Cholesterol and inflammation; Statins and alternatives (Part II)

Last week, I cited evidence that statins work to lower risk of heart disease, but their benefit is probably independent of their design function, which is to deprive the body of cholesterol. I believe the benefits of statin drugs come from anti-inflammatory action. Their effect on cholesterol is at best a subsidiary benefit, at worst a cause of multiple systemic problems. Reviewing a handful of studies over 30 years, I didn’t find any consistent relationship between heart risk and blood levels of cholesterol (HDL, LDL or TC). The only exceptions were at the very extremes. Both the top ½% and the bottom ½% had elevated risk of heart attack.

This 1994 study was titled Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. But if you read past the abstract to the data tables, you’ll find that people with low cholesterol had twice as many fatal heart attacks as people with high cholesterol [sic]. Deaths from other causes than heart disease were higher in subjects with high cholesterol, and this added up to a negligible difference in overall mortality rates for high or low cholesterol. (This was pointed out to me by Uffe Ravnskoff, a Danish doctor and researcher, author of The Cholesterol Myths.)

Statins tamper with body chemistry that doesn’t need tampering. This line of thinking suggests that alternative anti-inflammatory strategies might avoid the side effects while lowering risk of heart attacks as much or more than with statins.


CV mortality rates are falling

If our NIH had declared “war on heart disease” in 1965, they would be well-justified in crowing today. Since a peak in the 1960s, cardiovascular mortality in the Western world has been declining steadily.

Age-adjusted CV mortality, 1950 - 2006

Age-adjusted CV mortality, 1950 – 2006

The decline is the more impressive in that it has fought twin headwinds in the form of an epidemic of obesity and an aging population. The rise of statin prescriptions may be part of the story, but statins only came into widespread use beginning 1995-2000. The prevalence of smoking started declining steeply in 1965, and this is surely a contributing factor. Other than that, experts can’t seem to agree on the cause of our good fortune.


Side effects of statins

Statins don’t just affect blood chemistry, but interfere with the manufacture of cholesterol. But cholesterol is an important ingredient in cell membranes and nerve sheaths; it is also a substrate from which other essential molecules are manufactured, including vitamin D. It is no surprise that statins carry powerful complications. All the side-effects come from the cholesterol metabolism, and not the anti-inflammatory action, so they may be completely unnecessary.

  • Lowering inflammation ought to improve insulin sensitivity. But most statins are associated with elevated risk of diabetes. Since loss of insulin sensitivity is a primary driver of aging, even marginal effects on insulin resistance could be important. Diabetes is an independent risk factor for heart disease [ref]. Simvastatin seems to have the worst effect on insulin sensitivity, and pravastatin may actually improve insulin sensitivity [ref].
  • Cognitive impairment is of great concern for most of us, but it is difficult to measure reproducibly. There are enough subjective reports of cognitive impairment from statins to be worrisome [ref, ref] but there may be a slightly lowered risk of dementia (as you would expect from an anti-inflammatory) [ref].
  • Muscle cramping (myalgia) is reported in some industry-sponsored studies to be 18% or 5% or even as low as 3%. But in my small sample, everyone I know who takes statins notices muscle cramps. This rises from being a nuisance to a clinical risk when it interferes with patients’ ability to exercise, which is potentially a more powerful heart protector than statins.
  • Probably related, people on statin drugs report fatigue and intolerance to exercise. Statins interfere with the energy metabolism, and in particular reduce the concentration of CoQ10=ubiquinone, which already declines with age and is essential for mitochondrial function. Everyone who chooses to take statins should be supplementing with CoQ10.


