Showing posts with label C-reactive Protein. Show all posts

Thursday, March 6, 2014

Early atherogenesis and visceral fat in obese adolescents

A H Slyper, H Rosenberg, A Kabra, M J Weiss, B Blech, S Gensler and M Matsumura

Background/Objectives:

Little information is available as to the cause of increased thickening of the intima-media of the carotid artery (cIMT) in the pediatric population. Therefore, cIMT was compared in obese adolescents and normal-weight controls, and associations between cIMT and lipid and non-lipid cardiovascular risk factors were assessed.

Subjects/Methods:

Subjects included 61 obese non-diabetic male and female volunteers aged 12–18 years inclusive with a body mass index (BMI) >95th percentile for age and 2-h blood glucose <200 class="mb" span="">

mg dl⁻¹ matched to 25 normal-weight control volunteers with normal glucose levels. Each subject underwent a 2-h glucose tolerance test and measurement of hemoglobin A1c, ultrasensitive C-reactive protein, fasting insulin, blood lipids, visceral, subcutaneous abdominal and hepatic fat, and cIMT.

Results:

Maximum cIMT was 0.647±0.075 mm in the obese subjects versus 0.579±0.027 mm in normal-weight controls (P<0 .001="" 2-h="" and="" assessment="" between="" bmi="" cholesterol="" cimt="" correlations="" difference="" fasting="" female="" glucose="" hdl="" high-density="" homeostasis="" in="" insulin="" ldl="" lipoprotein="" low-density="" male="" maximum="" model="" no="" significant="" sub="" subjects.="" there="" total="" very="" was="" were="" z-score="">2

cholesterol, HDL₃ cholesterol, triglycerides, remnant lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, lipoprotein(a), apoprotein B100, abdominal subcutaneous fat volume, visceral fat volume and hepatic phase difference. On multiple regression analysis, visceral fat was the most significant predictor of maximum cIMT. Two-hour blood glucose, HOMA and systolic blood pressure were also significant predictors of maximum cIMT.

Conclusions:

cIMT was increased in the obese adolescents compared with the normal-weight-matched controls. Visceral fat was a key predictor of arterial wall thickening in these subjects. The results suggest that the focus of cardiovascular disease prevention in the adolescent obese should be visceral obesity, and not blood lipids or lipid subclasses.

Saturday, March 30, 2013

Why Women Should Stop Their Cholesterol Lowering Medication - Hyman

Why Women Should Stop Their Cholesterol Lowering Medication

by Dr Mark Hyman January 19th, 2012

If you are a post-menopausal women with high cholesterol, your doctor will almost certainly recommend cholesterol lowering medication or statins. And it just might kill you. A new study in the Archives of Internal Medicine found that statins increase the risk of getting diabetes by 71 percent in post-menopausal women.

Since diabetes is a major cause of heart disease, this study calls into question current recommendations and guidelines from most professional medical associations and physicians. The recommendation for women to take statins to prevent heart attacks (called primary prevention) may do more harm than good.

Statins have been proven to prevent second heart attacks, but not first heart attacks.

Take it if you already have had one, but beware if your doctor recommends it for you if have never had a heart attack.

This current study adds to an increasing body of literature questioning the benefits of statins, while highlighting their potential risks.

New Study Shows 48 Percent Risk of Diabetes in Women Who Take Statins

This study examined the data from the large government sponsored study called the Women’s Health Initiative, the same study that disabused us of the idea that Premarin prevented heart attacks in postmenopausal women.

In fact, based on this randomized controlled trial, estrogen replacement therapy, once considered the gold standard of medical care for the prevention of heart disease, was relegated to the trash bin of history joining medicine’s many other fallen heroes including DES, Thalidomide, Vioxx, Avandia, and more.

In this new study researchers reviewed the effect of statin prescriptions in a group of 153,840 women without diabetes and with an average age of 63.2 years. About 7 percent of women reported taking statin medication between 1993 and 1996. Today there are many, many more women taking statin medications, thus many more are at risk from harm from statins.

During the 3-year period of the study, 10,242 new cases were reported – a whopping 71 percent increase in risk from women who didn’t take statins. This association stayed strong at a 48 percent increased risk of getting diabetes, even after taking into account age, race/ethnicity, and weight or body mass index. These increases in disease risk were consistent for all statins on the market.
This effect also occurred in those with and without heart disease. Surprisingly disease risk was worse in thin women. Minority women were also disproportionately affected. The risk of diabetes was 49 percent for white women, 57 percent for Hispanic women, and 78 percent for Asian women.
But in a typical “my mind’s made up, don’t confuse me with the facts” statement by the medical establishment, the researchers said we should not change our guidelines for statin use for the primary prevention of heart disease.

In a large meta-analysis published in the Lancet last year, scientists found that statins increased the risk of diabetes by 9 percent. If current guidelines were followed for those who should take statins, and people actually took them (thank God only 50 percent of prescriptions are ever filled by patients), there would be 3 million more diabetics in America. Oops.

Other studies have recently called into question the belief that high cholesterol levels increase your risk of heart disease as you get older. For those over 85 it turns out having high cholesterol will protect you from dying from a heart attack, and, in fact, from death from any cause.

Low Cholesterol May Kill You

A recent study showed that in healthy older persons, high cholesterol levels were associated with lower non-cardiovascular-related mortality. This is extremely concerning because millions of prescriptions are written every day to lower cholesterol in the older population, yet no association has been found between higher cholesterol and heart disease deaths for those aged 55 to 84; and for those over 85, the association seems to be inverse — higher cholesterol predicts lower risk of death from heart disease.

The pharmaceutical industry, medical associations, and academic researchers whose budgets are provided by grants from the pharmaceutical industry continue to preach the wonders of statins, but studies like these should have us look good and hard at our current practices. Are we doing more harm than good?

Cardiologists recommend putting statins in the water and giving them out at fast food restaurants and having them available over the counter. They believe in driving cholesterol as low as possible. Statin prescriptions are handed out with religious fervor, but do they work to prevent heart attacks and death if you haven’t had a heart attack already?

