What if Medicine Were Taught Like a Science, Part 2: The Diet-Heart Hypothesis and Cholesterol

Yves here. To add some anecdata to KLG’s discussion about how statins became the magic bullet for lowering cholesterol, seen as a key way to reduce heart disease. First, for those concerned about dietary sources of cholesterol, it appears that humans make cholesterol from carbohydrates, and not fats. The ketogenic Atkins diet (which I don’t regard as healthy on a long-term basis but is a useful expedient for weight loss, since your body makes blood sugar way less efficiently when in a ketogenic state), where users get to eat lots of meat and eggs and fats but skimp on carbs, reduces blood cholesterol levels. But is that actually such a great idea? In women, the total cholesterol level correlated with the lowest all-cause mortality is 270. Similarly, and again for women, low LDL levels are correlated with higher stroke risk.

By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health

The first post on the Diet-Heart Hypothesis covered fat and carbohydrates (starch, sugar), leaving cholesterol for today. But this fascinating compound was present at the beginning.  A simple version of the first presentation of the Diet-Heart Hypothesis by Ancel Keys can be summarized as: (1) cholesterol level predicts heart disease, (2) saturated fat in the diet increases serum cholesterol levels, and that (3) monounsaturated fats protect against heart disease.

The history of cholesterol and heart disease is covered well by Joseph L. Goldstein and Michael S. Brown in this review from Cell in 2015.  Atherosclerotic plaques were first described in the late 19th century, and early in the 20th century cholesterol was identified as the primary constituent of these lesions.  In 1913 Nikolaj Anitschkow fed pure cholesterol to rabbits, who then developed plaques.

In my reading most descriptions of this work fail to note that the natural diet of a rabbit contains no cholesterol[1], which indicates the cholesterol that makes up as much as 50% by weight of the cell membrane in a rabbit (and all animals) is synthesized de novo from precursors.  It is not clear that these rabbits were studied to determine if they eventually died of heart disease caused by atherosclerosis.  Heart attacks proper were not recognized until the development of electrocardiography by James Herrick in 1919.  Familial hypercholesterolemia (FH) was described and an autosomal dominant genetic disease[2] in 1938.  Those with FH have elevated serum cholesterol and are susceptible heart attacks in middle age.  Brown and Goldstein note the Seven-Country Study of Ancel Keys, fully supports (with a nod to a few quibbles at the margin) the notion that dietary fat leads to an increase in serum cholesterol which leads to coronary heart disease (CHD).

The complex, energy intensive biosynthesis of cholesterol[3] was elucidated primarily by Konrad Block and Feodor Lynen in the 1950s, with the identification of HMG-CoA as the first intermediate committed to the cholesterol pathway.  The enzyme HMG-CoA reductase converts HMG-CoA to mevalonate, starting the cascade of reactions leading to cholesterol.  In the 1970s naturally occurring inhibitors of HMG-CoA reductase were isolated from the penicillin mold.  Now known as statins, the original and derivatives of these natural products were used to reduce serum cholesterol levels in experimental animals by inhibiting HMG-CoA reductase, which led to the upregulation of LDLR and subsequent increased uptake of dietary cholesterol into cells.  It was a natural and logical step to extend these results to the lowering of serum cholesterol in patients with high cholesterol.

Lovastatin (Merck: Mevacor) was the first statin approved for use in humans in 1987 because it lowers plasma cholesterol/LDL and is tolerated well by most people.

The big question was then whether statins reduce the incidence in heart attacks.  The Scandinavian Simvastatin Survival Study (4S) was one of the first comprehensive clinical trials of statins and showed this to be the case, and statins were destined to be blockbusters all around.  4S (1994) enrolled 4,444 patients with CHD/heart attack to test whether Zocor (Merck) lessened the likelihood of future cardiac events in this population.  At the end of the trial, which lasted 5+ years, 8% of the patients in the statin group had died versus 12% of the patients who received the placebo.  Over the course of the study, the statin group had a 91.3% probability of surviving, while those in the placebo group had an 87.6% chance of surviving.

Of the many trials since 4S, few seem to have produced the same level of protection.  Moreover, those who refer to this trial in the biomedical literature, or otherwise use it as positive evidence of the efficacy of statins, do not always note that this trial included patients at very high risk of heart attack, so this demonstration of secondary prevention cannot be used to make conclusions about primary prevention of CHD/heart attack.  While it is not clear that any subsequent well designed trial has produced results this strong, meta-analyses of many trials in the tradition of Evidence-Based Medicine can be made to support the hypothesis.

In a test of statins for primary prevention the AFCAPS/TexCAPS trial (1998) enrolled 5,608 men and 997 women with average plasma cholesterol levels.  Of those in the statin arm of the trial, 3.3% had heart attacks, and 5.6% of those taking the placebo had heart attacks.  It apparently remained unmentioned by the authors that 80 patients in the statin group died, while 77 in the placebo group died.  This can be explained because 63 subjects in the statin group died of non-cardiovascular causes versus 52 in the placebo group.

Nevertheless, the conclusion was confirmation that reducing plasma LDL cholesterol is beneficial.  In another primary prevention test of statins, the ASCOT-LLA trial (2003) enrolled 10,305 subjects with high blood pressure or other risk factors for cardiovascular disease (CVD) but with average/normal plasma cholesterol levels.  These were potential patients who probably would be prescribed statins today.  1.9% of the subjects in the statin group had a heart attack or died from heart disease, while 3.0% of the placebo group died of CVD/CHD.  Thus, the absolute risk of death from heart disease was 1.1% higher in the placebo group.  This was reported as a 37% reduction in relative risk associated with statins, however, which is arithmetically correct.[4]  But what is heard by the public is naturally, “If you have normal cholesterol plus one or more risk factors, you are 37% less likely to die of a heart attack if you take this drug!”  This trial was halted early because of its positive results.  There was no significant difference in all-cause mortality between the statin and placebo groups.

