Thursday, June 20, 2013

Antibiotics and Statins: A Deadly Combo? - Laino

Antibiotics and Statins: A Deadly Combo?

Prescribing clarithromycin or erythromycin to older patients taking the most commonly prescribed statins, which are metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4), raised the risk for statin toxicity, according to a population-based retrospective cohort study.

Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome CYP3A4, and that inhibition increases blood concentrations of statins that are metabolized by CYP3A4 to potentially dangerous levels, Amit M. Patel, MD, of the London Health Sciences Center in Ontario, and colleagues reported online in the Annals of Internal Medicine.

Compared with azithromycin, co-prescription of atorvastatin, simvastatin, or lovastatin with clarithromycin or erythromycin was associated with a 0.02% increase in the absolute risk of hospitalization with rhabdomyolysis within 30 days (95% CI 0.01%-0.03%). That translates to a relative risk increase of 2.17 (95% CI, 1.04-4.53).
Risks were also increased for:
  • Acute kidney injury -- absolute risk increase, 1.26% (95% CI 0.58%-1.95%); RR 1.78 (95% CI 1.49-2.14)
  • All-cause mortality -- absolute risk increase, 0.25% (95% CI 0.17%-0.33%); RR 1.56 (95% CI 1.36-1.80)

"Statins are the No. 1 class of drugs prescribed in North America," co-author Amit Garg, MD, PhD, also from the London Health Sciences Center, said in a statement.

Coprescription of a statin with a macrolide antibiotic is very common. Until now, the clinical and population-based consequences of this potential drug-drug interaction were unknown, he said.
While the absolute risk increase is relatively small, "given the frequency at which statins are prescribed and the high rate of coprescription seen in our study and in other jurisdictions, this preventable drug-drug interaction remains clinically important. The results suggest many deaths and hospitalizations due to acute kidney injury in Ontario may have been attributable to this interaction, the researchers wrote.

For the study, the researchers examined the frequency of statin toxicity in continuous statin users older than 65 years who were prescribed clarithromycin (n=72,591) or erythromycin (n=3,267), compared with azithromycin (n=68,478) in Ontario from 2003 to 2010.

The primary outcome was rhabdomyolysis within 30 days of the antibiotic prescription.
The most commonly prescribed statin was atorvastatin (73%), followed by simvastatin (24%) and lovastatin (3%).

American Heart Association spokesperson Robert Eckel, MD, of the University of Colorado at Denver, said that although the potential for drug-drug interactions between certain antibiotics and statins was known, this study really underscores the potential for dangerous, even fatal complications.
"And while the study was only done in elderly patients, this "provides a signal" these complications could develop in younger people as well," he told "The Gupta Guide."

There's another option too, said John Higgins, MD, of the University of Texas Health Science Center at Houston. "If you have a patient on a statin and you need a mycin antibiotic, the study suggests you choose azithromycin.

"But there is also a statin that is not metabolized by the CYP3A4 system -- pravastatin. So you really have two choices here. Switch the antibiotic or switch the statin," he said.

The study has several major strengths, including its large size, Eckel said
But there are limitations, too, Higgins said. "For example they only studied people over 65, with a median age of 74, who may have a lot of comorbidities. So these patients may be more prone to some of these problems anyway," he said.

Additionally, it is an observational study and therefore subject to all the biases of such an analyses -- that is, they show associations, but cannot prove casual relationships, he said.
Finally, "coders record the health problems and we know that coders often don't note complications in all patients," Higgins said. "So, if anything, the risks may have been higher than those found in the study," he said.

Also, the researchers themselves noted that despite the large sample size, they could "not meaningfully examine interactions with each CYP3A4-metabolized statin individually. However, given the known effect on CYP3A4 statin pharmacokinetics, it remains prudent to generalize the coprescription warning to atorvastatin, simvastatin, or lovastatin with clarithromycin or erythromycin," they wrote.

Said Patel, "The results provide important safety information regarding these commonly prescribed medications. When prescribing clarithromycin or erythromycin to patients on these statins, preventive measures should be considered, such as cessation of the statin for the duration of the antibiotic therapy, increased monitoring for adverse events, or use of a different antibiotic that does not interact with these statins."

The authors also suggested that clinicians take advantage of free online drug interaction programs and/or software aimed at improving the overall safety of polypharmacy in older adults.
And there's always the obvious solution: Better multidisciplinary collaboration between departments, Eckel added.

Do you double-check what statins your patients are on before prescribing an antibiotic? Add Your Knowledge below. -- Sanjay Gupta, MD.
The investigators received grant support from the Academic Medical Organization of Southwestern Ontario to conduct this research. This project was conducted at the Institute for Clinical Evaluative Sciences site at Western University. The Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. The Institute for Clinical Evaluative Sciences site at Western University is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician Scientific Award.
Eckel and Higgins have no financial conclicts of interest to disclose.

Primary source: Annals of Internal Medicine
Source reference:
Patel AM, et al "Statin toxicity from macrolide antibiotic coprescription" Ann Intern Med 2013; DOI: 10.7326/0003-4819-158-12-201306180-00004.
Read the complete article here.

Tuesday, June 18, 2013

Will 2015 Dietary Guidelines Advisory Committee address Dr. Rimm’s legitimate concerns? - Watson

Why was a respected Harvard researcher afraid he would get “kicked off the stage”?

| May 10, 2012 
On October 31, 2008, during that first meeting of the 2010 Dietary Guidelines Advisory Committee (DGAC), Dr. Eric B. Rimm, Associate Professor of Medicine, Harvard Medical School, questioned what he called the “artificial limit” on dietary fat in the U.S. Dietary Guidelines.
Dr. Rimm: “I wanted to make a radical point, one for which I’ll probably get kicked off the stage, but the whole issue of total fat and the 20 to 35 percent of calories from fat is one that has troubled me…”

Dr. Rimm:  “… But the high end, 35 percent of calories from fat, actually was not really based on much science; it’s based on the fact that we don’t have a lot of science beyond 35 percent, and there was a concern that higher fat diets would lead to obesity.”

Dr. Rimm:  I think if you look at the science, there is actually no good human data to suggest that higher fat diets lead to obesity. If anything, higher fat diets, at 35 to 40 percent, lead to lower triglycerides because it’s a lower carbohydrate intake.

Dr. Rimm:  “… I think there is the dogma that low-fat diets are beneficial, and you can go in the grocery store and see a lot of low-fat foods that are essentially just high in carbohydrate, highly processed sugars.”

Dr. Rimm did not get “kicked off the stage,” but the issue never came up again. He was simply ignored. The final report of the 2010 Dietary Guidelines ultimately contained even more stringent reductions in saturated fats – recommending that most Americans reduce saturated fat intake to just 7 percent of calories.

In an interview with Melissa Healy in the Los Angeles Times, June 28, 2010, Dr. Walter C. Willett, Chairman, Department of Nutrition, Harvard School of Public Health, agreed with his Harvard associate:

“The best available evidence demonstrates that percent of calories from fat in a diet has no bearing on weight loss – a point the dietary guidelines committee acknowledges.”
“It makes no sense to base the dietary guidelines on an outdated recommendation.”
Why did the Committee table Dr. Rimm’s concerns about artificial limits on dietary fat? Why was a respected Harvard researcher afraid he would get “kicked off the stage”? Are Committee members not allowed to question “low fat equals good health”? If so, why has USDA and HHS convened a 2015 Dietary Guidelines Advisory Committee?

New evidence exonerating saturated fats as a cause of heart disease continues to accumulate:

Dr. Ronald Krause – a highly respected American Diet Heart researcher – reviewed 21 studies involving 350,000 subjects to assess the correlation between saturated fat consumption and cardiovascular disease. The conclusion:

Intake of saturated fat was not associated with an increased risk of heart disease or stroke (American Journal of Clinical Nutrition, Jan. 13, 2010).
A prospective study from Australia looked at adults over a period of 15 years and found that people who ate the most full-fat dairy products had a 69 percent lower risk of cardiovascular death than those who ate the least (European Journal of Clinical Nutrition, April 7, 2010).
The Japan Collaborative Cohort Study for Evaluation of Cancer Risk found that saturated fat intake was inversely associated with mortality from stroke (American Journal of Clinical Nutrition, Aug. 4, 2010).

Researchers at Louisiana State University found that eating eggs for breakfast resulted in greater weight loss and better energy levels than eating two bagels even though the number of calories was about the same (The FASEB Journal 2007; 21:538.1).

Will the 2015 Dietary Guidelines Advisory Committee address Dr. Rimm’s legitimate concerns?
Read the complete article here.