Bottom line: NO! If you want to learn why this is true, read on.

Statins Don’t Work to Prevent First Heart Attacks

Recently, the Cochrane Group did a review of all the major statin studies by an international group of independent scientists. The review failed to show benefit in using statins to prevent heart attacks and death. In addition, many other studies support this and point out the frequent and significant side effects that come with taking these drugs. (i) If scientists found that drinking two glasses of water in the morning prevented heart attacks, even if the evidence was weak, we would jump on board. Big up side, no down side.

But this is not the case with statins. These drugs frequently cause muscle damage, muscle cramps, muscle weakness, muscle aches, exercise intolerance (ii) (even in the absence of pain and elevated CPK – a muscle enzyme), sexual dysfunction, liver and nerve damage and other problems in 10-15 percent of patients who take them. (iii) They can also cause significant cellular, muscle, and nerve injury as well as cell death in the ABSENCE of symptoms. (iv)

There is no lack of research calling into question the benefits of statins. Unfortunately, that research doesn’t get the benefit of billions of dollars of marketing and advertising that statins do. One big trial was touted as proving statins work to prevent heart attacks, but the devil is in the details.

It was the JUPITER (v) trial that showed that lowering LDL (or bad cholesterol) without a reduction in inflammation (measured by C-reactive protein) didn’t prevent heart attacks or death. (vi) Statins happen to reduce inflammation so the study has been touted as proof of the effectiveness of these medications.

Mind you it wasn’t lowering the cholesterol that helped (which is the intended purpose of statins), but the fact that they lower inflammation. What is ignored by people who use this study to “prove” that statins work is the fact that there are so many better ways to lower inflammation than taking these drugs.

Yet other studies have shown no proven benefit for statins in healthy women (vii) with high cholesterol or in anyone over 69 years old. (viii) Some studies even show that aggressive lowering of cholesterol can cause MORE heart disease. The ENHANCE trial showed that aggressive cholesterol treatment with two medications (Zocor and Zetia) lowered cholesterol much more than one drug alone, but led to more arterial plaque and no fewer heart attacks. (ix)

Other research calls into question our focus on LDL or the bad cholesterol. We focus on it because we have good drugs to lower it, but it may not be the real problem. The real problem is low HDL that is caused by insulin resistance (diabesity).

In fact studies show that if you lower the bad (LDL) cholesterol in people with low HDL (good cholesterol) that is a marker of diabesity – the continuum of obesity, prediabetes and diabetes – there’s no benefit. (x)

Most people simply ignore the fact that 50-75 percent of people who have heart attacks have normal cholesterol. (xi) The Honolulu Heart Study showed older patients with lower cholesterol have higher risks of death than those with higher cholesterol. (xii)

Some patients with multiple risk factors, or who have had previous heart attacks do benefit, but when you look closely the results are underwhelming. It’s all in how you spin the numbers. For high-risk males (those who are overweight and have high blood pressure, diabetes, and/or a family history of heart attacks) and are younger than 69 there is some evidence of benefit, but one hundred men would need to be treated to prevent just one heart attack.

That means that 99/100 men who take the drug receive no benefit. Drug ads say the risk is reduced by 33 percent. Sounds good, but that just means the risk of getting a heart attack goes down from 3 percent to 2 percent.

Despite the extensive data showing that statins are a questionable therapy at best, they are still the number one selling drug in the US. What isn’t so well known is that 75 percent of statin prescriptions are written for people who will receive no proven benefit. The cost of these prescriptions? Over $20 billion a year.

Yet somehow the 2004 National Cholesterol Education Program guidelines expanded the previous guidelines to recommend that even more people without heart disease take statins (from 13 million to 40 million) (xiii) What are we thinking?

Why would respected scientists go against the overwhelming research that statins don’t prevent heart disease in people who haven’t already had a heart attack?

You can find the answer if you follow the money. Eight of the nine experts on the panel who developed these guidelines had financial ties to the drug industry. Thirty-four other non-industry affiliated experts sent a petition to protest the recommendations to the National Institutes of Health saying the evidence was weak.

What Should Women Do?
It is time to push the sacred cow of statins overboard.
But first let me say this. If you have had a heart attack, or have heart disease, the evidence shows they do in fact help protect against a second heart attack, so keep taking them. However, you should be aware that most prescriptions for statins are given to healthy people whose cholesterol is a little high. For these folks the risk clearly outweighs the benefit.

The editorial that accompanies the recent study on women taking cholesterol-lowering medication that I opened this article with was quite clear. Dr. Kirsten Johansen from the University of California, San Francisco said that the increased risk of diabetes in women without heart disease has “important implications for the balance of risk and benefit of statins in the setting of primary prevention in which previous meta-analyses show no benefit on all-cause mortality.”

In plain English, she said that we shouldn’t be using statin drugs for women without heart disease because:

The evidence shows they don’t work to prevent heart attacks if you never had one.
They significantly increase the risk of diabetes.

Treating risk factors like high cholesterol is misguided. We must treat causes – what we eat, how much we exercise, how we handle stress, our social connections and environmental toxins are all more powerfully linked to creating health and preventing disease than any drug on the market.
Remember what you put at the end of your fork is more powerful than anything you will ever find at the bottom of a pill bottle.

My new book The Blood Sugar Solution, which comes out at the end of February, gives exact details on what you should put at the end of your fork to prevent and reverse diabesity. It provides a comprehensive solution to the health problems facing our nation today.

Now I’d like to hear from you …

What do you think of statins?

Have you taken statins? What has your experience been?

Why do you think the medical establishment prescribes drugs that research shows don’t work?
Please leave your thoughts by adding a comment below – but remember, we can’t offer personal medical advice online, so be sure to limit your comments to those about taking back our health!

To your good health,
Mark Hyman, MD

References:

(i) Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007 Jan 20;369(9557):168-9

(ii) Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008 Jun;8(3):333-8.

(iii) Kuncl RW. Agents and mechanisms of toxic myopathy. Curr Opin Neurol. 2009 Oct;22(5):506-15. PubMed PMID: 19680127.