If a drug works, then there should be a dose-response effect, i.e., a higher dose, if well tolerated with no untoward side effects, should work better or faster than a lower dose.  The Treating to New Targets (TNT, 2006) initiative addressed this hypothesis.

In this study of secondary prevention of CHD, either 10 mg or 80 mg doses of atorvastatin (Lipitor) were used to treat patients with CHD and metabolic syndrome.  At the end of 5 years 13% of 10 mg statin group had died, while 9.5% of 80 mg statin group had died.  The absolute risk reduction was 3.5%, which is statistically significant, and the relative risk reduction was approximately 27% (3.5/13).  All-cause mortality in the two groups was 6.3% versus 6.2%, which is not statistically significant.

But this may be clinically relevant, in that the higher dose of Lipitor decreased the incidence/risk of CHD in these at-risk patients, but that decrease may have been counterbalanced by a higher risk of death from other causes?  This study was a post-hoc analysis of the original TNT initiative, “Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease.”  The original included 10,001 patients with CHD and the average, i.e., “healthy,” plasma cholesterol level of 130 mg/dL.  Based on the way I read the results, the plasma cholesterol of the 10 mg group decreased to 101 mg/dL, while the high dose group cholesterol decreased to 77mg/dL.  10.9% of the 10 mg statin group died compared to 8.7% of the 80 mg group (absolute risk reduction of 2.2%; relative risk reduction of 20.1%, 2.2/10.9). Thus, the higher dose of statin reduced plasma cholesterol more effectively, and fewer people died in the high-dose group.

But as noted in the final sentence of the Results summary, “There was no difference between the two treatment groups in overall mortality.”  The entire Conclusion summary: “Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.”  I missed/could not find the absolute levels of alanine aminotransferase in the two populations.  The increase may not be clinically significant, but an increase in plasma liver enzymes is a marker of liver damage.  I will leave it to the reader to parse the meaning of the quotations in bold font.  But in keeping with my ongoing reading in EBM, I am now going to make two long lists, for which I apologize.  The primary authors of this paper are from the following distinguished academic and medical institutions:

From the State University of New York Health Science Center, Brooklyn (J.C.L.); the University of Texas Southwestern Medical Center, Dallas (S.M.G.); San Francisco General Hospital, San Francisco (D.D.W.); Pfizer, Groton, Conn. (C.S.); the Heart Research Institute, Sydney (P.B.); Institut Pasteur, Lille, France (J.-C.F.); Weill Medical College of Cornell University, New York (A.M.G.); Universitätsklinikum Eppendorf, Hamburg, Germany (H.G.); Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); the University of Glasgow, Glasgow, United Kingdom (J.S.); and Emory University School of Medicine, Atlanta (N.K.W.) (pdf, p. 1425)

The study was “Funded by Pfizer.”[5]  Dr. LaRosa reports having received consulting fees from Pfizer, Merck, Bristol-Myers Squibb, and AstraZeneca and lecture fees from Pfizer; Dr. Grundy lecture fees from Merck, Pfizer, Kos Pharmaceutical, Abbott, and AstraZeneca and grant support from Kos Pharmaceutical and Merck; and Dr. Waters consulting fees from AstraZeneca and Pfizer; lecture fees from Merck, Pfizer, and Novartis; and grant support from Merck and Johnson & Johnson. Dr. Shear is an employee of Pfizer and owns stock in that company. Dr. Barter reports having received consulting fees from Pfizer, AstraZeneca, and Sanofi-Aventis; lecture fees from Pfizer, AstraZeneca, FournierPharma, and Sanofi-Aventis; and grant support from Pfizer; and Dr. Fruchart consulting fees from Pfizer and Fournier and lecture fees from Merck, Fournier, Pierre Fabrie, and AstraZeneca. Dr. Gotto reports having received consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, ScheringPlough, Pfizer, Novartis, and Reliant and lecture fees from AstraZeneca, Merck, ScheringPlough, Pfizer, and Reliant and having testified before the Food and Drug Administration on behalf of Johnson & JohnsonMerck. Dr. Greten reports having received consulting and lecture fees from Pfizer, Merck, and ScheringPlough; Dr. Kastelein consulting fees, lecture fees, and grant support from Pfizer, Merck, ScheringPlough, AstraZeneca, Bristol-Myers Squibb, and Sankyo; Dr. Shepherd consulting fees from AstraZeneca, GlaxoSmithKline, Merck, ScheringPlough and Oxford Biosensors and lecture fees from AstraZeneca, Merck, and ScheringPlough; and Dr. Wenger consulting fees from Eli Lilly, Merck, Bristol-Myers Squibb, Pfizer, and Kos Pharmaceuticals; lecture fees from Eli Lilly, Pfizer, Novartis, Merck, Bristol-Myers Squibb, and Kos Pharmaceuticals; and grant support from Eli Lilly, Novartis, Bristol-Myers Squibb, and AstraZeneca. (pdf, p. 1434; emphasis added in both paragraphs)

From where does the evidence come?  This particular paper has been cited 2,444 times in the biomedical literature, so Big Pharma’s return on investment has been substantial.  This approach is bound up in the nature of EBM, covered in the book reviewed previously here, where among other things, the nature of grants from Big Pharma is discussed.  Current (2022) statin guidelines largely remain the same as they were 8 years ago and 30 years ago (Statin Use for the Primary Prevention of Cardiovascular Disease in Adults.  US Preventive Services Task Force Recommendation Statement, here and here,)  Some commentary on the updated guidelines remains on point, noting among other things that statins are cheap (depends on the definition) and a major problem remains that not enough people are taking them.  Also, see here.