Are statins and omega-3s incompatible? - Davis

Are statins and omega-3s incompatible?
Posted on June 18, 2013 by Dr. Davis

French researcher, Dr. Michel de Lorgeril, has been in the forefront of thinking and research into nutritional issues, including the Mediterranean Diet, the French Paradox, and the role of fat intake in cardiovascular health. In a recent review entitled Recent findings on the health effects of omega-3 fatty acids and statins, and their interactions: do statins inhibit omega-3?, he explores the question of whether statin drugs are, in effect, incompatible with omega-3 fatty acids.

Dr. Lorgeril makes several arguments:

1) Earlier studies, such as GISSI-Prevenzione, demonstrated reduction in cardiovascular events with omega-3 fatty acid supplementation, consistent with the biological and physiological benefits observed in animals, experimental preparations, and epidemiologic observations in free-living populations.

 2) More recent studies (and meta-analyses) examining the effects of omega-3 fatty acids have failed to demonstrate cardiovascular benefit showing, at most, non-significant trends towards benefit.

He points out that the more recent studies were conducted post-GISSI and after agencies like the American Heart Association’s advised people to consume more fish, which prompted broad increases in omega-3 intake. The populations studied therefore had increased intake of omega-3 fatty acids at the start of the studies, verified by higher levels of omega-3 RBC levels in participants.

In addition, he raises the provocative idea that the benefits of omega-3 fatty acids appear to be confined to those not taking statin agents, as suggested, for instance, in the Alpha Omega Trial. He speculates that the potential for statins to ablate the benefits of omega-3s (and vice versa) might be based on several phenomena:

 –Statins increase arachidonic acid content of cell membranes, a potentially inflammatory omega-6 fatty acid that competes with omega-3 fatty acids. (Insulin provocation and greater linoleic acid/omega-6 oils do likewise.)

–Statins induce impaired mitochondrial function, while omega-3s improve mitochondrial function. (Impaired mitochondrial function is evidenced, for instance, by reduced coenzyme Q10 levels, with partial relief from muscle weakness and discomfort by supplementing coenzyme Q10.)

–Statins commonly provoke muscle weakness and discomfort which can, in turn, lead to reduced levels of physical activity and increased resistance to insulin. (Thus the recently reported increases in diabetes with statin drug use.)

Are the physiologic effects of omega-3 fatty acids, present and necessary for health, at odds with the non-physiologic effects of statin drugs?

I fear we don’t have sufficient data to come to firm conclusions yet, but my perception is that the case against statins is building. Yes, they have benefits in specific subsets of people (none in others), but the notion that everybody needs a statin drug is, I believe, not only dead wrong, but may have effects that are distinctly negative. And I believe that the arguments in favor of omega-3 fatty acid supplementation, EPA and DHA (and perhaps DPA), make better sense.

 - See more at: http://blog.trackyourplaque.com/2013/06/are-statins-and-omega-3s-incompatible.html

Tuesday, June 11, 2013

Cholesterol and Why Statin Drugs are Harmful

Cholesterol and Why Statin Drugs are Harmful

For decades, health experts have told us to watch our cholesterol levels, lower our intake of saturated fats, and consume low-fat diets.

An estimated 102 million Americans have cholesterol levels higher than 200. More than 20 million Americans are on statin drugs to lower cholesterol.

In theory, if we were following recommendations from doctors, dietitians, fitness experts, and dutifully taking our medications, we should be see a reduction in disease.

But the fact is…
We don’t.

So, it’s important to ask…
  • Does eating high cholesterol foods correlate to rising cholesterol levels?
  • Do high cholesterol levels necessarily mean you are at higher risk for cardiovascular disease or heart attack?
  • Is the use of statin drugs safe and useful in reducing the levels of cholesterol in the body, thus lowering our disease risk?
A recent government study shows that raising levels of HDL “good” cholesterol using a drug did not diminish the chance of heart disease.
From the NY Times:
“Patients taking the medicine along with Zocor had higher levels of H.D.L. and lower levels of triglycerides, a fat in the blood. Despite these seeming improvements, the patients fared no better and may have done slightly worse than those taking Zocor alone. That is why the entire theory behind trying to increase H.D.L. levels in patients with heart disease may need rethinking.
In 2010 the British Medical Journal published a study revealing that the use of statin drugs was connected to liver, muscle, eye, and kidney problems. The results showed increased risk of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy and cataracts.

Dietary cholesterol levels are not related to serum cholesterol levels

According to Nora Gedgaudas, of Primal Body – Primal Mind:
“No study to date has adequately shown any significant link between dietary and serum cholesterol levels…or any significant causative link between cholesterol and actual heart disease. Other than in uncommon cases of genetically based ‘familial hypercholesterolemia’ (where natural mechanisms which regulate cholesterol production fail and the body cannot stop overproduction-even here the proof of the problematic nature of cholesterol is dubious, at best), cholesterol is perhaps only potentially deleterious in and of itself in oxidized forms, occurring as a result of food processing methods (such as in “reduced fat” milks, powdered milk/eggs) and high heat cooking/frying. Inflammatory processes can also be oxidizing of cholesterol in the body. Other than this, ALL cholesterol in the body is the same. ‘HDL’ and ‘LDL’ only reflect transport mechanisms for healthy cholesterol and are meaningless measures of coronary heart disease risk (Enig, Ravnskov).
It is also important to realize that ‘HDL’ and ‘LDL’ are NOT actual cholesterol at all, but merely the protein transport mechanism for cholesterol. Again, All cholesterol is exactly the same. LDL takes cholesterol away from the liver to the extremities and other organs for various purposes and HDL merely returns the same cholesterol to the liver where it may be recycled.”
Gedgaudas believes it is more important to find out why your cholesterol levels are up. When we have stress, infections, clogged arteries, high carbohydrate diets which cause insulin resistance and diabetes, weight issues, free radical activity, and low thyroid function, these can cause the liver to produce more cholesterol in order to deal with excess inflammation. If cholesterol levels are rising, it’s always a sign of some underlying problem, but it doesn’t mean cholesterol is causing the problem.

Doctors are missing the problem

Prescriptions for high cholesterol go hand-in-hand with recommendations for low-fat diets. This type of diet is not only tasteless and unsatisfying, it is also grossly deficient in the most nutrient-dense and health supporting foods on the planet: foods with healthy fats and cholesterol.

In the last five years, doctors have started recommending that obese children take statin drugs. Of course, there is little to no thought given to the staples of the Standard American children’s diet: highly processed, increasingly lower and lower in fat ast time goes on, high-carb, sugary foods with little to no nutritional content.

It’s a wonder doctors don’t draw the obvious conclusion that these foods might possibly be the culprit to children’s health and obesity issues. But they don’t. What’s more, they fail to give good, sound nutritional advice. The result is that some children end up on drugs because apparently providing real, healthy foods that support growth and development is not what they believe will solve the problem.

Truths about cholesterol:

  • Cholesterol is vital to health. Without it, we have hormonal, brain, heart, endocrine, and nervous system issues and damage. Lack of adequate cholesterol in the body leads to blood sugar imbalance, mineral deficiencies, chronic inflammation, infertility, allergies, and asthma.
  • Cholesterol is beneficial to the gastrointestinal environment and lining because it improves cell-membrane integrity and can also help reduce excessive permeability of substances through the intestinal wall and into the bloodstream.
  • Every cell in our bodies is made of cholesterol. Without it they would become leaky and porous, causing a flood of cholesterol taken from other parts of the body to repair damage.
  • Cholesterol is the precursor to Vitamin D, which is now known to be a hormone rather than a vitamin, and is responsible for helping to digest fats, mineral metabolism, protecting bones, strengthening the immune system
  • Cholesterol is a powerful anti-oxidant which protects the body from free-radical damage and aging
  • The theory of cholesterol being unhealthy was originally created by food processing industries to villanize animal fats and products, which are direct competitors to vegetable oils, and also from the pharmaceutical industry to develop a market to sell cholesterol-lowering drugs. Lipitor and other Statin drugs are enormous profit-bringers for pharmaceutical companies.