(iv) Tsivgoulis G, et. al, Presymptomatic Neuromuscular Disorders Disclosed Following Statin Treatment, Arch Intern Med. 2006;166:1519-1524

(v) Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)–can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol. 2006 Jan 16;97(2A):33A-41A.

(vi) Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.

(vii)Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007 Jan 20;369(9557):168-9

(viii) IBID

(ix) Brown BG, Taylor AJ Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? Engl J Med 358:1504, April 3, 2008 Editorial

(x) Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007 Sep 27;357(13):1301-10.

(xi) Hansson GK Inflammation, Atherosclerosis, and Coronary Artery Disease N Engl J Med 352:1685, April 21, 2005

(xii) Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001 Aug 4;358(9279):351-5.

(xiii) http://www.nhlbi.nih.gov/about/ncep/index.htm

About Dr Mark Hyman

MARK HYMAN, MD is dedicated to identifying and addressing the root causes of chronic illness through a groundbreaking whole-systems medicine approach called Functional Medicine. He is a family physician, a four-time New York Times bestselling author, and an international leader in his field. Through his private practice, education efforts, writing, research, and advocacy, he empowers others to stop managing symptoms and start treating the underlying causes of illness, thereby tackling our chronic-disease epidemic. More about Dr. Hyman or on Functional Medicine. Click here to view all Press and Media Releases

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Friday, November 16, 2012

Why Cholesterol May Not Be the Cause Of Heart Disease - Hyman

Why Cholesterol May Not Be the Cause Of Heart Disease

by Dr Mark Hyman

WE HAVE ALL BEEN LED TO to believe that cholesterol is bad and that lowering it is good. Because of extensive pharmaceutical marketing to both doctors and patients we think that using statin drugs is proven to work to lower the risk of heart attacks and death.

But on what scientific evidence is this based, what does that evidence really show?

Roger Williams once said something that is very applicable to how we commonly view the benefits of statins. “There are liars, damn liars, and statisticians.”

We see prominent ads on television and in medical journals — things like 36% reduction in risk of having a heart attack. But we don’t look at the fine print. What does that REALLY mean and how does it affect decisions about who should really be using these drugs.

Before I explain that, here are some thought provoking findings to ponder.

If you lower bad cholesterol (LDL) but have a low HDL (good cholesterol) there is no benefit to statins. (i)
If you lower bad cholesterol (LDL) but don’t reduce inflammation (marked by a test called C-reactive protein), there is no benefit to statins. (ii)
If you are a healthy woman with high cholesterol, there is no proof that taking statins reduces your risk of heart attack or death. (iii)
If you are a man or a woman over 69 years old with high cholesterol, there is no proof that taking statins reduces your risk of heart attack or death. (iv)
Aggressive cholesterol treatment with two medications (Zocor and Zetia) lowered cholesterol much more than one drug alone, but led to more plaque build up in the arties and no fewer heart attacks. (v)
75% of people who have heart attacks have normal cholesterol
Older patients with lower cholesterol have higher risks of death than those with higher cholesterol. (vi)
Countries with higher average cholesterol than Americans such as the Swiss or Spanish have less heart disease.
Recent evidence shows that it is likely statins’ ability to lower inflammation it what accounts for the benefits of statins, not their ability to lower cholesterol.

So for whom do the statin drugs work for anyway? They work for people who have already had heart attacks to prevent more heart attacks or death. And they work slightly for middle-aged men who have many risk factors for heart disease like high blood pressure, obesity, or diabetes.

So why did the 2004 National Cholesterol Education Program guidelines expand the previous guidelines to recommend that more people take statins (from 13 million to 40 million) and that people who don’t have heart disease should take them to prevent heart disease. Could it have been that 8 of the 9 experts on the panel who developed these guidelines had financial ties to the drug industry? Thirty-four other non-industry affiliated experts sent a petition to protest the recommendations to the National Institutes of Health saying the evidence was weak. It was like having a fox guard the chicken coop.

People with the lowest cholesterol as they age are in fact at highest risk of death. Under certain circumstances, higher cholesterol can actually help increase life span.

It’s all in the spin. The spin of the statistics and numbers. And it’s easy to get confused. Let me try to clear things up.

When you look under the hood of the research data you find that the touted “36% reduction” means a reduction of the number of people getting heart attacks or death from 3% to 2% (or about 30-40%).
And that data also shows that treatment only really works if you have heart disease already. In those who DON’T have documented heart disease, there is no benefit.

In those at high risk for heart disease about 50 people would need to be treated for 5 years to reduce one cardiovascular event. Just to put that in perspective: If a drug works, it has a very low NTT (number needed to treat). For example, if you have a urine infection and take an antibiotic, you will get near a 100% benefit. The number needed to treat is “1″. So if you have an NTT of 50 like statins do for preventing heart disease in 75% of the people who take them, it is basically a crap shoot.

Yet at a cost of over $28 billion a year, 75% of all statin prescriptions are for exactly this type of unproven primary prevention. Simply applying the science over 10 years would save over $200 billion. This is just one example of reimbursed but unproven care. We need not only prevent disease but also prevent the wrong type of care.

If these medications were without side effects, then you may be able to justify the risk – but they cause muscle damage, sexual dysfunction, liver and nerve damage and other problems in 10-15% of patients who take them. Certainly not a free ride.

So if lowering cholesterol is not the great panacea that we thought, how do we treat heart disease, and how do we get the right kind of cholesterol – high HDL, low LDL and low triglycerides and have cholesterol particles that are large, light and fluffy rather than small, dense and hard, which is the type that actually causes heart disease and plaque build up.

We know what causes the damaging small cholesterol particles. And it isn’t fat in the diet. It is sugar. Sugar in any form or refined carbohydrates (white food) drives the good cholesterol down, cause triglycerides to go up, creates small damaging cholesterol particles, and causes metabolic syndrome or pre-diabetes. That is the true cause of most heart attacks, NOT LDL cholesterol.