This conventional wisdom is based on the biochemistry and physiology of atherosclerosis, abstracted from how people live in a world where food might be a food-like substance, especially what is available to working people in and out of food deserts.

Still, a reasonable citizen might ask, “If heart disease can be prevented by statins, where is the proof after 40 years and hundreds of billions of dollars spent on research, clinical trials, and statins as prescription drugs, and why are we still arguing about this?”

Going back to the 4S Study of 1994, about 88 of 100 people on average in the placebo group died, while 91 of 100 died in the statin group.  Statistically significant, yes, and much more than that for the three whose deaths may have been due to non-treatment with statins.  But if higher plasma cholesterol is the culprit, the level of protection perhaps should be higher?  Statistical arguments can prove the hypothesis, even when the underlying pathophysiology is unknown.  When Richard Doll and Bradford Hill completed their survey on smoking and health among 41,000 British physicians from 1951 to 1954, 789 deaths were reported and 36 of these were attributed to lung cancer.  All 36 of these physicians were smokers.[6]  No statistical analysis required.

But not everyone agrees with the current dogma!  For example, in a commentary this month (October 2022) in JAMA Internal Medicine, Anand R. Habib, Michael H. Katz, and Rita F. Redberg ask if it is “time to curb our enthusiasm” for the use of statins for primary cardiovascular disease prevention: “The updated evidence synthesis found that statins yielded a smaller, but still statistically significant, reduction in all-cause mortality…(but) these recommendations should be considered in the context of a meta-analysis (2010) which enrolled only patients receiving high-risk primary prevention; this study showed no benefit on all-cause mortality with statins (and) the benefit for CVD mortality was not statistically significant…”

More importantly, and this is one of the very few such statements I have encountered in my reading of the primary literature, “There is a difference between statistically significant and clinically meaningful benefit (and) the purported benefits of statins in terms of relative risk reduction are fairly constant across baseline lipid levels and cardiovascular risk score categories for primary prevention.  Therefore, the absolute benefit for those in lower-risk categories is likely small given that their baseline absolute risk is low, which the chance of adverse effects is constant across risk categories.”  Adverse effects such as excess deaths in the statin branch of the trial, perhaps?  It gets even better in this commentary, as noted in comments here last week:

The practice of medicine is an art as well as a science…In the US, about $25 billion is spent annually on statins (but) cardiovascular disease incidence and mortality are the upshot of myriad social determinants.  Although statins lower LDL cholesterol in individuals, investments at the community level to construct a more salubrious environment that enables healthy eating and promotes physical activity are more likely to have widespread multiplicative and pleiotropic effects on improving quality of life.  The 2022 USPSTF recommendations are an opportunity to pause and refocus efforts to meaningfully improve CVD outcomes for all, rather than extol the marginal, likely small, and uncertain absolute benefits of statins for the few in primary CVD prevention.(pdf, p. 1023)

At last!  A multi-level, multi-system view from physicians with a platform of the “Diet-Health Hypothesis” instead of only the “Diet-Heart Hypothesis.”

Finally, my interest in this subject began as I prepared a presentation with the goal of modifying the medical curriculum on nutrition and the social determinants of health to place responsibility for the obesity epidemic where it belongs.  Which is not on the people.  My gloss on the history of the Diet-Heart Hypothesis was surprising to some but well received.  One colleague did remind me that CVD/CHD patients would still be discharged from the hospital with an obligatory statin prescription and the advice to eat a low-cholesterol, low-fat diet and, above all, to take their medicine.  Another colleague sent me references showing that statins are useful because of their anti-inflammation activities.  True, but a healthy, balanced diet that includes fruits and vegetables is also an anti-inflammation diet.  Not only that, research over the past 20 years indicates that obesity itself is a condition associated chronic inflammation.

But I also come back to the essential roles of cholesterol in normal biological membrane structure and function.  Does it make sense to interfere with cholesterol absorption and synthesis when every cell in our bodies depends on cholesterol for their physical integrity?  Then there is the role of cholesterol as the precursor for the synthesis of the steroid hormones –  androgens, estrogens, corticosteroids – without which we would not exist.  It does not make sense that artificially lowering cholesterol levels will have only benign effects.

Cholesterol appeared on the cover of Time magazine in March 1984: “Cholesterol – And Now the Bad News.”  In 2015, the USDA Dietary Guidelines Committee stated:

Previously, the Dietary Guidelines for Americans recommended that cholesterol intake be limited to no more than 300 milligrams per day. The 2015 DGAC [Dietary Guidelines Advisory Committee] will not bring forward this recommendation because available evidence shows no appreciable relationship between consumption of dietary cholesterol and serum cholesterol, consistent with the conclusions of the AHA/ACC report. Cholesterol is not a nutrient of concern for overconsumption. (Original reference can be found here; AHA is American Heart Association and ACC is the American College of Cardiology).

This channeling of Emily Litella has not gotten nearly the attention it deserves.

To be fair, butter appeared on the cover of Time 30 years later in June 2014: “Scientists labeled fat the enemy.  Why they were wrong.”  The difference in influence of Time between 1984 and 2014 is large.