Alternatives for lowering CV risk without statins

  • Exercise. The #1 most cardioprotective form of exercise is interval training. The #1 most difficult discipline to maintain is: interval training. Establish an exercise program you can live with, and then live with it.  Intense exercise makes a world of difference, but even taking a walk a few times a week has significant benefit.
  • Lose weight.
  • Less meat, more Mediterranean in your diet. Vegan seems to help. If you can tolerate it, a raw foods vegan diet is all-purpose for weight loss, heart health, anti-inflammation, and anti-cancer.
  • Daily aspirin or ibuprofen after age 50. (A reader has recently made me aware of a link between macular degeneration and daily aspirin. No such link seems to be documented for ibuprofen. If you have AMD in the family, you may want to substitute ibuprofen for aspirin, or lower the dosage. There is no evidence that a full aspirin daily is better for your hear than ¼ aspirin, but it does seem that the full pill is worse for AMD.)
  • Other anti-inflammatories include turmeric, fish oil, boswellia, cat’s claw. A reader has alerted me to the potential of anatabine citrate. This is an alkaloid compound found in small quantities in nightshade vegetables and tobacco. Some people who have taken it say it is the best anti-inflammatory ever, but it was taken off the market 2 years ago based on a scandal that was purely political and had nothing to do with the biological merits of anatabine.
  • Supplement with CoQ10 [Ref1, Ref2, Ref3, Ref4] or ubiquinol, which is offers enhanced absorption for a closely-related molecule.
  • Both kinds of dietary fiber decrease heart risk. (The reasons for this are still debated, and may include intestinal flora, appetite control, and speed of food absorption.) Wheat bran and leafy greens are the best sources of insoluble fibre (“roughage”). Oat bran, beans and nuts are the best sources of soluble fibre.
  • 8 cardioprotective foods (garlic and ginger should be on this list, but were not as I found it)
    • avocado
    • lentils
    • edamame
    • nuts
    • olive oil
    • pears
    • tea (black is good, green is better)
    • tomatoes
  • Get your vitamin D blood levels up to 70 (In people like me, this can require 10,000 to 30,000 iu daily. Whole body sun exposure can help, too, but it ages the skin.)
  • Supplement with niacin (vit B3). Niacin raises HDL and cut risk of heart attacks by 30% in people not taking statins in a meta-analysis. Mechanism of niacin explained here.
    Am I being inconsistent in saying that cholesterol has nothing to do with heart risk and then recommending a vitamin that raises HDL (good cholesterol) levels?  Perhaps so, or perhaps I’m hedging my bets.  In include this recommendation because there is independent evidence linking niacin not just to HDL but also to a lower rate of CV events.
  • Hawthorn(e) berry seems promising, and some naturopaths have had good results prescribing it for congestive heart failure.
  • Don’t worry about salt.
  • Trans fats (or partially hydrogenated vegetable oils) do not exist in nature, but are created in food processing because they retard spoilage. Trans fat consumption is associated with heart risk as well as all-cause mortality, and should be avoided. (I’ll bet you already knew that.)
  • Cut sugar and grains to keep up your insulin sensitivity. Diabetes is a heart risk factor.
  • Avoid foods high in iron. Don’t supplement iron, unless you have been diagnosed with a deficiency. [Ref1, Ref2] Donate blood.


Chinese medicine

Despite high rates of smoking (men 62%), Chinese has a low rate of heart disease (less than a third of the US). The rate in cities has begun to climb to rates more typical of Western societies, but remains low in the countryside [read more]. Part of the reason may be the Chinese diet and traditional Chinese medicine. Astragalus and ginseng are considered to be cardioprotective in TCM. Auricularia (木耳=“wood ear” ) is a mushroom-like fungus common in Chinese soups, which also is used in traditional Chinese medicine. It tends to raise HDL and prevent inflammatory damage to blood lipids, and it mitigates damage in the event of a heart attack. Oyster mushrooms are a natural source of simvastin. [Read about traditional Chinese medical approach to heart disease]

If you have a heart attack, the Chinese herb Fuzi (附子=aconite) is both toxic and protective in case of traumatic tissue damage. Definitely not to be added to your daily supplements, but it may mitigate damage to your heart after a heart attack. It is the single red pill packed with Yunnan Baiyao.  Meldonium is a promising plant extract in early stages of testing for power to mitigate heart damage.  (It is claimed that statin drugs also mitigate heart damage.)


The Bottom Line

Heart disease is no longer the #1 Killer that it was decades ago. Doctors are still looking at blood cholesterol to tell people when they are at high risk, and in fact, for most people, cholesterol levels are not related to risk of heart disease. BMI, physical activity and blood pressure are much better predictors of heart risk.

Statin drugs lower your risk of heart disease, but there are other measure you can take that are both more effective and have less side effects. John Aronson says the only proven benefits for statins are for males who have already had one heart attack.