Truths about statin drugs:

  • Taking them only masks the problem going on in your body (for a little while) and doesn’t get to the cause of the problem, which is usually chronic inflammation due to poor dietary habits which cause nutritional deficiencies
  • They deplete your body of vital nutrients, such as C0Q10, which is essential to heart health. Cardiologist Dr. Peter Langsjoen conducted a study involving 20 patients with completely normal heart function. Six months later, after being on 20 mg daily of Lipitor (a low dose), two-thirds of the patients were found to have abnormalities in the filling phase of the heart. Langsjoen’s conclusion was that this occurred due to the depletion of CoQ10. A lack of C0Q10 causes muscle pain and weakness, due to the prevention of energy being produced in the mitrochondria in the cell.
  • These medications can also cause other types of muscle weakness and pain. In Denmark, researchers who studied 500,000 residents (approximately 9 percent of the population) discovered that those taking prescription medications to lower cholesterol were more likely to develop polyneuropathy, characterized as weakness and pain or tingling in the hands or feet and difficulty walking.
  • They cause a marked decrease of cholesterol-production in the brain. According to Dr. Barry Sears, this leads to a loss of memory due to diminished production of new synaptic connections and loss of memory.
  • They are costly in more ways than one: for your wallet and for your health. Eating healthy foods that naturally maintain normal cholesterol levels in the body costs less.
  • They causes other side-effects, one of them being liver damage. Liver damage is dangerous and can lead to other health issues that are very unpleasant, expensive, and time-consuming to treat

Would the real enemies please stand up?

  • Industrial fats – industrially-produced, polyunsaturated fats: canola, soybean, cottonseed, corn, peanut, safflower, and sunflower oils, shortening, butter substitutes and spreads, and other fake butter products. Some of these oils come from living things, but they are processed and chemically-altered which transforms them into trans-fats (even though the label may specifically read “no trans fats”), deodorized, and subjected to high- heat temperatures, rendering them nutritionally bankrupt and rancid.
  • Sugar - which causes metabolic syndrome and blood sugar imbalance, leading to insulin resistance and diabetes, and heart attacks. In 2009, the United States was ranked 4th in sugar consumption levels in the world.
  • Lack of nutrient-dense foods – modern diets are largely represented by nutritionally-deficient and heavily processed convenience foods which do not support the health of the human body. They cause build up in our arteries, liver damage, diabetes, premature aging, and cardiovascular disease.
  • Stress - periods of stress deplete nutrients in the body causing inflammation, which triggers disease.
Watch this informative video by Dr. Mark Hyman about cholesterol:

How to keep inflammation and cholesterol levels normal in your body

Real, traditional fats from healthy animals and birds on pasture actually make us healthier because they are easy to digest and are some of the most nutrient-dense foods available. Looking back over the historical past, the human diet has always contained large amounts of fat and cholesterol.
Dr. Weston A. Price, author of Nutrition and Physical Degeneration, analyzed foods consumed by traditional, primitive peoples all over the world. In these populations, health was robust and disease nearly non-existent. He discovered that their diets allowed for at least four times the calcium and other minerals, and at least 10 times the fat-soluble vitamins and amino acids as the modern diet which were obtained from animal foods such as eggs, fish, shellfish, animal fats like butter, lard, and tallow, and organ meats. All these foods were high in cholesterol and fat.
If you want to maintain good health:
  • Eat olive and coconut oil
  • Eat organic fruits and vegetables
  • If you do eat grains, eat them sparingly and prepare them properly through soaking, sprouting, or fermenting. Eat grains with healthy fats such as milk, cream, butter, cheese, and other healthy foods containing fats such as olive oil, coconut oil, lard, tallow, bone marrow, and grass-fed meats and poultry.
  • Avoid sugar – that means any refined carbohydrates – crackers, breads, rice cakes, cereals, pretzels, chips, bagels, pasta, desserts, sugary beverages (including juice and power “electrolyte” drinks).
  • Avoid unhealthy vegetable oils such as canola, soy, cottonseed, or safflower. These oils are too high in Omega 6s (which cause inflammation, cancer, and heart disease), are highly-processed at high temperatures making them rancid, and many of these oils are also likely to be genetically-modified as well, which has its own set of health risks.
  • Lower stress levels with moderate and enjoyable exercise and relaxation strategies. Stress can severely deplete nutrients in the body, leading to heart disease.
For more information:
Importance of Dietary Fats
Cholesterol and Health – Chris Masterjohn
The Benefits of High Cholesterol – Weston A. Price Foundation
Dangers of Statin Drugs: What You Haven’t Been Told About Popular Cholesterol-Lowering Drugs – WAP Foundation
The Oiling of America – Sally Fallon and Dr. Mary G. Enig, PhD
I have high cholesterol, and I don’t care – The Healthy Skeptic
Medication Sense – Dr. Jay S. Cohen
Suggested reading:
Fat and Cholesterol are Good for You by Uffe Ravnskov, MD, PhD
The Cholesterol Delusion by Ernest N. Curtis, M.D.

This post is part of Sarah The Healthy Home Economist’s Monday Mania.

Healthy Men Should Not Take Statins Says JAMA - Dach

Healthy Men Should Not Take Statins Says JAMA by Jeffrey Dach MDHealthy Men Should Not Take Statins Says JAMA by Jeffrey Dach MD

The title speaks for itself. This bombshell
article by Rita Redberg, MD, editor of the Archives of Internal Medicine, appeared in April 2012 JAMA advising healthy men with high cholesterol to stay away from statin anti-cholesterol drugs, pointing out there is no mortality benefit.  Dr Redberg goes on with a list of adverse side effects of statin drugs,  namely, myopathy, cognitive dysfunction, etc.   This JAMA article and debate is an outgrowth of the "Less is More" series in the Archives of Internal Medicine.    For fairness, JAMA also posted the opposing view by Dr. Blaha. 

For your convenience, I have posted Dr. Rita Redberg's
article here with links to the original.  Above left image: Statin Drug, Lipitor 40 mg tablets, Courtesy of The Week. Click Here for link to Dr Rita Redberg article in April 2012 JAMA.


Healthy Men Should Not Take Statins

by Rita F. Redberg, MD; Mitchell H. Katz, MD , 

Author Affiliations: Division of Cardiology, Department of Medicine, University of California, San Francisco (Dr Redberg); and Department of Health Services, County of Los Angeles, Los Angeles, California (Dr Katz).

Rita_Redberg_MD_Statins_Cholesterol_Jama_Wall_Street_JournalLeft Image: Courtesy of Wall Street Journal and Dr Rita Redberg.

Dr Redberg is also Editor, Archives of Internal Medicine. Dr Katz is also Deputy Editor, Archives of Internal Medicine.

Here is the Quote from the JAMA Article:

"Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD be treated with a statin?No "says Rita Redberg MD.

"Extensive epidemiologic data demonstrate that higher cholesterol levels are associated with a greater risk of heart disease. At the population level, higher levels of cholesterol are associated with a diet greater in fatty foods, particularly trans fat and meat, and low intake of fruits and vegetables.

The important questions for clinicians (and for patients) are as follows:

(1) does treatment of elevated cholesterol levels with statins in otherwise healthy persons decrease mortality or prevent other serious outcomes?

(2) What are the adverse effects associated with statin treatment in healthy persons?

(3) Do the potential benefits outweigh the potential risks? The answers to these questions suggest that statin therapy should not be recommended for men with elevated cholesterol who are otherwise healthy.

Benefits of Statin Therapy in Healthy Men With High Cholesterol?

Dr Ray Archives Int Med - NO Reduction in Mortality

    What is the benefit of statin therapy in healthy men with high cholesterol levels? Data from a meta-analysis of 11 trials including 65 229 persons with 244 000 person-years of follow-up in healthy but high-risk men and women showed no reduction in mortality associated with treatment with statins.(1 )

Cochrane Review - No Reduction in Mortality

A 2011 Cochrane review of treatment with statins among persons without documented coronary disease came to similar conclusions.(2) The Cochrane review also observed that all but one of the clinical trials providing evidence on this issue were sponsored by the pharmaceutical industry.

Biased Reporting in Industry Sponsored Drug Trials

It is well established that industry-sponsored trials are more likely than non–industry-sponsored trials to report favorable results for drug treatment because of biased reporting, biased interpretation, or both of trial results.(6)

Adverse Effects of Statins

What adverse effects are associated with statin treatment in healthy persons?

Myopathy, Muscle Pain, Weakness

All treatments designed to prevent disease—such as death from coronary disease—can also result in adverse effects. Data from observational studies show much higher rates for statin-associated myopathy and other adverse events in actual use than the 1% to 5% rate reported in clinical trials. This underestimation of adverse events occurs because the trials excluded up to 30% of patients with many common comorbidities, such as those with a history of muscular pains, as well as renal or hepatic insufficiency.(3)

Many randomized trials also excluded patients who had adverse effects of treatment during an open-label run-in period. For example, in the Treat to New Targets trial, after initial exclusions based on comorbidities, an additional 35% of eligible patients, or 16% of patients, were excluded during an 8-week, open-label, run-in phase because of adverse events, ischemic events, or participants' lipid levels while taking the drug not meeting entry criteria.7 Additionally, the results of randomized trials of statin treatment likely underestimate common symptoms such as myalgia, fatigue, and other minor muscle complaints because these studies often only collect data on more quantifiable adverse effects such as rhabdomyolysis.