And to his considerable credit, Ancel Keys, who is primarily responsible for the Diet-Heart Hypothesis (which was, lest we forget, eminently reasonable in theory) was himself quoted in The New York Times in 1980: “I’ve come to think that cholesterol is not as important as we used to think it was.  Let’s reduce cholesterol by reasonable means, but let’s not get too excited about it.” (quoted in Gary Taubes, Good Calories, Bad Calories, p. 79)

Which brings us back to my title: “What if Medicine Were Taught Like a Science?”  And no, this does not imply that each medical practitioner must be an historian of his or her profession.  We do not have to be historians or anthropologists to understand and appreciate the history of Reconstruction as presented by Eric Foner or the meaning of anthropology according to David Graeber and David Wengrow.

But just as the pathology textbooks state that Alzheimer’s disease is caused by amyloid plaques and tau tangles, they also say, “The HMG-CoA reductase inhibitors, commonly known as ‘statins,’ are the most commonly prescribed lipid altering therapy by virtue of their potency, tolerability, and impact on reduction of cardiovascular events.”  All mostly true, as far as the statement goes.[7]  But it does not go nearly far enough.

“Evidence-based medicine” sounds a lot like “science-based medicine.”  But that all depends on whose evidence and what medicine, used for whose purpose.  This can only be understood if the science and practice of medicine are taught, not told, with the history attached, at least at the margins.  In any case, the margins are where the most meaningful discoveries are made.


[1] Rabbits are herbivores.  Plants contain phytosterols, which are the cholesterol-like component of cell membranes in plants.  Without getting too far into the weeds, biological membranes are composed of inner and outer leaflets of phospholipids with cholesterol/phytosterol inserted between the phospholipids.  Sterols are large planar (flat) molecules that maintain fluidity of biological membranes while also contributing to requisite local stiffness.  OK, that was in the weeds, but it is also evidence that cholesterol has other functions than to cause heart attacks.  Such as being the starting material for sex hormones.  I have wondered, but not so much as go searching through the literature, what the result would have been if rats, which are omnivores with a physiology very similar to humans, had been used in these initial animal experiments instead of rabbits.

[2] Autosomal dominant: Presence of mutation on one of the paired 22 non-sex chromosomes leads to disease.  In this case the gene encodes the LDL receptor (LDLR) which is responsible for removing LDL from the circulation (LDL: low-density lipoprotein, so-called “bad” cholesterol; cholesterol is not water soluble, so it is transported in the circulation in lipoprotein particles).  A heterozygote for the mutation with half the normal complement of LDLR has markedly elevated serum cholesterol.  Homozygous FH patients complete lack LDLR and cannot clear LDL/cholesterol from the circulation.  Huntington disease is another autosomal dominant disease.  Compare with autosomal recessive traits, which result in disease only if both chromosomes carry the mutated gene, e.g., Tay-Sachs disease.  Most autosomal recessive traits involve enzymes, for which 50% of the normal amount is usually “good enough.”

[3] If you really want to go there, you can start here (registration required) or any good biochemistry textbook.  I once or twice memorized the entire pathway (structures included, with a memory half-life of 60 minutes) so as to regurgitate on exams.  The key, though, is HMG-CoA reductase and its actions in reducing plasma cholesterol/LDL.

[4] Absolute risk and relative risk are often conflated, especially in marketing.  This is covered concisely in Chapter 13 of Fineman’s Nutrition in Crisis.  For example, if on average 1 of 10,000 people treated with a drug do not die from disease X, while 2 of 10,000 people in the same population die if they do not take the drug, the absolute risk of death is 0.01% (0.02%-0.01%, or 1-in-10,000).  The relative risk of not taking the drug is 50%, however (0.01/0.02).  50% is the much more impressive number.  But still, the difference is 9,999 healthy people versus 9,998.  Which is not to ignore the death of that one person, on average.  But if the drug has off-target effects that might lead to death from other causes, the calculation necessarily changes.

[5] A history of Lipitor.  Wikipedia, but the included references seem mostly correct and complete. “Further reading” in this entry is a good place to begin.

[6] Siddhartha Mukherjee, The Emperor of All Maladies: A Biography of Cancer, 2010.  Part Four: Prevention is the Cure.

[7] L.S. Lilly, Pathophysiology of Heart Disease, Seventh Edition, LWW, 2020.  The “same” passage in the 4th edition (2007) reads, “The HMG CoA reductase inhibitors, commonly known as statins, are the most effective drugs for reducing LDL cholesterol.  By virtue of their potency, excellent tolerability, and mortality benefits, they are the most widely prescribed lipid-regulating drugs.” The 2020 version is toned down somewhat and is more accurate, but no medical student and very few academics will compare textbooks in such a close reading.

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  1. Carla

    “Going back to the 4S Study of 1994, about 88 of 100 people on average in the placebo group died, while 91 of 100 died in the statin group. Statistically significant, yes, and much more than that for the three whose deaths may have been due to non-treatment with statins.”

    I’m confused by this. Appears to me those three deaths could have been related to treatment with statins, rather than non-treatment with statins.

    1. crantok

      I assume it’s an error. It contracts the earlier mention of the 4S study. In the quote you gave, “died” should have been “lived.”

  2. Bill Carson

    Somewhat off topic, but it really irks me when I see Jon Stewart get so much applause for confronting the Arkansas Attorney General because Arkansas’s ban on transgender therapy in children goes against the recommendations of the AMA and pediatric groups. We treat the AMA and medical standards of care as though they were handed down on Mount Sinai, when in fact modern medicine has promoted a myriad of treatments and therapies that later were debunked and disproven. I have only compassion for those who suffer from gender dysphoria, but I worry that the medical remedies being promoted today will be viewed as damaging and perhaps even barbaric a few decades from now.