Keep in mind that everything I have reported here is based on a general population, averaged over all genetic types. A number of different genetic variations may make you more or less vulnerable to heart disease in a particular way, and may mandate a particular treatment. Take your 23andMe profile to someone who knows how to interpret it.



Appendix: Why do doctors prescribe drugs that don’t work?

A friend of mine recently retired after working as a VA doc for 25 years. She saw her most effective role as getting patients off some of their many medications. When a student of mine told me that her doctor was prescribing statins, I asked my friend for a doctor who would give her a different perspective. She said she knew of no one who would advise against statins?

How could that be? The explanation involves liability law. There are no guarantees from any treatment, and every doctor knows that some of his patients will have heart attacks. If a patient suffers a heart attack and sues the doctor who had managed his regimen, the doctor can be liable even if he has given the best advice and prescribed the best course. He cannot be liable if he does the same thing that everyone else does. The doctor’s liability depends not on whether he did the right thing, but whether his advice conforms to the prevailing standard of care.

It gets worse. Suppose a brave doctor decides that he’s going to do the right thing and, he’s willing to take the risk that his patients might sue him later. His insurance company won’t let him do that. He becomes uninsurable, and without insurance he dares not practice medicine.

This is how liability law and insurance economics work to effectively suppress diverse diverse approaches and hold back innovation for decades after the consensus of the medical community may have shifted.

When your doctor suggests statins (Part 1: Mechanism of Action)

High blood pressure is statistically associated with cardiovascular risk. Avoiding salt lowers blood pressure, but it does not affect cardiovascular risk.

Inflammation is statistically associated with cardiovascular risk. NSAIDs lower the body’s inflammation, and also lowers cardiovascular risk.

Statin drugs reduce LDL cholesterol levels in the blood and also quell inflammation. Statins seem to reduce cardiovascular risk.  Does this have to do with cholesterol or with inflammation?

For almost everyone, LDL cholesterol levels rise during middle age.  Most doctors will prescribe statin drugs as your first line of defense to lower risk of heart attack. The link between LDL cholesterol and heart disease is not well-established.  And in any case, there are many things you can do to lower heart risk that are both more effective and have less side-effects than statins.  I have become convinced that statins are over-prescribed.

(Too many doctors are still telling patients to cut back on salt.  They are out of touch with an emerging consensus.)


Two years ago, I spent a few weeks reading the literature on cholesterol and heart disease, and I reported finding a deep split in the community [Part 1, Part 2]:  There are two camps in the research field, one saying that lowering cholesterol levels is the most effective way to control heart risk, and the other saying that cholesterol levels are completely unrelated to heart risk.  At the time, I didn’t take sides; but now I’m inclined toward the latter group, based on politics as much as science.

It is difficult to get a man to understand something, when his salary depends upon his not understanding it.
         — Upton Sinclair

John Abramson, a professor at Harvard Med and author of Overdosed America, lists statins as America’s #1 most overprescribed drug class.  Even for the class of patients most at risk, he estimates that of every 140 people are taking statins, only 1 of them avoids a heart attack. He tells a story of an entire sub-field of medicine that has been touched by money from the pharmaceutical industry.  Most scientists are smart, honest, and independent.  But I have found in several areas that scientists are not immune from herd mentality.  We tend to be trusting creatures, specialized in a narrow field, with faith to accept others’ findings in areas where we are less expert.  Hence, it is not as difficult as you might think for money to influence a scientific paradigm.  This is especially so in epidemiology, where large studies of diverse humans are amenable to various interpretations.  The specialists in physiology are not good at statistics, and the statisticians are not senior authors, but are hired to put numbers together in support of a thesis  The predominance of private money from drug companies over public money from NIH makes pharmacological science especially vulnerable.

Abramson’s advice is that statins are appropriate therapy only for men who have already suffered one heart attack.  For your reference, I’ve posted the key pages from Chapter 9 of his book here.  What he reports is enough to foment a rebellion against for-profit health care, and especially the corporate role in health research.  After reading it, I was moved to write a column dismissing statin drugs as a well-funded scientific fraud.  I did not find evidence to support that.

What I did find, is that the prevailing theory about LDL cholesterol and CV disease has very little support.  I believe that statin drugs work to lower CV mortality, but that the mechanism for the benefit has more to do with inflammation than with cholesterol.  This leads to the question:  Are there better ways to lower inflammation that do not impose the substantial side-effects of statin drugs?