One of the reasons we don’t hear about this is because there is no good drug to raise HDL. Statin drugs lower LDL — and billions are spent advertising them, even though they are the wrong treatment.

If you’re like most of the patients I see in my practice, you’re convinced that cholesterol is the evil that causes heart disease. You may hope that if you monitor your cholesterol levels and avoid the foods that are purported to raise cholesterol, you’ll be safe from America’s number-one killer.

We are all terrified of cholesterol because for years well-meaning doctors, echoed by the media, have emphasized what they long believed is the intimate link between cholesterol and death by heart disease. If only it were so simple!

The truth is much more complex.

Cholesterol is only one factor of many — and not even the most important — that contribute to your risk of getting heart disease.

First of all, let’s take a look at what cholesterol actually is. It’s a fatty substance produced by the liver that is used to help perform thousands of bodily functions. The body uses it to help build your cell membranes, the covering of your nerve sheaths, and much of your brain. It’s a key building block for our hormone production, and without it you would not be able to maintain adequate levels of testosterone, estrogen, progesterone and cortisol.

So if you think cholesterol is the enemy, think again. Without cholesterol, you would die.

In fact, people with the lowest cholesterol as they age are at highest risk of death. Under certain circumstances, higher cholesterol can actually help to increase life span.

In reality, the biggest source of abnormal cholesterol is not fat at all — it’s sugar. The sugar you consume converts to fat in your body. And the worst culprit of all is high fructose corn syrup.

To help clear the confusion, I will review many of the cholesterol myths our culture labors under and explain what the real factors are that lead to cardiovascular disease.

Cholesterol Myths
One of the biggest cholesterol myths out there has to do with dietary fat. Although most of us have been taught that a high-fat diet causes cholesterol problems, this isn’t entirely true. Here’s why: The type of fat that you eat is more important than the amount of fat. Trans fats or hydrogenated fats and saturated fats promote abnormal cholesterol, whereas omega-3 fats and monounsaturated fats actually improve the type and quantity of the cholesterol your body produces.

In reality, the biggest source of abnormal cholesterol is not fat at all — it’s sugar. The sugar you consume converts to fat in your body. And the worst culprit of all is high fructose corn syrup.
Consumption of high fructose corn syrup, which is present in sodas, many juices, and most processed foods, is the primary nutritional cause of most of the cholesterol issues we doctors see in our patients.
So the real concern isn’t the amount of cholesterol you have, but the type of fats and sugar and refined carbohydrates in your diet that lead to abnormal cholesterol production.

Of course, many health-conscious people today know that total cholesterol is not as critical as the following:

Your levels of HDL “good” cholesterol vs. LDL “bad” cholesterol
Your triglyceride levels
Your ratio of triglycerides to HDL
Your ratio of total cholesterol to HDL

Many are also aware that there are different sizes of cholesterol particles. There are small and large particles of LDL, HDL, and triglycerides. The most dangerous are the small, dense particles that act like BB pellets, easily penetrating your arteries. Large, fluffy cholesterol particles are practically harmless–even if your total cholesterol is high. They function like beach balls and bounce off the arteries, causing no harm.

Another concern is whether or not your cholesterol is rancid. If so, the risk of arterial plaque is real.
Rancid or oxidized cholesterol results from oxidative stress and free radicals, which trigger a vicious cycle of inflammation and fat or plaque deposition under the artery walls. That is the real danger: When small dense LDL particles are oxidized they become dangerous and start the build up of plaque or cholesterol deposits in your arteries.

Now that we’ve explored when and how cholesterol becomes more problematic, let’s take a look at other factors that play a more significant role in cardiovascular disease.

Prime Contributors to Cardiovascular Disease
First of all, cardiovascular illness results when key bodily functions go awry, causing inflammation, (vii) imbalances in blood sugar and insulin and oxidative stress.

To control these key biological functions and keep them in balance, you need to look at your overall health as well as your genetic predispositions, as these underlie the types of diseases you’re most likely to develop. It is the interaction of your genes, lifestyle, and environment that ultimately determines your risks — and the outcome of your life.

This is the science of nutrigenomics, or how food acts as information to stall or totally prevent some predisposed disease risks by turning on the right gene messages with our diet and lifestyle choices. That means some of the factors that unbalance bodily health are under your control, or could be.
These include diet, nutritional status, stress levels, and activity levels. Key tests can reveal problems with a person’s blood sugar and insulin, inflammation level, level of folic acid, clotting factors, hormones, and other bodily systems that affect your risk of cardiovascular disease.

Particularly important are the causes if inflammation, which are many, and need to be assessed. Inflammation can arise from poor diet (too much sugar and trans and saturated fats), a sedentary lifestyle, stress, autoimmune disease, food allergies, hidden infections such as gum disease, and even toxins such as mercury. All of these causal factors need to be considered anytime there is inflammation.

Combined together, all of these factors determine your risk of heart disease. And I recommend that people undergo a comprehensive medical evaluation to see what their risk really is.

Zeroing in on Key Factors for Heart Disease
There’s no doubt about it, inflammation is key contributor to heart disease. A major study done at Harvard found that people with high levels of a marker called C-reactive protein (CRP) had higher risks of heart disease than people with high cholesterol. Normal cholesterol levels were NOT protective to those with high CRP. The risks were greatest for those with high levels of both CRP and cholesterol.

Another predisposing factor to heart disease is insulin resistance or metabolic syndrome, which leads to an imbalance in the blood sugar and high levels of insulin. This may affect as many as half of Americans over age 65. Many younger people also have this condition, which is sometimes called pre-diabetes.

Although modern medicine sometimes loses sight of the interconnectedness of all our bodily systems, blood sugar imbalances like these impact your cholesterol levels too. If you have any of these conditions, they will cause your good cholesterol to go down, while your triglycerides rise, which further increases inflammation and oxidative stress. All of these fluctuations contribute to blood thickening, clotting, and other malfunctions — leading to cardiovascular disease.