Cognitive Impairment

    Numerous anecdotal reports as well as a small trial (8 - 9) have suggested that statin therapy causes cognitive impairment, but this adverse outcome would not have been captured in randomized trials. The true extent of cognitive impairment associated with statins remains understudied. It is disappointing that more data are not available on important adverse events associated with statin treatment, despite millions of prescriptions and many years of use. This information could be easily collected in observational studies and from registries. (8)(9)

One population-based cohort study in Great Britain of more than 2 million statin users found that statin use was associated with increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract.(4)

The risk of diabetes with statin use has been seen in randomized clinical trials such as JUPITER, which found a 3% risk of developing diabetes in the rosuvastatin group, significantly higher than in the placebo group.

In observational data from the Women's Health Initiative, there was an unadjusted 71% increased risk and 48% adjusted increased risk of diabetes in healthy women taking statins.(5)

Do the potential benefits outweigh the potential risks?

Based on all current evidence, a healthy man with elevated cholesterol will not live any longer if he takes statins. For every 100 patients with elevated cholesterol levels who take statins for 5 years, a myocardial infarction will be prevented in 1 or 2 patients.(7)

Preventing a heart attack is a meaningful outcome. However, by taking statins, 1 or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss. (3)


There are effective methods for reducing cardiovascular risk in otherwise healthy men: dietary modification, weight loss, and increased exercise.

These strategies are effective in increasing longevity and also result in other positive benefits, including improved mood and sexual function (10) and fewer fractures. Although these strategies are challenging, prescribing a statin may undermine them. For example, some patients derive a false sense of security that because they are taking a statin they can eat whatever they want and do not have to exercise.

Belief in Benefits of Statins for Patients Without CAD

For some clinicians, evidence that statins reduce the risk of recurrent coronary events in patients with documented coronary disease leads to the belief that statins also “must” be beneficial for patients without coronary disease.

However, recent history is rife with examples of interventions that are proven to work in patients with serious disease yet are not efficacious when generalized to patients without serious disease.

CABG Not a Good Choice for Single Vessel Disease

For example, coronary artery bypass graft (CABG) surgery is lifesaving for patients with symptomatic left main disease. However, CABG surgery would not be a good choice for single-vessel coronary artery disease (CAD) because risks would outweigh benefits in less extensive CAD. Similarly, the benefits of carotid endarterectomy in preventing stroke outweigh the risks for symptomatic patients with tight carotid artery stenosis, but not for asymptomatic patients with less critical stenosis. In addition, the use of aspirin is similar to statins for prevention.

Aspirin Not Useful For Primary Prevention

The data show clear benefit for aspirin in secondary prevention of cardiovascular disease, but not for primary prevention. Practitioners should not be generalizing from other settings when good data indicate that statins are not effective in improving length or quality of life when used for primary prevention.

For the 55-year-old man in this scenario, his risk of myocardial infarction in the next 10 years based on the Framingham Risk Score varies from 10% to 20%. His risk is driven mostly by his age rather than by his cholesterol level. Increasing age has a much larger influence on risk for cardiovascular disease than do increasing levels of cholesterol.

Recent data on increased risk of diabetes, cognitive dysfunction, and muscle pain associated with statins suggest that there is risk with no evidence of benefit.

Advising healthy patients to take a drug that does not offer the possibility to feel better or live longer and has significant adverse effects with potential decrement in quality of life is not in their interest.

At the same time, there are significant opportunities for improvement in lifestyle counseling and interventions. Even small changes in diet and increases in physical activity and smoking cessation can lead to significant personal and population health benefits. Such positive lifestyle changes have the key advantage of helping patients feel better and live longer. Lifestyle counseling should remain the focus of primarily prevention efforts—at the physician and public health levels.

AUTHOR INFORMATION: Corresponding Author: Rita F. Redberg, MD, Division of Cardiology, University of California, San Francisco, 505 Parnassus Ave, M1180, San Francisco, CA 94143 (redberg@medicine.ucsf.edu).

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: We thank Deborah Grady, MD, University of California, San Francisco, for her input in the writing of this Viewpoint. She was not compensated for her contribution." end quote

REFERENCES1) Ray KK, Seshasai SR, Erqou S,  et al.  Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants.  Arch Intern Med. 2010;170(12):1024-1031, PubMed

2) Taylor F, Ward K, Moore TH,  et al.  Statins for the primary prevention of cardiovascular disease.  Cochrane Database Syst Rev. 2011;(1):CD004816

3) Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy: a common dilemma not reflected in clinical trials.  Cleve Clin J Med. 2011;78(6):393-403. PubMed

4) Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database.  BMJ. 2010;340c2197.

5) Culver AL, Ockene IS, Balasubramanian R,  et al.  Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative.  Arch Intern Med. 2012;172(2):144-152.

6) Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review.  BMJ. 2003;326(7400):1167-1170

7) LaRosa J, Grundy SM, Waters DD,  et al.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  N Engl J Med. 2005;352(14):1425-1435 PubMed

8) Muldoon MF, Barger SD, Ryan CM,  et al.  Effects of lovastatin on cognitive function and psychological well-being.  Am J Med. 2000;108(7):538-546
PubMed CrossRef

9) Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults.  Am J Med. 2004;117(11):823-829
PubMed CrossRef

10) Gupta BP, Murad MH, Clifton MM, Prokop L, Nehra A, Kopecky SL. The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction: a systematic review and meta-analysis.  Arch Intern Med. 2011;171(20):1797-1803


Links to Articles with Related Content:

You Tube Videos by Dr Dach:

Links to all four parts of this series on You Tube:

part one: http://youtube.com/watch?v=b-iUJd4IxRM

part two: http://youtube.com/watch?v=RozkhmdHPac

part three: http://www.youtube.com/watch?v=_To64-NWKao

Part four: http://youtube.com/watch?v=gd6f8_GjAsg

Links to related articles of interest:

Lipitor and The Dracula of Modern Technology by Jeffrey Dach MD

Getting Off Statin Drug Stories

How to Reverse Heart Disease with the Coronary Calcium Score by Jeffrey Dach MD

Cholesterol Lowering Statin Drugs for Women, Just Say No

Reversing Heart Disease without Drugs

Cholesterol Lowering Drugs for the Elderly, Bad Idea by Jeffrey Dach MD

A Choirboy for Cholesterol Turns Disbeliever by Jeffrey Dach MD

More links and references

Listen to Debate Audio

Audio of Debate on Statins for Healthy Men in JAMA article with  Dr Rita Redberg vs Michael Blaha (opposition)

Author in the Room: Should a Healthy 55-Year-Old Man Be Treated with a Statin?
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May 2012 Author in the Room® Teleconference

Authors and Articles:

Michael Blaha, MD, MPH, suggests that the available data do support treatment:
Statin Therapy for Healthy Men Identified as “Increased Risk

Rita Redberg, MD, MSc, suggests that the available data do not support treatment.
Healthy Men Should Not Take Statins

Summary Points:Summary Points from Dr. Michael Blaha: High-quality literature supports statins for reduction of first heart attack and stroke, in addition to a mild decrease in all-cause mortality over 3 to 5 years.
    The key to efficient use of statins in primary prevention is risk stratification.
    We must demand high-quality evidence for benefit and for harm in a potentially beneficial medication class such as statins.
    Physicians should adhere to national guidelines to guide statin use in primary prevention.

Dueling viewpoints: Should a healthy middle-aged man with elevated cholesterol take a statin drug?  Posted by Gary Schwitzer in Journal practices

Should statins be used in primary prevention? JAMA gets in on the debate
April 10, 2012 Michael O'Riordan

Should everybody over fifty take statins to reduce health risks?  By Dr Robert Lefever


Healthy men should not take statin drugs for cholesterol
Apr 12, 2012- In the latest issue of the Journal of the American Medical Association (JAMA – April 11, 2012) opposing viewpoints are offered by two leading cardiologists with regard to the following question:
Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature coronary artery disease, be treated with a statin?

Statin Drugs – the JAMA Debate - The April 14th issue of the Journal of the American Medical Association inaugurated a new feature called "Viewpoint" -- an "in magazine" debating forum for arguing out key medical issues of the day. Think of it like a civilized version of Dan Aykroyd and Jane Curtain's Point/Counterpoint sketches on Saturday Night Live.1
Date: 04/23/2012 Written by: Jon Barron

Should statins be used in primary prevention?
theheart.org April 12 2012 Michael O'Riordan
Baltimore, MD and San Francisco, CA - Differing opinions on the use of statins in primary prevention make the pages of one of the leading medical journals this week, with the Journal of the American Medical Association (JAMA) the latest in a line of professional and mainstream media outlets getting in on the contentious topic [1,2]. Introduced by the JAMA editors to encourage discussion and debate [3], the inaugural "dueling viewpoints" kicks off its new series by considering the clinical question of whether or not a healthy 55-year-old male with elevated cholesterol levels should begin taking the lipid-lowering medication.