    1. voislav

      There is an important distinction though. You may or may not agree with treatment options that are proposed, but the medical decisions should be left to doctors and patients. This was the point Jon was making, what qualifications do the legislators have that makes them suitable to make these decisions instead of doctors and patients themselves? Why is this one medical issue subject of legislation and not cancer treatment?

      You can say whatever you like about the medical community, but their decisions and treatments have been mostly beneficial to humanity. There have been mistakes, we are discussing one of those, but the success rate has been, what, 95%? 99%? Do you have the same confidence in politicians?

      1. Duke of Prunes

        Why are there any laws for any drugs? After all, according to your argument, doctors always know best.

  3. SocalJimObjects

    Thanks for this. Very illuminating. My doctor is one of those who does not subscribe to “high LDL, let’s pump this guy full of Statin” school, instead he is a fan of the cholesterol ratio and the CRP.

    From this Mayo Clinic article https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/expert-answers/cholesterol-ratio/faq-20058006. “For predicting your risk of heart disease, many doctors now believe that determining your non-HDL cholesterol level may be more useful than calculating your cholesterol ratio. And either option appears to be a better risk predictor than your total cholesterol level or even your low-density lipoprotein (LDL, or “bad”) cholesterol level.”

    I have a high LDL (which may come down according to my doctor because I recently got sick and lost 7 pounds rapidly) but I also have a high HDL, while my Trig and CRP are all normal. When I asked my doctor whether I needed to take Statin or any other medication to lower my LDL, he simply said no because my cholesterol ratio and CRP looked good. My BMI is also in the normal range while in the past I used to be obese. I should also say, I lost the majority of my weight thanks to diet and exercise and not due to my recent sickness ;)

    1. SocalJimObjects

      I may be mistaken on this, but shouldn’t this article be dated 10/12/2022, not 10/11/2022? Could have sworn I did not see this article yesterday.

    2. Yves Smith Post author

      I neglected to mention this in the lead-in, but my understanding (and this was true as of over a decade ago) is that triglyceride and homocysteine are recognized as vastly better indicators of heart disease risk than cholesterol.

      1. Jack

        I have heard the same. You can easily get a Homocysteine blood test. Another blood test marker is the C-Reactive protein test (hs-CRP). Both are cheap, less than $100 for both. Many people don’t know this but you can order your own blood work if you are willing to pay for it. No Doctor required. And most tests are not expensive. I know about these markers and tests because the VA will not test you for them unless there is indication of heart disease. However, if your cholesterol levels approach anywhere near the “recommended limits” they will push statins on you. I have always refused them because of the possible side effects and the paltry evidence that they work as a preventive.

        1. katiebird

          An organization called Life Extension (mostly a supplement company) sells blood tests. They are national but have a contract with local labs all over the country to do the tests. My dad didn’t like fighting with doctors about the blood tests he wanted so he waited for LE’s big annual sale and would buy all his tests for the year at once. They are/were a pretty honorable company. After he died, they gave us a refund for all his unopened supplements.

      2. JB

        The Calcium Score Test may be a far superior predictor of heart disease – my dad had that done, and then went on to have a quadruple bypass 2 and half years ago (all good now – at 72, exercise bike every day, still doing DIY builder work around the house, retrofitting showers/boiler, working on his classic cars – little different to 30 years ago) – but the radiation from the CT requires more careful screening on when people should be given such tests.

        My dad even specifically asked to have that calcium score test done – can’t remember what prompted him to – so if a person is approaching the same ballpark in age, and/or hasn’t always kept active throughout life (my dad had done karate for decades) – then worth them asking their doctor for a referral for one of these tests, if they’re not at too early of an age for the radiation dosage.

    3. Robert Hahl

      I recall having cholesterol values from 230 to 270 over the last forty years (considered high enough to start talking about statins), and these values always seem totally unrelated to my state of health. At some point I started biking to work (15 mile round trip) and decided to loose 30 pounds to climb hills more easily. I then felt ten years younger and have maintained the lower weight ever since, and improved my diet generally. You would think that all these healthy habits should improve my cholesterol tests, but no. The drug pushers continued suggesting I take statins. And don’t get me stared on recommendations to take metformin for “pre-diabetes.”

      1. cpm

        Please say more about Metformin and pre-diabetes.
        I’m in this group. Didn’t know of any controversies here.

        As you know some “experts” in the extending life/anti-aging
        Community recommend Metformin for a longer healthier life.


        1. SKM

          type 2 diabetes is entierly preventable. If you have pre-diabetes and do nothing but take drugs you will get worse over time. You need to cut carbohydrates as drastically as possible. Too many CHOs in some people lead to insulin resistance which is the real cause of the ” metabolic syndrome” which leads to type 2 diabetes, hypertension, cardiovascular disease, increased risk of cognitive decline and dementia. None of these latter scourges have anything to do with saturated fats, high serum cholesterol.
          There are many brave souls who have de-bunked all this out there both in the scientific literaure and in popular book form (but backed up with studies to support claims made)
          My total cholesterol is now over 300mg and I am keeping it that way!
          The minuscule effect seen with statins in SOME studies in certain groups (secondary prevention, older males) is likely NOTHING to do with cholesterol lowering (no such effect was seen with other cholesterol lowering drugs) but likely due to 2 other effects of statins – an anti-inflammatory action (cf studies on the use of say aspirin) and a stimulatory effect on NO (dilates blood vessels, is a powerful anti-coagulant) prodn in the endothelium
          Re pre diabetes please simply look up the story of British GP David Unwin – a patient taught him the above re carbohydrate etc – he has many many cases of reversal of the process – people come OFF metformin etc. He has reduced his practice drug bill by (I think) a third. His patients blood pressure normalises etc etc
          An excellent book delving into the real causes of CHD is “The clot thickens” by Malcolm Kendrick – more fun than many for his humour and more interesting as he tries to trace the REAL causes of heart disease with proper referenced research. Do try it, it`s a great read, and it`s good science. There are of course many others – also ones examining in details the studies down the years, the bad, dishonest methodology, the “burying” of studies that come to the “wrong” conclusions etc etc Some of this Kendrick deals with but so do many many others

