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.
- The placques are predominantly cholesterol.
- The breakage of the plaques is an inflammation process.
- 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.
- 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.
- 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.
- 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  :
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”
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]
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.