Why Asians Should Ignore the Cholesterol Sham, and Why Healthy People Should Not Take Statins.  Anthony Colpo | Saturday, April 28th, 2012

'Duel' over statins' use in healthy people moves to new venue
By Susan Perry | 04/17/12

January 23, 2012     
Rita Redberg and Roger Blumenthal Clash Over Statins for Primary Prevention in the Wall Street Journal 8    by Larry Husten • Uncategorized • Tags: mortality benefit, primary prevention   

The debate over whether statins should be used for primary prevention moved to the Wall Street Journal with opposing perspectives from cardiologists Roger Blumenthal and Rita Redberg.

Blumenthal argues that “there is a mountain of high-quality scientific evidence” to support the use of statins in people without known heart disease but “demonstrated to be at high risk for heart disease.”
Redberg argues that “for most healthy people, data show that statins do not prevent heart disease, nor extend life or improve quality of life. And they come with considerable side effects. That’s why I don’t recommend giving statins to healthy people, even those with higher cholesterol.”

Healthy Men Should Not Take Statins-Neither should Women! 04/23/2012
Most of you know what cholesterol lowering drugs are.  Below is a list of the names of the most common drugs out there.  The most unethical event is taking place to people that you know and care about.  The amount of cholesterol drugs consumed is up and the drug companies bottom line has gone up, but there is no change in the amount of heart disease.  In fact heart disease is still the number one killer by far and it continues to go up and up and up.  So what in the health are the statins for?

    Advicor  (lovastatin with niacin) – Abbott
    Altoprev (lovastatin) – Shionogi Pharma
    Caduet [atorvastatin with amlodipine (Norvasc)] – Pfizer
    Crestor (rosuvastatin) - AstraZeneca
    Lescol (fluvastatin) – Novartis
    Lipitor (atorvastatin) - Pfizer
    Mevacor (lovastatin) – Merck
    Pravachol (pravastatin) -- Bristol-Myers Squibb
    Simcor (niacin/imvastatin) – Abbott
    Vytorin (ezetimibe/simvastatin) – Merck/Schering-Plough
    Zocor (simvastatin) – Merck


Rita Redberg, F.A.C.C., M.Sc., M.D.

Cardiologist Dr. Rita Redberg is a cardiologist specializing in heart disease in women. She earned her medical degree from the University of Pennsylvania School of Medicine, in Philadelphia. She completed her residency at Columbia-Presbyterian Medical Center in New York, where she went on to complete a fellowship in cardiology. Then she completed a fellowship in non-invasive cardiology at Mount Sinai Medical Center, also in New York. In addition, Redberg has a masters of science in health policy and administration from the London School of Economics in England. Also she is currently a Robert Wood Johnson health policy fellow.
Redberg has written, edited and contributed to many books, including "You Can Be a Woman Cardiologist," "Heart Healthy: The Step-by-Step Guide to Preventing and Healing Heart Disease," and "Coronary Disease in Women: Evidence-Based Diagnosis and Treatment."

Clinics Cardiovascular Care and Prevention Center at Mission Bay
535 Mission Bay Blvd. South
San Francisco, CA 94158
Phone: (415) 353-2873
Fax: (415) 353-2528
Hours: Monday to Friday
8 a.m. – 5 p.m.

Statins for healthy people
Commentary by Prof John E Deanfield

Recently, prescribing statins to healthy people was discussed in the Journal of the American Medical Association. The main question is: should a healthy man aged 55 who has a blood pressure of 110 mm Hg, an LDL-cholesterol level of 6.46 mmol /L without family history take statins? Besides, the New England Journal of Medicine published a reflective publication on statins and the risk of diabetes. Links to these articles you will find below.

According to prof. John E. Deanfield (University College, London), statin therapy is a key part of multifactorial risk reduction strategies. Long term surveillance of risks and benefits are required, particularly for drugs given to very large numbers of people. The data we have so far are highly encouraging for statins.

Deanfield gives four good reasons to continue prescribing statins:

    The benefits of a healthy lifestyle should always be emphasised, but this is rarely adopted by patients.
    Statins provide an effective way of prolonging an event free survival and are generally safe, with increasing benefit over time.
    Thirdly the extremely well investigated potent statins atorvastatin and simvastatin are both generic and cheap
    It is important to consider the lifetime benefits of cardiovascular risk reduction in discussions with patients and not merely 5 and 10 year risks in those with cardiovascular disease..


Healthy Men Should Not Take Statins :
JAMA. 2012;307(14):1491-1492. doi:10.1001/jama.2012.423
Rita F. Redberg, MD; Mitchell H. Katz, MD

Statin Therapy for Healthy Men Identified as “Increased Risk”
JAMA. 2012;307(14):1489-1490. doi:10.1001/jama.2012.425
Michael J. Blaha, MD, MPH; Khurram Nasir, MD, MPH; Roger S. Blumenthal, MD

Statins: Is It Really Time to Reassess Benefits and Risks?
N Engl J Med 2012; 366:1752-1755May 10, 2012
Allison B. Goldfine, M.D.

Wall Street journal - <<<<<<<<<<>>>>>>>>>>


Should Healthy People Take Cholesterol Drugs to Prevent Heart Disease?


Healthy But With High Cholesterol: Should You Be Taking Statins?
Posted By Rob Leighton On 04/16/2012 - 8:05 am in the following categories :
Your healthy and feeling great, but you just found out that your LDL (bad) cholesterol is high. You do not have any of the standard risk factors, like a parent with heart disease.  Should you be taking a statin medication – perhaps for the rest of your life?

More and more doctors are coming to the conclusion that the answer is no.
In the April 2012 Journal of the American Medical Association (JAMA), two perspectives were presented.

Jeffrey Dach MD
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Davie, Fl 33314

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Saturday, June 8, 2013

Dietary Fats and Health - Lawrence

Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence1

Glen D. Lawrence* Department of Chemistry and Biochemistry, Long Island University, Brooklyn, NY
*To whom correspondence should be addressed. E-mail: lawrence@liu.edu.


Although early studies showed that saturated fat diets with very low levels of PUFAs increase serum cholesterol, whereas other studies showed high serum cholesterol increased the risk of coronary artery disease (CAD), the evidence of dietary saturated fats increasing CAD or causing premature death was weak. Over the years, data revealed that dietary saturated fatty acids (SFAs) are not associated with CAD and other adverse health effects or at worst are weakly associated in some analyses when other contributing factors may be overlooked. Several recent analyses indicate that SFAs, particularly in dairy products and coconut oil, can improve health. The evidence of ω6 polyunsaturated fatty acids (PUFAs) promoting inflammation and augmenting many diseases continues to grow, whereas ω3 PUFAs seem to counter these adverse effects. The replacement of saturated fats in the diet with carbohydrates, especially sugars, has resulted in increased obesity and its associated health complications. Well-established mechanisms have been proposed for the adverse health effects of some alternative or replacement nutrients, such as simple carbohydrates and PUFAs. The focus on dietary manipulation of serum cholesterol may be moot in view of numerous other factors that increase the risk of heart disease. The adverse health effects that have been associated with saturated fats in the past are most likely due to factors other than SFAs, which are discussed here. This review calls for a rational reevaluation of existing dietary recommendations that focus on minimizing dietary SFAs, for which mechanisms for adverse health effects are lacking.


Since the Framingham Heart Study reported that high serum cholesterol was a major risk factor for coronary heart disease (1), there has been an aggressive campaign in the medical community to decrease serum cholesterol. It has been a widely accepted belief that dietary saturated fats and dietary cholesterol cause an increase in serum total cholesterol, as well as LDL-cholesterol (LDL-C)2 and thereby increase the risk of heart disease if consumed (2). Over the years, it became clear that high levels of LDL circulating in the blood are susceptible to lipid peroxidation, which results in the oxidized LDL being scavenged by macrophages lining certain arteries, particularly around the heart, leading to atherosclerosis (3). Although this mechanism provides a role for high serum LDL-C causing atherosclerosis, evidence of the involvement of saturated fats is lacking, even though it is well established that a diet high in saturated fat increases serum cholesterol and a diet high in polyunsaturated oil decreases serum cholesterol (4, 5). In fact, PUFAs are the components that are oxidized and generate antigenic substances that are recognized by immune cells for clearance of oxidized LDL in atherogenesis (68).
Numerous reports and reviews in recent years have begun to call the perceived pernicious effects of dietary saturated fatty acids (SFAs) into question. The purpose of this review is to summarize the scientific understanding as it relates to dietary fats in health and disease, particularly with regard to the innocuous nature of SFAs and the physiological effects that have implicated PUFAs in numerous disorders and diseases. The role of dietary fats in cardiovascular disease (CVD) and many other diseases is complex, yet there is a powerful inertia that has allowed the saturated fat doctrine to endure.