      2. britzklieg

        My story is the similar, with slightly lower levels (220) over the years and not as diligent as you to have kept the weight off (when I left Manhattan, where I walked everywhere on top of regular exercise, there was no easy way to compensate – car culture sucks and walking is what I miss most about the city). I am fortunate to have encountered doctors early on who cautioned against statins, maybe because I’ve always preferred D.O.’s to M.D.’s. No statins for me. Re: metaformin, one told me “there’s no such thing as pre-diabetes – lay off the donuts and muffins, you’ll be fine.” In so doing, I’ve come to believe that most sugars, especially refined sugars, should be illegal. Sugar is the main and most destructive dietary problem, imho.

  4. PlutoniumKun

    I have to confess to being totally confused by the evidence over statins. I’ve asked several medics/medical scientists I know – at least two of whom are unusually skeptical about official data, and they have universally stated that they consider statins as working for CVD, albeit probably not as effectively as once thought. When I ask further, I’m pointed to the Cochrane reviews, which generally fall on the favorable for CVD (not for anything else) side. I don’t have the patience or knowledge or statistical background to delve deeply into those reviews.

    What does seem unclear is whether statins work better than pretty standard dietary advice. In my experience, people respond with a certain amount of shock (impending mortality I guess) when given a diagnosis of early CVD and immediately get their walking boots on and at least make a show of refusing dessert. Whether this skews the bigger non-randomized studies, I don’t know.

    But the

    1. Yves Smith Post author

      My understanding is that statins are helpful only in active cases of heart disease, not as a preventative. But doctors have been sold on the idea that they are harmless, so why not overprescribe. I don’t see how administering something that messes with your liver function can be a good idea on a long-term basis.

      1. Ignacio

        It is also my sense. You can have relatively high levels of cholesterol and not a history of heart burns & attacks and no familiar history of the same. Someone decided that some level of cholesterol is universally baaad but I don’t agree. It is bad use of statistics in medicine and it is possible to argue that in different genetic/phenotypic contexts the tolerance to what is deemed as high cholesterol might be very very different. Statins might help a few or many while damaging another few or many.

        Said this, I haven’t done a thorough search but here KLG does a good job of showing how we are sold to statins with little real evidence or with dubious evidence. Looks like a moving goal post game sometimes.

        1. Ignacio

          Sorry to reply myself though this is somehow a comment on KLG’s title. In my opinion medicine shouldn’t be taught as science even if there is a lot of science in medicine. Very much like engineering, medicine relies on science but both, physicians and engineers mostly do applied stuff so their formation has to rely heavily in procedures, protocols, safeguards etc rather than science itself while science is about curiosity and some times breaking the rules. This said, there are of course lots of physicians and engineers that are excellent scientists or have scientific knowledge on par or better when compared with their “specialized” science peers. IMO, sometimes there is over-reliance in protocols or these have been written down without the necessary warnings that the same jacket doesn’t fit all patients.

      2. PlutoniumKun

        I’ve found Dr. Brad Stansfield on YT to be a pretty good source of lifestyle information – this is his most recent video on statins and cholesterol. He talks about statins from 07.00. From what I know (which isn’t much), this is close what most doctors who have delved a little deeper into the data believe (there are of course some very anti-statin doctors so there will be contrary voices).

    2. Gyan Brard

      One way to look at the effectiveness of statins is to figure they lower relative risk but 30-40%. If you are a high risk patient (20% chance of needing a stent or dying over the next 10 years) then you might lower your risk to 12-14% which is still not great but better. If your risk is 1-2% for having an event over the next 10 years then you are not really getting nearly as much benefit. We treat patients based on risk and LDL is just one factor in determining that risk and not all that strong of a factor as been pointed out here by many already.
      As far as statins versus diet, consider all the trials to be done with dietary instruction for all so to whatever extent people can modify their diet, it is already factored in there

  5. JohnM_inMN

    Alex Christoforou put up a twitter post from Alan Watson the other day. In addition to his dietary advice, he has some interesting posts on Russia/Ukraine, like this one of Zelensky welcoming GMO seeds to Ukraine:


    He is a big advocate of cooking with lard. Not sure I’m on board.


    Related – this from a James Li segment on Breaking Points:


    Lots of interesting tidbits. I did not know about the connection between Proctor & Gamble and the American Heart Association wrt to the replacement of animal fat and butter with hydrogenated vegetable oils.

    1. JohnM_inMN

      I neglected to mention the main topic of the James Li segment is seed oils – and whether or not they are partly responsible for the increase in obesity in the population.

  6. Sutter Cane

    I didn’t see much discussion of the side effects of statins here. I had elevated cholesterol at my annual physical years ago, and of course my doctor prescribed me statins. There wasn’t much discussion about them or about the possible side effects, just “Here, take this, it’s the standard remedy.” I started taking them and immediately felt like absolute garbage – fatigue, muscle aches, just feeling generally sick and unhealthy. It was a night and day difference. I quit the statins and the side effects disappeared. I did not continue them because I didn’t view the plusses of possibly preventing a hypothetical heart attack in the future as outweighing the very not-hypothetical minus of feeling terrible 24/7 when I had previously felt fine. I also was not keen on the idea of me taking this medication that made me feel terrible for the rest of my life.