What’s more, elevated levels of a substance called homocysteine (which is related to your body’s levels of folic acid and vitamins B6 and B12) appears to correlate to cardiovascular illness. Although this is still somewhat controversial, I often see this inter-relationship in my practice. While genes may play a part, tests done as part of a comprehensive evaluation of cardiac risk can easily ascertain this factor. Where problematic levels occur, they can be easily addressed by adequate folic acid intake, along with vitamins B6 and B12.

Testing for Cardiovascular Risk Factors
Heart disease is not only about cholesterol. It is important to look at many factors that contribute to your overall risk. And it seems that insulin and blood sugar imbalances, and inflammation are proving to be more of a risk that cholesterol.

If you want to test your overall risk, you can consider asking your doctor to perform the following tests:

Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Your total cholesterol should be under 200. Your triglycerides should be under 100. Your HDL should be over 60. Your LDL should be ideally under 80. Your ratio of total cholesterol to HDL should be less than 3.0. Your ratio of triglycerides to HDL should be no greater than 4, which can indicate insulin resistance if elevated.
NMR Lipid Profile. This looks at your cholesterol under an MRI scan to assess the size of the particles, which can determine your cardiovascular risk. This is a very important test that can further differentiate the risk of your cholesterol and can be an important factor to track as your system improves and your cholesterol transforms from being small dense and dangerous to light and fluffy and innocuous. It is done by a company called Liposcience and is also available through LabCorp.
Glucose Insulin Tolerance Test. Measurements of fasting and 1 and 2 hour levels of glucose AND insulin helps identify pre-diabetes and excessively high levels of insulin, and even diabetes. Most doctors just check blood sugar and NOT insulin, which is the first thing to go up. By the time your blood sugar goes up, the train has left the station.
Hemaglobin A1c. This measures your average blood sugar level over the last 6 weeks. Anything over 5.5 is high.
Cardio C-reactive protein. This is a marker of inflammation in the body that is essential to understand in the context of overall risk. Your C-reactive protein level should be less than 1.
Homocysteine. Your homocysteine measures your folate status and should be between 6 and 8.
Lipid peroxides or TBARS test, which looks at the amount of oxidized or rancid fat. This should be within normal limits of the test and indicates whether or not you have oxidized cholesterol.
Fibrinogen, which is another test looking at clotting in the blood. It should be less than 300.
Lipoprotein (a), which is another factor that can promote the risk of heart disease, often in men. It should be less than 30.
Genes or SNPs may also be useful in terms of assessing your situation. A number of key genes regulate cholesterol and metabolism, including Apo E genes and the cholesterol ester transfer protein gene. The MTHFR gene, which regulates homocysteine is also important and may be part of an overall workup.
Get a high-speed CT or (EBT) scan of the heart if you are concerned that you have cardiovascular disease. This may be helpful to assess overall plaque burden and calcium score. A score higher than 100 is a concern, and a score higher than 400 indicates severe risk of cardiovascular disease.

Next I will review how to lower your risk of heart disease and fix your cholesterol. We’ll do this not by lowering the LDL, but by getting more light and fluffy LDL particles, which are protective and more HDL cholesterol, which is THE most important cholesterol.

References
(i) Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007 Sep 27;357(13):1301-10.
(ii) Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.
(iii) Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007 Jan 20;369(9557):168-9
(iv) IBID
(v) Brown BG, Taylor AJ Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? Engl J Med 358:1504, April 3, 2008 Editorial
(vi) Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001 Aug 4;358(9279):351-5.
(vii) Hansson GK Inflammation, Atherosclerosis, and Coronary Artery Disease N Engl J Med 352:1685, April 21, 2005
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Read the complete article here.

Wednesday, October 3, 2012

Know All 10 Heart Disease Risk Factors? - Alan Watson

Do You & Your Doctor Know All 10 Heart Disease Risk Factors?

March 7, 2012 by Alan Watson

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Heart disease is the #1 cause of death. About 50 percent of all people who die suddenly from heart disease have low or normal cholesterol. To protect yourself from heart disease, ask your doctor for a complete lipid evaluation. Fast 10-12 hours before blood is drawn (you can drink water). Because Total Cholesterol (TC) and LDL cholesterol are not the most reliable predictors of heart disease, they are not posted in the following chart.

QUICK SUMMARY:

Focus on Fasting Glucose, HDL, Triglycerides (TG) and the all important TG:HDL ratio. Keep in mind that before the advent of cholesterol-lowering statin drugs, the normal range for Total Cholesterol (TC) was: 180 mg/dl to 340 mg/dl. Also, it’s important to note that LDL is actually a family of particles. A discussion about LDL subclasses and LDL subclass testing follows in the summary of this article.

1. C-reactive protein (CRP) is produced by the liver in response to inflammation in the body. If monitored early enough, elevated CRP can be an early warning of a heart attack several years in advance. Optimum levels are below 1 mg/l. (You will have to request this test with most doctors.)

2. Fasting Glucose (FG) measures fasting blood sugar. Lowest all-cause mortality is associated with fasting glucose in the range of 80-89 mg/dl. According to the clinical experience of Dr. Robert Atkins, the risk of heart disease increases in linear manner as your Fasting Glucose goes over 100 mg/dl. (Specifically ask for this inexpensive test.)

3. Fibrinogen is a protein that in excess promotes blood clots. Elevated fibrinogen = thicker blood. Thicker blood flows less easily through partially blocked arteries. Consistent elevated fibrinogen (over 350 mg/dl) conveys a 250 percent increased risk of heart disease compared to people with fibrinogen levels below 235. (People who have recently suffered a heart attack will have elevated fibrinogen levels.)

4. Homocysteine is normally rapidly cleared from the bloodstream. Elevated homocysteine is a result of B-vitamin deficiencies, particularly folic acid, B-6 and B-12. Elevated homocysteine is associated with increased risk of heart attack, stroke, and all cause mortality. Levels less than 8 mmol/L are associated with longevity. (Again, you may have to request this test.)