Dietary fatty acids and serum cholesterol

Dietary fat studies in the mid-20th century stressed the relationship of dietary SFAs and PUFAs to serum cholesterol levels with an aim toward decreasing the likelihood of the development of coronary artery disease (CAD) and premature death (4, 5). Once lipoprotein fractions were separated in the blood, it became evident that LDL and VLDL were the carriers of cholesterol that were most closely associated with risk of heart disease (9). Later it was found that the ratio of total serum cholesterol to HDL-C was a better indicator of heart disease risk (10). By the 1990s, the mechanisms by which dietary fats and specific types of fatty acids were regulating serum cholesterol and lipoproteins were beginning to be revealed.
A family of proteins known as sterol regulatory element binding proteins (SREBPs) were discovered in the early 1990s. These proteins move to the nucleus in cholesterol-depleted cells to alter transcription of several genes involved in lipid metabolism (11). When intracellular cholesterol levels are low, SREBP-1 promotes expression of genes for synthesis of cholesterol and LDL receptors that remove cholesterol from the circulation. When intracellular cholesterol levels are high, SREBP-1 is not activated by protease cleavage, and the genes for cholesterol production and LDL receptors are downregulated. SREBP-1 also activates promoters for genes involved in fatty acid synthesis and lipid storage (12). PUFAs, particularly docosahexaenoic acid and others to a lesser extent, regulate expression of the SREBP genes (13, 14). Consequently, when PUFAs are present, there is less expression of SREBPs and enzymes for cholesterol synthesis, and the serum cholesterol pool decreases.
There appears to be a number of proteins that bind PUFAs and are involved in regulating gene expression, including a family of G protein–coupled receptors (15), as well as peroxisome proliferator–activated receptors-α and -γ, retinoid X receptors, and various other nuclear receptors (16). The liver uses a variety of these receptors or sensors for PUFAs to regulate storage and utilization versus oxidation of PUFAs (17). In this way, PUFAs can stimulate fatty acid oxidation in the liver to minimize their potential for free radical oxidation in the body when their levels are high in the diet. One must keep in mind that this complex array for regulation of expression of a wide range of genes is also subject to an even more complex array of responses to dietary PUFAs and other dietary factors.
Single nucleotide polymorphisms in genes for many of the above factors, as well as in genes for several apolipoproteins, TNFs, glutathione peroxidases, and other proteins result in a wide range of individual responses to dietary constituents. The consequences of such genetic variation can be either little change or very large changes in serum lipids and lipoproteins in response to diet, depending on an individual’s genetic makeup (18). However, one should not lose sight of the fact that levels of many other proteins are being altered in the process, which can give rise to a wide array of physiological responses that influence susceptibility to many unhealthy conditions, such as CVD and cancer.
Short-chain SFAs, such as those in dairy fat and coconut oil, can also influence gene expression via interactions with various G protein–coupled receptors that are linked to several hormonal responses, including insulin and leptin, that regulate overall energy metabolism in the body (19). It is clear that there are numerous sensors that respond to dietary PUFAs and short- or medium-chain SFAs (20).                     

Genetic factors

Brown and Goldstein (21) received the Nobel Prize in Physiology or Medicine in 1985 for their work on genetic defects in LDL receptors of people with familial hypercholesterolemia (FH). They identified several mutations that produce nonfunctional LDL receptors, resulting in death from atherosclerosis and heart disease at an early age. Individuals with FH have serum LDL-C in excess of 300 mg/dL (or 8 mmol/L), although LDL-C may be as high as 650 mg/dL (17 mmol/L) in homozygous individuals. Goldstein and Brown (22) also identified several genes that code for other proteins involved in cholesterol transport and metabolism, such as apolipoprotein B-100 (apo B), which is a component of LDL that binds to LDL receptors. There are other proteins involved in LDL synthesis, transport, and clearance that can result in a genetic predisposition to increased serum LDL cholesterol and FH (2325).
In the early 1990s, it was discovered that men with CVD tended to have smaller HDL particles than healthy controls (26). It was later found that LDL particle size was also significantly smaller in men with CAD than in case-matched controls (27), although another study showed the ratio of total serum cholesterol to HDL-C was a better predictor of CAD risk than LDL particle size (28). A prospective, population-based cohort study also found an increased risk of CAD in middle-aged men with smaller, dense LDL particles than in men with larger LDL particles, although the relationship did not show a linear dependence on particle size (29). It later became evident that LDL particle size was influenced by several factors and was not necessarily a useful predictor of heart disease risk; the nature of LDL is influenced by both dietary and genetic factors (30).
Lipoprotein (a) [Lp(a)] is a complex lipoprotein that has several properties in common with LDL. Like LDL and VLDL, Lp(a) contains apo B, but also contains highly variable forms of apolipoprotein(a) that strongly influence its atherogenicity and propensity to promote heart disease (31). The wide array of apolipoprotein(a) isoforms present in the human population may have caused some confusion regarding the role of Lp(a) in atherogenesis and CVD. The association of apo B with oxidized phospholipids was found to be dependent on Lp(a) (32). The presence of oxidized phospholipids and Lp(a) tend to be proinflammatory and promote atherogenesis.
Small, dense LDL particles rarely occur as an isolated condition, but are often associated with a specific phenotype that is characterized by hypertriglyceridemia, low HDL-C, abdominal obesity, insulin resistance, and other metabolic irregularities that lead to endothelial dysfunction and susceptibility to thrombosis (33). Small, dense LDL is also more susceptible to lipid peroxidation due to changes in the lipid composition, making it more atherogenic (34). LDL particles from the atherogenic phenotype contain less cholesterol and phospholipid, but more triglyceride. This phenotype is generally referred to as phenotype B and is characterized by elevated levels of apo B, which is found in LDL and VLDL (35).
There have been a host of proteins linked to lipoprotein metabolism and transport and a wide range of genetic variations identified that result in alterations of those proteins. Many are associated with HDL and larger HDL particle size, which is consistently associated with a decreased risk of CAD (36). HDL is important in reverse-cholesterol transport, bringing cholesterol from arterial deposits to the liver for processing, where it is converted to useful metabolites and eventually cleared from the body via bile secretions. A family of lipoprotein lipases, including hepatic lipase and endothelial lipase, are intimately involved in HDL metabolism. Endothelial lipase is upregulated during inflammation, a condition that increases LDL oxidation and atherogenesis (37). Genetic variation in apolipoprotein A-I, a major protein component of HDL, can result in larger but less stable HDL particles and decreased levels of circulating HDL (38). Cholesteryl ester transfer protein is generally considered to be protective, although this protein may transfer lipids from HDL to other lipoproteins that result in a less desirable serum lipid profile (39). HDL is emerging as a fascinating lipoprotein with a complex array of functions that involve both protein and lipid components. HDL has been found to influence immune function, vascular inflammation, glucose metabolism, and platelet function as well as other physiological phenomena unrelated to CVD (40).
Paraoxonase 1 (PON1) is another protein associated with HDL that exhibits esterase and lactonase enzyme activity, including metabolism of toxic organophosphorus pesticides and oxidized lipids in oxidized LDL particles. The levels of PON1 activity varies tremendously among humans, which depends to a large degree on genetic variation. However, environmental factors, such as dietary antioxidant consumption, alcohol consumption, and certain drugs can also influence PON1 activity (41). Dietary olive oil can increase levels of serum PON1 in some individuals, which is genotype dependent (42), whereas MUFAs and PUFAs can inhibit PON1 enzymatic activity (43). SFAs (palmitic and myristic) had virtually no effect on PON1 enzymatic activity. A recent study found that HDL isolated from patients with CAD lacks endothelial anti-inflammatory properties, has lower PON1 enzyme activity, and does not promote endothelial nitric oxide production (44), all of which are most likely tied to genetic rather than dietary factors.