    I told my doctor about the side effects and he was pretty dismissive, and still wanted me to take the medication. Instead, I improved my diet and lost some weight, and got my levels lower – still high but not as high as they had been. Reading about statins, the evidence seemed not particularly convincing to me, especially taking the side effects into consideration, and I didn’t like that this medication that had such profound effects on my body had been prescribed so casually. This experience left me viewing doctors, big pharma, the medical system, etc. with a jaundiced eye forever after.

    1. CanCyn

      Yes, I was wondering about side effects too. I have heard about muscle fatigue and generally feeling poorly. My brother had a heart attack in his early 50s (playing hockey, common enough to be called a hockey heart attack. I guess a lot of guys play hockey to keep in shape instead of keeping in shape to play hockey)… anyhow, he was put on statins and has been kind of a tired bump on a log ever since. I tried to talk to him about the statin side effects but he trusts his doctor implicitly.

  7. larry silber

    Statins appear to be exactly what they are- a great profit to the pharmaceutical industry. Whose funding studies that simply track healthy eating and exercise over a life time? Where is the boondoggle for that common sense idea. We humans are too interested in finding support for our abominable animal exploiting consumption habits. There’s always an industry funded study mitigating and deflecting the obvious , even going so far as to infer the obvious is too simple to be true. Eat fat be fat, Just make fun of it, too silly to have any truth in it. Nobody wants to hear they contribute to a horror show three times a day, preferring to dote on their pets while professing love for animals. Statins are an easier choice than life style changes, plus the profiteering is too hard to reject. Simple as that. Show me studies that indicate plant based diets are detrimental to our environment, unhealthy in the long term contributing to cancer and heart disease, as well as displacing animals in the wild while torturing those in big ag on their way to an early demise. I think there is an illuminating statistic that shows 90% of the biomass representing large fauna alive in the late nineteenth century has been displaced today by domesticated animals on their way to a plate. There are plenty of insanely sad statistics related to Hunan consumption of animals.https://www.ecowatch.com/biomass-humans-animals-2571413930.htmlhttps://www.theguardian.com/environment/2018/oct/30/humanity-wiped-out-animals-since-1970-major-report-finds
    Obviously a quick google on the subject can put into context our current rapacity towards eating the planet alive. Sorry for the preaching, i just get a bit angry when i hear anything that seems to infer eating animals isnt so horrid, even though this piece is about statins and their effect on the reduction of mortality respecting cholesterol levels. a take away is still cholesterol isnt as unhealthy as thought, and since consuming excess cholesterol over and above what the liver makes only comes from animal products, I get the uneasy feeling this author is sympathetic to our ridiculously unhealthy animal based western diet., Hes just referencing industry hacks through their literature making the same old tired tobacco like propaganda format misdirection strategy. Im sure he means well, but like so many others, doesn’t want to face the simple obvious truths relating to consumption of sentient animals when there’s plenty of evidence supporting a plant based diet is optimum. No profitable statins needed. Cows pigs poultry and trawling of the depths doesnt need to be the main part of modern diets. Call that evidence based, scientific fact, or whtatever you want, it is simply the truth. Maybe fats and cholesterol arent as detrimental to ones health in small quantities as some studies might infer. But eating animals is surely damaging to their own well being , the environment on an industrial scale, since most animals we consume are via that route, and most importantly- absolutely unnecessary in todays modern world. Its just a choice of taste over kindness and making the wrong choice certainly risks ones health and contributes greatly to anthropogenic climate change. Maybe we cant reduce fossil fuel use quick enough on a national level, but on an individual level we can certainly choose benevolent healthy plant based sources three times a day. No divisive politics needed, just empathy. Judging how we turn the horrors of war into video games and make the enemy less than, im sure veganism will remain just a fringe tree hugger movement.

    1. VH

      Agree with you on all counts. Being healthy doesn’t require drugs for a lot of people if you stop eating animals of any kind. The added and necessary bonus is to decrease the horrific factory farming machine. Humans are omnivores and do not need animals in their diet to be healthy – the opposite is true. When I see the ads on TV for burgers I want to hurl. Besides the obvious cruelty it visits on the animals raised for this sick industry, the food looks disgusting! How did we get to the point where this stuff actually is appealing to so many people!? Apropos of cholesterol, the medical industry is just that, an industry made to profit and in order to hold onto your money and your life, you need to research and critically digest all the info coming out of said industry and don’t trust your doctor just because he has prestigious degrees. Docs and nurses are taught an awful lot about drugs and very little about nutrition. Doctors are protecting their licenses and if you go to them they are obligated to give you tests, the tests will reveal your cholesterol that may be higher than some possibly arbitrary number and then they are obligated to give you a drug. You can take it or not but their job seems to be done at that point.

  8. CanCyn

    Second post, kind of about side effects. My most scientifically and medically literate friend (pharmacist, epidemiologist by education, career spent as a health economist) admitted to me that statins may not be the great heart attack preventer that everyone should take (I have heard people say this!) but taking them has a correlation with reduced stroke. Again though more for people with cardiovascular or metabolic disease, rather than a preventative for the general population. Not sure if there is a study or review to back this up.