5. Lipoprotein(a) has been called the “heart attack cholesterol.” Lipoprotein(a) is a sticky protein that attaches to LDL and accumulates rapidly at the site of arterial lesions or ruptured plaque. Readings of 30 mg/dl or more indicate serious increased risk of heart disease, especially in the presence of elevated fibrinogen (>350). While the Lp(a) level is largely genetically determined, it can be influenced by nutritional factors, such as high blood sugar and trans fatty acid consumption. (This test may not be as important as the rest and is seldom done routinely.)

6. HDL is made in the liver and acts as a cholesterol mop, scavenging loose cholesterol and transporting it back to the liver for recycling. HDL is associated with protection from heart disease. You want as much HDL as possible. HDL of 60 or more is associated with protection for men—70 or more for women.

7. Triglycerides (TG) should be under 100 mg/dl. Triglycerides are blood fats made in the liver from excess energy – especially carbohydrates. Risk is linear—the higher the number, the greater the risk, especially for women. While doctors may insist that a reading up to 150 is okay, Dr. Atkins’ clinical experience suggested otherwise.

8. TG:HDL ratio is the most reliable predictor of heart disease. Calculate your ratio by dividing TG by HDL. As an example, if TG = 80 and HDL = 80, your ratio is 1:1 representing low risk of heart disease. If your TG = 200 and your HDL = 50, your ratio is 4:1 representing serious risk of heart disease.

9. VLDL – Increasingly, Very Low Density Lipoprotein is measured/calculated. VLDL is sent out from the liver to deliver those liver made fats (Triglycerides) – as opposed to a Chylomicron that delivers dietary fat from the gut. Generally, VLDL is one fifth of your triglyceride level, although this is less accurate if your triglyceride level is greater than 400 mg/dl. (Beyond the scope of this article, LDL is the offspring of VLDL – they are closely-related.)

LDL particle size: Small dense Pattern B/Large fluffy Pattern A

An illustration from the Berkeley Heart Labs showing these particles

LDL – low density lipoprotein – is a family of particles. A lot of people with elevated LDL do not develop coronary artery disease, while individuals with low or modest levels often develop serious disease. This can be explained by the LDL particle number and size. Routine cholesterol testing only reveals the amount of LDL; not the quality of LDL.

We now know (my doctor didn’t) that there are different subclasses of LDL (and HDL). Under an electron microscope, some LDL particles appear large and fluffy; others small and dense. The big, fluffy particles are benign, while the small dense particles are strongly associated with increased risk of heart disease.

In excess, small dense LDL is toxic to the artery lining (the endothelium), and much more likely to enter the vessel wall – become oxidized – and trigger atherosclerosis. It’s becoming consensus medical opinion that only oxidized LDL can enter the macrophages in the lining of the arteries and contribute to plaque buildup.

HOW DO YOU KNOW WHAT LDL YOU HAVE? Certain clinical factors predict the presence of small dense LDL. These markers include HDL below 40 in men; below 50 in women – and Triglycerides (TG) higher than 120 mg/dl. Diabetes or pre-diabetes also predicts small dense LDL (Pattern B).

To determine LDL particle size, ask your doctor for a VAP (Vertical Auto Profile) test, which separates lipoprotein particles using a high speed centrifuge. The VAP test measures the basic information provided by a routine cholesterol test, but also identifies lipoprotein subclasses, LDL and HDL. (Go to http://thevaptest.com for more information.)

There are other tests as well. The NMR LipoProfile analyzes the number and size of lipoprotein particles by measuring their magnetic properties (http://theparticletest.com). Also Berkeley HeartLab’s LDL Segmented Gradient Gel Electrophoresis test measures all seven subclasses of LDL. (http://bhlinc.com).

If you don’t have insurance and can pay for just one test, get your fasting blood sugar checked. Any number over 100 – over 95 according to the late Dr. Atkins – is an early warning of diabetes, metabolic syndrome, and heart disease. If you have insurance or can afford a complete lipid panel, consider additional testing to determine the size and number of LDL particles. “A stitch in time saves nine.”
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Read the complete article here.

Wednesday, August 22, 2012

Coronary artery calcium bests other risk markers.. - O'Riordan

Coronary artery calcium bests other risk markers for CVD risk assessment

August 22, 2012 Michael O'Riordan

Winston-Salem, NC - A comparison of multiple risk markers suggests that coronary artery calcium (CAC) provides the most improvement in the assessment of cardiovascular disease risk in patients at intermediate risk for future events [1]. Ankle-brachial index, high-sensitivity C-reactive protein (CRP), family history, and CAC were all independent risk predictors for incident coronary heart disease and cardiovascular disease, but CAC provided superior discrimination and risk reclassification compared with the other risk markers.

"If you go to any cardiologist, all that they're doing while you're sitting in front of them is trying to put you into one of three risk categories," lead investigator Dr Joseph Yeboah (Wake Forest University School of Medicine, Winston-Salem, NC) told heartwire. "We know what we should do for low-risk people. We just emphasize lifestyle changes, and most of the time over 10 years nothing happens to them. We know that in high-risk patients, in addition to lifestyle, certain medications work. What we don't know how to do is treat people who fall into the intermediate group. They're in no-man's land. Yet we know a chunk of the people who have heart attacks are within this group. This tells us that there are people who are wrongly put into this category based on current risk tools."

In an editorial accompanying the study [2], Dr J Michael Gaziano (Brigham and Women's Hospital, Boston, MA) and Dr Peter Wilson (Atlanta Veteran Affairs Medical Center, GA) agree that a CAC scan might help guide clinical decisions, but radiation exposure and costs remain important considerations. "Coronary artery calcium findings also are somewhat resistant to change even in the face of improvement in risk factors and may be useful as a single measure for assessment, especially when refinement of a risk estimate is important, but might not be useful for tracking risk over time," according to the editorialists.

The study and editorial are published in the August 22, 2012 issue of the Journal of the American Medical Association.