Fatty acids involved in atherogenesis and CVD

Linoleic acid makes LDL more susceptible to lipid peroxidation and subsequent deposition of the oxidized LDL in macrophages lining the arteries (45). Several lipid peroxidation products have been shown to trigger transformation of circulating monocytes to macrophages that line the arteries and ultimately become foam cells (46, 47). Lipid peroxidation products also signal cells in the arterial intima to encapsulate foam cells by surrounding them with extracellular matrix proteins and eventually calcify the matrix (48). It would stand to reason that a greater abundance of PUFAs, relative to SFAs and MUFAs, during conditions of oxidative stress would provoke atherogenesis. The fibrous cap that is formed over fatty deposits makes them inaccessible to apolipoproteins such as apolipoprotein A-I or E, which are components of HDL, the lipoprotein that removes cholesterol from these deposits (49). The protein cap is characteristic of advanced atherosclerotic plaque and erosion of this protective cap by extracellular metalloproteases can release collagen and collagen-like fragments that trigger blood platelets to initiate a blood clot, which results in myocardial infarction or stroke (3).
Because saturated fats are not susceptible to lipid peroxidation, they have not been found to be involved in these mechanisms. This begs the question of how dietary polyunsaturated oils seem to lower the risk of CAD, even though many studies have shown no such effect. One important consideration is that foods that are considered sources of predominantly saturated fats, such as meats, are often cooked at high temperatures, which can induce lipid peroxidation in the minor amounts of PUFAs present in those animal products (5052). Oxidative stress and lipid peroxidation products are known to promote heart disease, cancer, and several other chronic diseases (53, 54). High-temperature cooking can also oxidize carbohydrates, producing a range of toxic oxidation products that promote oxidative stress, type 2 diabetes, and CVD (55). The preparation and cooking methods used for foods that are traditionally classified as saturated fat foods may be producing substances from PUFAs and carbohydrates in those foods that are promoting disease.
Human food preferences tend to favor foods with both fats and sugar (56), which complicates any attempts to correlate saturated fats with disease. Sugars readily undergo oxidation, with fructose generally getting oxidized many times faster than glucose, whereas sucrose is relatively resistant to oxidation (57). The oxidation products of these monosaccharides include glyoxal, methylglyoxal, and formaldehyde. Methylglyoxal has been shown to promote endothelial dysfunction as well as hypercholesterolemia in rats (58). Methylglyoxal is also associated with increased atherosclerosis and hypertension in humans (59). Formaldehyde and methylglyoxal have been implicated in endothelial injury, oxidative stress, and angiopathy (60).
Many clinical studies show that there are fewer coronary events when polyunsaturated oils replace saturated fats in the diet (61). However, a recent meta-analysis found that interventions using mixed ω3 and ω6 PUFAs resulted in a significant (22%) decrease in CAD events compared with control diets with fewer PUFAs. However, interventions that used ω6 polyunsaturated oils with no ω3 PUFAs showed ∼16% more cardiovascular events compared with the control diets, although the increased number was not statistically significant (62). It would seem that even moderate amounts of ω3 PUFAs in the diet result in attenuation of inflammatory responses that are reflected in the significant reduction in coronary events observed with increasing dietary PUFAs. Of the common vegetable oils, soy oil contains ∼7% ω3 PUFAs and canola oil as much as 10% ω3 PUFAs, whereas corn, safflower, and sunflower oils generally contain <1 a="" class="xref-bibr" href="http://advances.nutrition.org/content/4/3/294.long#ref-63" id="xref-ref-63-1" pufas="">63
). Another systematic review found insufficient evidence to support an association (positive or negative) between CAD and several dietary factors, including SFAs or PUFAs, α-linolenic acid, total fat, meat, eggs, and milk (64).

Lipid peroxidation and inflammation

Lipid peroxidation is invoked as a mechanism for numerous adverse health effects, such as aging, cancer, atherosclerosis, and tissue necrosis. The greater in vivo susceptibility of ω6 PUFAs relative to the ω3 PUFAs, has placed the spotlight on these fatty acids as contributing to or exacerbating many ailments (68). The metabolism of arachidonic acid to bioactive eicosanoids is responsible for many of the biological processes that lead to inflammation. Indeed, steroidal and nonsteroidal anti-inflammatory drugs suppress inflammation by blocking the release of arachidonic acid from membranes or its subsequent metabolism to eicosanoids.
Studies of inflammation in rats have found that dietary manipulation of relative amounts of ω6 PUFA precursors can have profound effects on the degree of inflammation. Predominantly SFAs in the diet result in far less inflammation than diets with either ω3 (69) or ω6 PUFAs (70). Several studies have shown that dietary supplementation with ω3 PUFAs can reduce inflammation and make patients less dependent on drug therapy to manage the pain and stiffness of arthritis (7173). Patients should be advised to minimize their intake of ω6 oils when attempting ω3 supplementation as a therapeutic approach to reduce the inflammation of arthritis and other inflammatory syndromes (74, 75). Small amounts of ω3 supplements in a sea of dietary ω6 oils would have relatively little chance of changing the course of an inflammatory response. Because dietary saturated fats do not promote inflammation, it may be wiser to minimize ω6 PUFAs and consume more SFAs to reduce various types of inflammation; most sources of MUFAs contain significant amounts of PUFAs as well. There have been few scientific studies along these lines because of the misguided concern that saturated fats, even those from vegetable sources such as palm and coconut oil, would be detrimental to one’s health.
The efficacy of ω3 supplements for inflammatory syndromes other than rheumatoid arthritis are less persuasive, although study designs are questioned regarding whether patients are advised to reduce their ω6 fatty acid intake (76). Fish oil supplements improved pulmonary function in some asthmatics (responders) but not in others (nonresponders). A relatively high ratio (10:1) of dietary ω6 to ω3 PUFAs resulted in diminished respiratory function in methacholine-provoked asthmatics, whereas a lower ratio (2:1) produced significant improvement in >40% of the study participants (77). A study in Japan showed beneficial effects of ω3 supplements in asthmatic children in a controlled hospital ward environment (78). A comparison of dietary saturated fats with polyunsaturated oils was not found in the literature for asthma studies. Such an approach would be logical for this life-threatening condition, in view of the benign nature of saturated fats and the fact that carbohydrates, especially sugars, may actually be augmenting the incidence of asthma (79).

Are low-fat, low-saturated fat diets healthier?

