disease. .

Life is precious. All best wishes for you as a person, protecting the adaptive capabilities life requires in you to survive in a world where you presume it is all just a lottery. Because that’s required to uphold the post-marketing assumption that safe and effective drugs in clinical trials are always better than unsettled science about cause of death later on.

May Life and Health be with you..

Expand full comment

I am on statins now and am wondering if the low grade leg pain and quadriceps weakness are due to my age (69) or the statins....how long of a trial off the statin would be appropriate to see if I am suffering these side effects?

Expand full comment

Many complain of aching muscles and joints while on statins. My impression is that the symptoms usually go away within 2 or 3 weeks. Then you need to rechallenge by resuming the drug and see if the symptoms return. I have very little direct experience since I only prescribed them one time during the 15 years or so that statins came onto the market before I retired. I did see a number of patients who were prescribed statins by other doctors and wanted a second opinion. Most had diffuse aches and pains and just "felt terrible". Often they would say that they didn't even realize how bad they felt until they stopped the drugs.

Expand full comment

My LDL went down to a “desired” level and I can’t say that I had a quick onset of the apparent side effects, but just have had a gradual onset. Plan to go off it for two to three weeks and see if symptoms go away. If they do, may try it on an every other day schedule.

Expand full comment

"The advantage of lifestyle intervention is that the unknown unknowns from a taking a drug for decades are absent."

Yeah, no. That's not how science works, or reality, because it assumes that both the studies and the reporting are unbiased and they simply are not. Scientists should stop pretending that because there's been some studies, we have this level of knowledge. By making this statement you act like these studies and a simple history of people taking drugs have removed all unknown unknowns and that's intellectually dishonest.

It removes all the unknowns that it measured and that the statisticians (if they were not baited by the typical incentivizing that goes on in research, which is doubtful) can report. I do deeply appreciate you acknowledging the cancer risk. That's a known unknown. There's a lot of others that are not and will never be reported by researchers simply either because it's not in their framework OR, unfortunately, they have institutional blinders on.

Expand full comment

The advice is reasonable and I appreciate the writing. Thank you.

My questions are how far to take the new line of thinking? Using statins as an example: some believe that lowering seemingly healthy young people’s LDL to neonatal levels and keeping it there for decades is warranted, for all of the reasons mentioned in this substack. Others believe that extrapolating that far outside the dataset is risky; certainly the interventions may bear fruit but we don’t have solid evidence of that, and there is always a possibility of harm - although we lack evidence for that as well.

So, where do you draw the line? What group of people would you be unwilling to prescribe a statin for, assuming the patient requested it?

The other statin-specific comment I will make is this: all the data I have ever seen show a reduction in CVD with lower LDD. All of it. However, as a patient I care about quality of life (QoL) and duration of life - i.e. - all cause mortality. The question when prescribing a statin to a seemingly healthy 25 year old with normal LDL is: what is the effect on all-cause mortality (ACM) and QoL?

I think too often cardiology cares only about CVD, and if something reduces CVD they are happy and stop thinking. But QoL and ACM are what matters to patients, not CVD. So we need to ensure we don’t have blinders on. But the substack did not mention ACM when discussing statins at all. Isn’t this a concern?

Expand full comment

Correction: I wrote LDD in one place, I meant LDL.

A comment from Twitter on Dr. Mandrola’s substack: “Dr. Mandrola, fantastic essay. As a vascular surgeon, I could not agree more. I actually recommend statins -I know that that was not the sole purpose of your essay - in almost everyone, because of the pleiotripic anti-inflammatory effects, admittedly, in vitro. The rationale that you’ve outlined, and I know it was not purely about statins, is exactly the reason I do so.”

“actually recommend statins ... in almost everyone” very common thinking. The questions are: who should be treated? “almost everyone”??? In what populations can we infer a benefit for QoL and ACM? Hard questions in my view.

Expand full comment

Please read my comment

Expand full comment

I am an 80 year old male with pre-diabetes (A1c = 5/7%), but a coronary calcium score of zero. They took me off my statins, as they said I don't have enough time to develop plaques. My LDL is less than 100mg/dl.

Expand full comment

Mortality figures for WOSCOPS study in comment below were reversed. Should read 3.2% for pravastatin and 4.1% for controls.

Expand full comment