Data from the MESA study

Using data from the Multiethnic Study of Atherosclerosis (MESA), the researchers identified 1330 intermediate-risk patients without diabetes mellitus who had data available for all six of the following cardiovascular risk markers: CAC, carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), and CRP, as well as family history of coronary heart disease. The purpose of the study, explained Yeboah, was to test the effectiveness of these "top-tier" risk markers for cardiovascular risk stratification when added to conventional risk scores in the same group of patients.

After a median follow-up of 7.6 years, there were 123 cardiovascular events. CAC, ABI, high-sensitivity CRP, and family history of coronary heart disease were independently associated with incident coronary heart disease, defined as a composite of MI, angina followed by revascularization, resuscitated cardiac arrest, and coronary heart disease death.

Association of risk markers with incident coronary heart disease*

Risk marker	Hazard ratio (95% CI)
Ankle-brachial index	0.79 (0.66-0.96)
Brachial flow-mediated dilation	0.93 (0.74-1.16)
Coronary artery calcium	2.60 (1.94-3.50)
Carotid intima-media thickness	1.17 (0.96-1.45)
Family history	2.18 (1.38-3.42)
High-sensitivity CRP	1.28 (1.00-1.64)

*Adjusted for age, sex, race/ethnicity, systolic blood pressure, total cholesterol, HDL cholesterol, smoking status, body-mass index, use of blood-pressure medication, and use of statins

For coronary and cardiovascular disease events, which included stroke and cardiovascular death, the addition of each of the six markers to the Framingham risk score significantly improved the discrimination of clinical events compared with the Framingham score alone. The area under the curve (AUC) improved for all the risk markers but improved the most with CAC scoring. With the addition of CAC, the AUC improved from 0.623 to 0.784.

Similarly, CAC fared best when assessed by net reclassification improvement (NRI), a measure of the relative improvement in the classification of risk with the additional variable. The researchers note that 25.5% of the events were reclassified correctly to the high-risk category, while 40.4% of nonevents were reclassified into the low-risk group. The NRI for the addition of CAC to the Framingham risk score, plus race/ethnicity, was 0.659, the highest reported NRI of the six risk markers.

CAC fares best, but there are caveats

While CAC performed the best of the six markers, Yeboah said that there are important caveats to the results. Echoing the editorialists, he told heartwire that only CAC scoring exposes patients to a small, but not trivial, amount of radiation. He said the long-term effects of radiation on patients remain unknown and will need to be determined before widespread screening using CAC can be used to help the decision-making process.

There would be no benefit to society if we drastically reduce the number of heart attacks only to find out that everybody is developing cancer.

"There would be no benefit to society if we drastically reduce the number of heart attacks only to find out that everybody is developing cancer," said Yeboah.

In addition, there are no outcome studies showing that adding CAC screening to traditional risk scoring systems in intermediate-risk patients reduces the risk of cardiovascular events. If these caveats are addressed, said Yeboah, then CAC screening should be used for the 28 million US adults who fall within the intermediate-risk category. Currently, the American Heart Association and the European Society of Cardiology say it is "reasonable" to use CAC as a screening method for intermediate-risk patients.

In their editorial, Gaziano and Wilson note that research into general cardiovascular disease prevention is timely, given that the National Cholesterol Education Program (NCEP) Adult Treatment Panel 4 treatment guidelines are expected this year, and the addition of novel risk markers to Framingham or the Reynolds risk score might help physicians make a decision about whether or not to start a patient on lifelong statin therapy.

They note, however, that if a patient is near a boundary for lipid-lowering therapy, the doctor can simply choose to see the patient again in a few months rather than order a costly CAC imaging test. Reassessing vascular risk with a patient visit to repeat tests might improve accuracy and reveal trends that could help guide treatment decisions, according to Gaziano and Wilson. While CAC scores can help augment the risk-assessment process, they have limited utility in tracking a patient's progress, as the test is not likely to be repeated over time.

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Read the full article here.

Effects of low carbohydrate diets on cardiovascular risk factors.

Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors.

Santos FL, Esteves SS, da Costa Pereira A, Yancy WS, Nunes JP.

Source

Centro Hospitalar Vila Nova Gaia/Espinho, Gaia, Portugal Centro Hospitalar do Porto, Porto, Portugal Faculdade de Medicina da Universidade do Porto, Porto, Portugal Veteran Affairs Medical Center, Durham, NC, USA Duke University Medical Center, Durham, NC, USA.

Abstract

A systematic review and meta-analysis were carried out to study the effects of low-carbohydrate diet (LCD) on weight loss and cardiovascular risk factors (search performed on PubMed, Cochrane Central Register of Controlled Trials and Scopus databases). A total of 23 reports, corresponding to 17 clinical investigations, were identified as meeting the pre-specified criteria. Meta-analysis carried out on data obtained in 1,141 obese patients, showed the LCD to be associated with significant decreases in body weight (-7.04 kg [95% CI -7.20/-6.88]), body mass index (-2.09 kg m(-2) [95% CI -2.15/-2.04]), abdominal circumference (-5.74 cm [95% CI -6.07/-5.41]), systolic blood pressure (-4.81 mm Hg [95% CI -5.33/-4.29]), diastolic blood pressure (-3.10 mm Hg [95% CI -3.45/-2.74]), plasma triglycerides (-29.71 mg dL(-1) [95% CI -31.99/-27.44]), fasting plasma glucose (-1.05 mg dL(-1) [95% CI -1.67/-0.44]), glycated haemoglobin (-0.21% [95% CI -0.24/-0.18]), plasma insulin (-2.24 micro IU mL(-1) [95% CI -2.65/-1.82]) and plasma C-reactive protein, as well as an increase in high-density lipoprotein cholesterol (1.73 mg dL(-1) [95%CI 1.44/2.01]). Low-density lipoprotein cholesterol and creatinine did not change significantly, whereas limited data exist concerning plasma uric acid. LCD was shown to have favourable effects on body weight and major cardiovascular risk factors; however the effects on long-term health are unknown.
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Emphasis added by bd.
Read the full article here.