Studies with laboratory animals have shown that high-fat diets promote chemically induced cancers (80, 81). A study of chemically induced mammary tumors in rats found that ω6 PUFAs promoted tumor proliferation, whereas saturated fats or ω3 PUFAs did not promote tumors as much or even suppressed tumors, depending on what one uses as a reference (82, 83). Although 1 review and meta-analysis found that linoleic acid, the predominant ω6 fatty acid in vegetable oils, is not a risk factor for breast, colorectal, and prostate cancers in humans (84), there is evidence to the contrary that high intake of ω6 relative to ω3 PUFAs increases cancer risks (8587). There are multiple processes by which ω6 fatty acids can promote carcinogenesis; production of bioactive eicosanoids from arachidonic acid is 1 mechanism (88, 89). Nonsteroidal anti-inflammatory drugs as well as cyclooxygenase-2 inhibitors can suppress tumors by inhibiting production of prostaglandins, particularly those of the ω6 variety (90). Lipid peroxides are also known to promote chemically induced tumors (91), and PUFAs are highly susceptible to lipid peroxidation.
Investigators often seem to have a particular bias against saturated fats. One report showed that red meat alone was not significantly associated with colorectal cancer, although there was some increase in colorectal cancers with higher red meat intake [HR = 1.17 for highest vs. lowest intakes (95% CI = 0.92–1.49, P-trend = 0.08)]. Processed meats were significantly associated [HR = 1.42 (95% CI = 1.09–1.86, P-trend = 0.02)]. The authors then combined the data for red meat and processed meat to give a significant association and concluded that red and processed meat are positively associated with colorectal cancer (92). When specific types of meat were analyzed, significant risk was associated with pork [HR = 1.18 (95% CI = 0.95–1.48, P-trend = 0.02)] and lamb [HR = 1.22 (95% CI = 0.96–1.55, P-trend = 0.03)], but not with beef/or veal [HR = 1.03 (95% CI = 0.86–1.24, P-trend = 0.76)]. It is interesting to note that in 1 study, beef had a much lower ratio of PUFAs to SFAs than pork, but nearly the same ratio of PUFAs to SFAs as sheep (93). The ratio of MUFAs to SFAs in beef also varies, as it does in most meats, with the ratio ranging from ∼0.8 to 1.8, depending on breed and feeding practices (94).
Nitrite used in the preservation of many processed meats is known to form a carcinogen with secondary amines under acidic conditions that would prevail in the stomach (95). Others have found no association of red meat and only a very weak association of processed meat with breast cancer (96) and prostate cancer (97). Most studies find no differences in cancer risk with different types of fat, but do find associations with high levels of fat in the diet (81).
A recent meta-analysis (98) reviewed 20 studies with >1 million subjects and found that red meat was not associated with CAD events [RR = 1.00 (95% CI = 0.81–1.23, P-trend = 0.36)]. In contrast, processed meats were associated with increased incidence of CAD [RR = 1.42 (95% CI = 1.07–1.89, P-trend = 0.04)]. This indicates that saturated fat per se is not increasing CAD events, but other factors are, such as preservatives used in processed meats or other dietary substances that are being consumed in conjunction with processed meats. It is important to keep in mind that meats generally contain as much MUFA as SFA. Others are beginning to challenge the saturated fat hypothesis with closer analyses of past studies (99103).
Campaigns were waged against tropical oils (palm and coconut oils) in the early 1980s because of their high levels of SFAs, even though palm oil contains about as much MUFAs acids as SFAs and has an ample amount of PUFAs to keep serum cholesterol low. In fact, 2 studies showed that the higher ratio of SFAs to MUFAs in palm oil (1.1:1) compared with olive oil (0.22:1) had no effect on serum lipids in healthy volunteers (104, 105). Palm oil and olive oil have similar amounts (∼10%) of PUFAs. SFAs in coconut oil increase serum HDL-C more than LDL-C to give a more favorable lipid profile relative to dietary carbohydrates (10). Claims that tropical oils with a high SFA content increase the risk of CAD lack clear scientific evidence to that effect. Indeed, countries with high intake of tropical oils have some of the lowest rates of heart disease in the world (106).
Many of the shorter chain fatty acids found in milk fat and coconut oil have beneficial health effects. The shorter chain SFA in milk (C4–C12) are not only metabolized rapidly for energy in infants, but have been found to have important antiviral, antimicrobial, antitumor, and immune response functions (107). Lauric acid, which is present in milk and the most abundant fatty acid in coconut oil, is effective in preventing tooth decay and plaque buildup (108). Diets rich in coconut oils have also been shown to lower other risk factors for CAD, such as tissue plasminogen activator antigen and Lp(a) (109). The medium-chain SFAs in coconut oil and butterfat (milk) increase total serum cholesterol, but their positive effects on HDL-C are protective in many ways. There is also evidence that proteins, fats, and calcium in milk are beneficial in lowering blood pressure, inflammation, and the risk of type 2 diabetes (110, 111). Indeed, these constituents of milk have clear beneficial effects against metabolic syndrome, which is a major factor in promoting heart disease, as well as premature death from a variety of causes (112).
There has been a spate of recent publications in the biomedical literature that question the negative perception that dairy fats are bad for health. One meta-analysis showed that participants in prospective studies with the highest consumption of dairy products had a lower RR for all-cause mortality as well as for CAD, stroke, and diabetes compared with the lowest intake of dairy products (113). Many of the studies included in the analysis started before low-fat milk was available on the market. Another review arrived at the same conclusion that consumption of dairy products is not associated with higher risk of CVD (100). Although prospective cohort studies often find a significant reduction in the incidence of CAD with a larger ratio of PUFAs to SFAs in the diet (114), there are often many other factors related to overall health that correlate with the unsaturated to SFA ratio, such as exercise, a healthier lifestyle, and more fiber and less sugar in the diet.

Less fat generally means more carbohydrate

It should not be surprising that substitution of carbohydrates (starches) for saturated fats in the diet has relatively little effect on serum lipids. Excess carbohydrates are converted to fats for efficient energy storage, and the human body synthesizes primarily SFAs from excess carbohydrates, although MUFAs are also formed. Consequently, from a physiological viewpoint, there is no reason to believe that replacing fat in the diet with carbohydrate at a constant caloric intake will improve the serum lipid profile significantly. Indeed, a low-fat, high-carbohydrate diet causes an increase in serum triglycerides and small, dense LDL particles (115), which are more strongly associated with CAD than serum total cholesterol or LDL-C. When dietary fat is replaced by carbohydrate without changing the fatty acid composition of the fat, there is no change in LDL-C or HDL-C, but there is an increase in serum triglycerides (116). However, if there is a higher percentage of PUFAs and lower SFAs in a low-fat diet, serum total cholesterol and LDL-C will decrease (117).
Young children who consumed more fruit juice than their peers were shorter in stature and had greater BMI than their peers who drank less fruit juice (118). A trend of increased fruit juice consumption by infants and children in recent years has coincided with a decrease in milk consumption (119). The rates of childhood obesity have skyrocketed since the introduction of low-fat milk, although high fructose corn syrup (HFCS) became omnipresent in foods at the same time and is more strongly associated with obesity than dietary fat (120, 121). As stated previously, the short-chain SFAs in milk provide valuable antibacterial and antiviral activities, which would result in healthier children. The short-chain SFAs found in milk act as signaling agents in the immune system (122). Infections in children also correlated with higher levels of atherogenic oxidized LDL, as well as lower levels of HDL (123). It is possible that oxidized LDL and low HDL impart increased susceptibility to infection, although the combination of infections and an adverse serum lipid profile may both result from an undesirable diet, i.e., more sugar and fewer healthy fats.
Food processors generally add large amounts of sugar to fat-free or low-fat foods to make them more palatable to consumers. Fructose is 1 dietary constituent that is consistently found to have adverse health consequences, and the larger the proportion of fructose is in the diet, the more formidable the effect. The adverse effects of fructose that have been documented include increased serum triglycerides, particularly in men (124, 125); increased serum uric acid, which is associated with gout and hypertension (126); increased lipid peroxidation (57) and increased oxidation of LDL (127); increased oxidative stress in animal models (128); greater risk of the development of metabolic syndrome, including obesity, insulin resistance, hypertension, and CVD risk (129, 130); increased nonalcoholic fatty liver disease (131); and increased systemic inflammation and associated renal disease (132).
There are clearly many established physiological mechanisms by which fructose increases CVD and several other diseases. Whether the source of dietary fructose is sucrose or HFCS would seem irrelevant, although sucrose is 50% fructose, whereas the most common dietary source of HFCS (soft drinks) is generally 55% fructose and ∼43% glucose. Solutions of fructose are also highly susceptible to autoxidation, producing a host of toxic products (57), whereas sucrose is highly resistant to oxidation. The toxic products from fructose oxidation include formaldehyde and α-dicarbonyls. Although saturated fats have been implicated in many of the adverse health effects attributed to fructose, there is no scientific evidence to support a role for saturated fats in the physiological mechanisms. On the other hand, plausible mechanisms are proposed for all of the unhealthy conditions promoted by high fructose intake mentioned earlier.
It turns out that a high level of fructose in the diet increases plasma triglycerides, which leads to not only increased levels of VLDL and small, dense LDL particles, but increased levels of oxidized LDL, insulin resistance, and other metabolic consequences linked to metabolic syndrome and dyslipidemia (133). The mechanisms by which fructose promotes inflammation and elevated levels of uric acid and several cytokines have been reviewed (132).                       


Saturated fats are benign with regard to inflammatory effects, as are the MUFAs. The meager effect that saturated fats have on serum cholesterol levels when modest but adequate amounts of polyunsaturated oils are included in the diet, and the lack of any clear evidence that saturated fats are promoting any of the conditions that can be attributed to PUFA makes one wonder how saturated fats got such a bad reputation in the health literature. The influence of dietary fats on serum cholesterol has been overstated, and a physiological mechanism for saturated fats causing heart disease is still missing.
Various aldehydes produced in the oxidation of PUFAs, as well as sugars, are known to initiate or augment several diseases, such as cancer, inflammation, asthma, type 2 diabetes, atherosclerosis, and endothelial dysfunction. Saturated fats per se may not be responsible for many of the adverse health effects with which they have been associated; instead, oxidation of PUFAs in those foods may be the cause of any associations that have been found. Consequently, the dietary recommendations to restrict saturated fats in the diet should be revised to reflect differences in handling before consumption, e.g., dairy fats are generally not heated to high temperatures. It is time to reevaluate the dietary recommendations that focus on lowering serum cholesterol and to use a more holistic approach to dietary policy.


The sole author had responsibility for all parts of the manuscript.


  • 1 Author disclosure: G. D. Lawrence, no conflicts of interest.
  • 2 Abbreviations used: apo B; apolipoprotein B-100; CAD, coronary artery disease; CVD, cardiovascular disease; FH, familial hypercholesterolemia; HDL-C, HDL cholesterol; HFCS, high fructose corn syrup; LDL-C, LDL cholesterol; Lp(a), lipoprotein(a); PON1, paraoxonase 1; SFA, saturated fatty acid; SREBP, sterol regulatory element binding protein.
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