What is a heart attack?

Heart attacks result when an artery feeding the heart muscles becomes obstructed.  Most commonly, deposits (“plaques”) build up on the insides of artery walls over many years, and sometimes pieces of placque break off and become seeds for blood clots that can block the artery enough to cause an attack.

  1. The placques are predominantly cholesterol.
  2. The breakage of the plaques is an inflammation process.
  3. Clotting of blood is frequently the step that pushes the attack over the edge.

Viable therapies interrupt the process at any of these three stages.

  1. LDL the form of cholesterol in the blood that is most likely to form plaquest, while HDL can actually dissolve the plaques and re-metabolize choleserol.  Statin drugs lower LDL.  Exercise, weight loss, a Mediterranean diet, and niacin (vit B3) can raise HDL.
  2. Anti-inflammatories can help keep the artery walls intact.  Lowering inflammation also lowers risk of cancer, stroke and AD.  Common anti-inflammatory agents include NSAIDs, fish oil, curcumin, boswellia, and cat’s claw.  Statin drugs are powerful anti-inflammatories, and there is a school of thought that says that their anti-inflammatory action is more important than their cholesterol-lowering action for preventing heart attacks.
  3. Anti-coagulants, including NSAIDs and fish oil, protect against heart attacks as well.  Side effects include risk of internal bleeding, stomach ulcers, and hemorrhagic stroke.  (13% of strokes are hemorrhagic and come from blood flooding the brain; the rest are ischemic, which means that they are caused by a clogged artery, via mechanisms closely analogous to heart attacks.)

Congestive heart failure is a condition that sometimes precedes or predicts a heart attack, and is a health problem in its own right.  The cause is often partial blockage of arteries feeding the heart, causing the heart to become weak.  Common symptoms include decreased stamina, shortness of breath, fluid retention and swelling in the limbs.


Statin Drugs Interfere with the Manufacture of Cholesterol

Starting sixty years ago, medical thinking was that it was most powerful and sensible to interrupt this cycle at Stage 1 by lowering the cholesterol in the bloodstream.  Statins go a step further by actually interfering with the body’s manufacture of cholesterol.

The trouble with this reasoning is that cholesterol is not some unwanted byproduct of the metabolism like lipofuscin or glycated proteins.  It is not, like adipose tissue, the origin of pro-aging signals in the body.  Rather, cholesterol is an essential ingredient in the cell metabolism, which the body manufactures abundantly and uses in diverse waves.  Cholesterol lives in cell membranes, and cholesterol is concentrated in nerve cells, where it plays an essential role as insulator.  Cholesterol is a chemicl precursor to vitamin D and sex and steroid hormones.   Our brains have more cholesterol than any other part of us.  Cholesterol is the substrate for producing the bile acids that we need for digestion.  Here is a tutorial on the biochemistry of cholesterol in the body, its manufacture, uses and dangers.

It should be obvious that shutting off the body’s cholesterol factory is likely to cause many unwanted side-effects.  A smarter, more focused attack on the particular chemistry of deposits in the arteries is needed.


Choesterol and CV disease

Here are results from a classic epidemiological study, based on the Framingham Heart database [1993] :

The relationship between total cholesterol level and all-cause mortality was positive (ie, higher cholesterol level associated with higher mortality) at age 40 years, negative at age 80 years, and negligible at ages 50 to 70 years.

[Note: there are a lot more people dying at age 80 than at age 40.  The negative relationship at late ages is both more important and better established – JJM]

The relationship with CHD mortality was significantly positive at ages 40, 50, and 60 years but attenuated with age until the relationship was positive, but not significant, at age 70 years and negative, but not significant, at age 80 years.  Results for the relationship between low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and mortality help explain these findings. Non-CHD mortality was significantly negatively related to cholesterol level for ages 50 years and above.