  9. crantok

    I do love a good story about wobbly evidence underlying dogma. In a similar vein, I really enjoyed reading the TimeMoldSlimeMold “A chemical hunger” where they poo poo the evidence for calorie control having an effect on weight (beyond about 10 pound in either direction) and offer an alternative hypothesis for the trend of increasing BMI.


    I see equivalent links have been posted in comments on previous NC articles.

    1. Lysias

      I have controlled my weight by taking megadoses of Vitamin D. It reduces appetite. In addition to its other benefits.

  10. Rolf

    We do not have to be historians or anthropologists to understand and appreciate the history of Reconstruction as presented by Eric Foner or the meaning of anthropology according to David Graeber and David Wengrow.

    My post here has nothing to do with statins, but because of the above reference, as it gives me the opportunity to give a very large Thank You! to Yves’ recent post re Graeber and Wengrow’s The Dawn of Everything. I acquired this book after that post and am now deep into it, and have to say it’s one of the most mind-altering books I’ve ever read about the origins and evolution of Western thought. My reading is slow however, as I constantly find myself so stunned by the insights within that I have to stop reading and sit and think for an hour before continuing. It is a work of genius and completely uplifting — so much so I may even regain my optimism lost these several years. I can’t recommend it enough to all here: you will not regret the time invested.

    1. dearieme

      I once pointed out to Graeber, online, a howling error in his work. His reply was so intemperate that I couldn’t decide whether he was insane or drunk.

  11. WendyS

    I was taking statins for a short time years ago. They made me feel fuzzy headed and forgetful. I asked my chiropractor about it and she told me to stop taking them. I did and when the Dr. asked I told them about the forgetfulness and they have me down as being allergic to them. Cholesterol has gone down a bit with vitamin D, Omega 3’s, magnesium, vitamin K (both types).

  12. will rodgers horse

    When it was learned that all cause mortality did not fall but increased everyone fell all over themselves to explain that away. The deaths were mostly “accidental’
    What was not mentioned was that there was some fascinating Swedish Prison studies 50 years ago that linked violent behavior to very low levels of cholesterol. (which makes sense from an evolutionary standpoint if you think it through)

  13. Jeremy Grimm

    Reading this post I am gripped by a strong feeling that Health and Medicine are Public Goods which have no place in the realms of economics or politics — they are and must remain/be/become a part of the most basic constructs for the ‘Good Life’. The world that exists — its Neoliberal annexation of Medicine — is anathema to any faith in the sanity of life for Humankind. For the cholesterol/statins/lipidor campaigns toward wealth … I have no words.

    So what about “Medicine Taught Like a Science”? Indeed! What about Medicine taught like a healing Art?

  14. john smith

    “It does not make sense that artificially lowering cholesterol levels will have only benign effects”.

    Well said. Which isn’t to say that naturally lowering it via diet is a bad thing.

    One comment on Yves’ link to the study that low LDL is associated with higher stroke risk. The higher stroke risk is for the LDL-C levels <70 mg/dL. I believe that to get that low you have to be pretty close to vegan. Many vegans/vegetarians are B12 depleted/deficient which raises homocystene levels raising risk of stroke. The solution is to supplement with B12 for these groups. Supplements is how B12 finds it's way into animal products.

    Final note: Stroke is behind heart disease as a leading cause of death.

    1. katiebird

      My total cholesterol (also my father & half my siblings) has never been higher than about 70-75. My HDL is usually between 30-50. It has nothing to do with diet – it’s just something about our metabolism, I think. I do crave eggs if I don’t have at least one day. I mean craving to the point that I could eat 6 in a day. Maybe it’s all in my head. But I’ve always figured there was a relationship there.

  15. Brunches with Cats

    Been out for a few days and will be away next coupla weeks, but wanted to drop a quick thank you to KLG for writing this two-parter and to Yves for running it.

    I’m due for my semi-annual labs at the VA next week and have been dreading PCP’s response to what likely will be an increase in cholesterol. As another commenter noted above, the VA pushes statins on you if your total number is over their clinical guidelines, regardless of mitigating factors. I had to go to the ER (non-VA) last fall, ER staff diagnosed as stroke (TIA), sent me home with a bag of drugs, the usual suspects. I told both the discharge nurse and PCP — new guy, came from one of the big hospital groups — that I wasn’t going to take them, got the “you’re gonna die” lecture, only to have the neurologist disagree, when I finally got in to see her six weeks later. Definitely not a stroke she said, but she didn’t know what it was, ordered a follow-up in a year. Spent a traumatic 1.5 hrs in MRI tube week before last, see the neurologist to discuss results end of this month, but in the meantime have the PCP to contend with.

    ANYWAY … this article is uncannily timely for me and had the very real effect of tamping down my anxiety level. The finances aren’t going to improve anytime soon (just got a $1,600 estimate for badly needed dental work), but when things settle down, NC is tops on my list — exactly because of this kind of quality information. Again, many, many thanks.

    1. katiebird

      !!! I am so sorry for all you’ve been through. You are very strong to survive 1.5 hours in an MRI Tube. And everything else. You have my best wishes.

    1. john smith

      Last I checked (and it’s been a while) Dr Lustig seems a little too obsessed with added sugar as the sole cause of all your problems. While he is correct that sugar is not a health food and one should keep it to a minimum, it’s not the only, nor the main culprit.

  16. Tim

    Perhaps Statins have actually killed more people than they helped: There is pretty widespread belief that these “prevent heart attack” drugs are highly effective which and a subconscious level to homo sapiens means I can pig out now and drug up later and be okay, when the reality is they dialed up their risk factor higher than the drug could resolve, and ended up dying earlier than if they statins never existed and they took more care of what they ate instead.

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