[Translation: People under 70 who had higher levels of cholesterol had a greater chance of dying of heart disease, but this was compensated by a smaller chance of dying of other causes. – JJM]

In this study, funded by the life insurance industry which ought to have a neutral interest in prediction, only small relationships were found between cholesterol and mortality risk,* and risk was elevated both for low cholesterol and for high cholesterol.  LDL levels had no consistent relationship to mortality.  Average levels of HDL were better than either high or low.  High levels of total cholesterol (TC) presented no additional risk, but very low levels corresponded to a 50-75% increase in mortality.  These findings may be of limited utility because they are uncorrected for smoking or diet or statins, and are only very crudely stratified by age. The “sweet spot” for total cholesterol was about 180-230 for men, 170-220 for women.

These two graphs represent all-cause mortality risk for women and men over 60, graphed against their cholesterol level.  1.5 million life insurance applicants (yes – a huge subject pool) have been grouped by percentile.  The middle half is all lumped together, and the ends of the curve are finely divided.  What I get from this picture is consistent with noise from the 5th through the 95th percentiles.  There is no apparent relationship between mortality risk and either total cholesterol or HDL.  The exception seems to be at the extremes–the highest 1% and the lowest 1% both seem to be at higher risk.  The highest 1% corresponds to about 334 mg/dl (F) and 308 (M).  The lowest 1% corresponds to 146 (F) and 138 (M).  (There is no corresponding graph for LDL in the article, but the authors report, “Using LDL or non-HDL cholesterol instead of total cholesterol does not improve mortality risk discrimination; neither does using total cholesterol or triglyceride values in addition to the total cholesterol/HDL ratio”

Mortality_vs_Cholesterol_Fgt60 Mortality_vs_Cholesterol_Mgt60


Anti-Inflammatory action of Statins

  • Of potential interest is the statin-induced reduction of C-reactive protein (CRP), a marker for inflammation; recent data suggests that the CRP-lowering effect of statins might, in addition to lipid lowering, be relevant for progression of disease.
  • Data from experiments in cell culture and animal models show that statins can induce the cellular accumulation of endothelial nitric oxide synthase; inhibit the expression of adhesion molecules and chemokines that recruit inflammatory cells; inhibit expression of pro-coagulant factors and induce anti-coagulant substances; inhibit proliferation and promote apoptosis of vascular smooth muscle cells; and ameliorate platelet hyper-reactivity.  [ref]


Evidence for Benefits of Statin Drugs

(1) Here’s an example that is well-researched and well-reasoned with a British pedigree:

Reduction of LDL cholesterol with a statin reduced the risk of major vascular events , largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories. [Lancet, 2012]

The size of the benefit they find is a 22% reduction in risk of heart attack for a 40 point drop in LDL.

This finding, solid as it appears to be, is actually not inconsistent with the thesis that LDL cholesterol has nothing at all to do with risk of heart disease.  Statin drugs are both powerful anti-inflammatories and also lower LDL cholesterol.  People who take statin drugs may indeed have lower LDL and also lower inflammation.  The incidental correlation between LDL and inflammation would only show up in people taking statins, but it could completely account for the results of this meta-analysis.

(2) Here’s a trial of Rosuvastatin in which heart attack rates were slashed by more than half and stroke by almost that much, and the trial was stopped after just two years because it could no longer be justified to keep people on placebo.  These were people without elevated LDL going in.  Rather they were chosen on the basis of high C-Reactive Protein.  CRP is an inflammatory marker.

So this study is more evidence, perhaps, that statins are very effective anti-inflammatories, and can be read as consistent with the idea that LDL is a red herring.  Reporting included both CRP and LDL levles, but the body text emphasized LDL.

The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%…(hazard ratio for rosuvastatin, 0.56; P<0.00001)…Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. [review of JUPITER study]

Tentative Conclusion

I believe that to resolve questions about statins, their mode of action, and whether their benefit justifies the side-effects, what we need is a large scale study in which patients at high CV risk are randomized to a program of statins or to other anti-inflammatory agents.  There has not been such a study, and at present it would be considered unethical, so large is the presumption in favor of statins.

Next week, I’ll have more cholesterol stories, and suggest some alternatives to statins.

Caveat: I’m speculating on health advice out of my field.  I could well be wrong.  I invite readers who know things I don’t know to please comment, or contact me privately.


* In this context, “small relationships” mean less than a factor of 2 in death rate.  A doubled risk might not seem a small concern, but ratios less than 2 are difficult to distinguish from noise in actuarial studies. An easy-to-remember rule of thumb: a factor of 2 in mortality corresponds to about 10 years in age.