Thursday, May 31, 2012

More statin shenanigans

If you read the papers or watch the news you’ve probably heard about the recently published JUPITER study, advertised with bold headlines such as “Cholesterol drug causes risk of heart attack to plummet” and “Cholesterol-fighting drug shows wider benefit”. If you’ve been following this blog (and perhaps even if you haven’t), you are by now aware that such claims cannot be taken at face value.

You might suspect, for example, that the study was sponsored by a drug company and authored by researchers with financial interests tied to those drug companies. You might wonder if these associations could possibly – just possibly – influence not only the results of the study, but how those results are reported. You might also find yourself questioning the objectivity of a study with the title “Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin” (JUPITER).

If you’re asking yourself these questions, you are definitely on the right track. The study was indeed sponsored by a drug company, AstraZeneca. And each author of this study received money in the form of grants, consulting fees and honoraria from pharmaceutical companies – in some cases up to twelve different companies, including AstraZeneca, the study sponsor. Take a look at this list detailing the financial interests of the study authors (now required by the New England Journal of Medicine and other prominent publications):

Dr. Ridker reports receiving grant support from AstraZeneca, Novartis, Merck, Abbott, Roche, and Sanofi-Aventis; consulting fees or lecture fees or both from AstraZeneca, Novartis, Merck, Merck–Schering-Plough, Sanofi-Aventis, Isis, Dade Behring, and Vascular Biogenics; and is listed as a coinventor on patents held by Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease, including the use of high-sensitivity C-reactive protein in the evaluation of patients’ risk of cardiovascular disease. These patents have been licensed to Dade Behring and AstraZeneca. Dr. Fonseca reports receiving research grants, lecture fees, and consulting fees from AstraZeneca, Pfizer, Schering-Plough, Sanofi-Aventis, and Merck; and Dr. Genest, lecture fees from AstraZeneca, Schering-Plough, Merck–Schering-Plough, Pfizer, Novartis, and Sanofi-Aventis and consulting fees from AstraZeneca, Merck, Merck Frosst, Schering-Plough, Pfizer, Novartis, Resverlogix, and Sanofi-Aventis. Dr. Gotto reports receiving consulting fees from Dupont, Novartis, Aegerion, Arisaph, Kowa, Merck, Merck–Schering-Plough, Pfizer, Genentech, Martek, and Reliant; serving as an expert witness; and receiving publication royalties. Dr. Kastelein reports receiving grant support from AstraZeneca, Pfizer, Roche, Novartis, Merck, Merck–Schering-Plough, Isis, Genzyme, and Sanofi-Aventis; lecture fees from AstraZeneca, GlaxoSmithKline, Pfizer, Novartis, Merck–Schering-Plough, Roche, Isis, and Boehringer Ingelheim; and consulting fees from AstraZeneca, Abbott, Pfizer, Isis, Genzyme, Roche, Novartis, Merck, Merck–Schering-Plough, and Sanofi-Aventis. Dr. Koenig reports receiving grant support from AstraZeneca, Roche, Anthera, Dade Behring and GlaxoSmithKline; lecture fees from AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, DiaDexus, Roche, and Boehringer Ingelheim; and consulting fees from GlaxoSmithKline, Medlogix, Anthera, and Roche. Dr. Libby reports receiving lecture fees from Pfizer and lecture or consulting fees from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer, Sanofi-Aventis, VIA Pharmaceuticals, Interleukin Genetics, Kowa Research Institute, Novartis, and Merck–Schering-Plough. Dr. Lorenzatti reports receiving grant support, lecture fees, and consulting fees from AstraZeneca, Takeda, and Novartis; Dr. Nordestgaard, lecture fees from AstraZeneca, Sanofi-Aventis, Pfizer, Boehringer Ingelheim, and Merck and consulting fees from AstraZeneca and BG Medicine; Dr. Shepherd, lecture fees from AstraZeneca, Pfizer, and Merck and consulting fees from AstraZeneca, Merck, Roche, GlaxoSmithKline, Pfizer, Nicox, and Oxford Biosciences; and Dr. Glynn, grant support from AstraZeneca and Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported.

Now, the fact that these researchers receive money from all of these drug companies doesn’t mean that they are dishonest or that their data are invalid. However, if you think these conflicts of interest do not influence the outcomes of clinical research, then I suggest you read an article I published a few months ago called When It Comes To Drug Claims, Skepticism Is Healthy.

Now that you’ve put on your “Healthy Skeptic” goggles, we can move on and more closely examine the study itself. There are several things you need to be aware of as we discuss it.

First, although the press articles claim that the study looked at statin use in healthy populations, the subjects were people who had normal cholesterol but high CRP levels. CRP, or C-Reactive Protein, is a measure of inflammation in the body. It is now widely accepted even in the mainstream medical community that inflammation is a major risk factor for heart disease. And because inflammation is a sign of an underlying disease process, these patients were not, in fact, “healthy” as claimed.

There is little doubt that statins reduce inflammation, which can help prevent atherosclerosis. It appears that the benefits of statins are mainly due to this characteristic, rather than to their cholesterol-lowering effects. So it’s no surprise that the statins reduced rates of heart disease and mortality in this population that had inflammation going into the study.

I should also mention, however, that the predictive value of CRP for heart disease is highly controversial. Though some studies show a correlation between high CRP levels and heart disease, many others do not. Many physicians feel that CRP is not a useful indicator in clinical practice.

The second thing you need to be aware of is the difference between relative and absolute risk reduction. Relative risk reduction (RRR) measures how much the risk is reduced in the experimental group compared to a control group. Absolute risk reduction (ARR) is just the absolute difference in outcome rates between the control and treatment groups.

To make this more clear, let’s consider an example. Say that 2000 people enter a study for a particular drug and 1000 of them are randomized to placebo. At the end of the study, one person in the drug group died versus two people in the placebo group. The relative risk reduction of the drug group would thus be 50% (0.002 – 0.001/0.002). That sounds really impressive! The headline for this study might read “New drug reduces chance of dying by 50%!”. While technically true, you can see how misleading this can be. Why? Because when most people read that headline, they will interpret it to mean that if they take that drug, their risk of dying will be reduced by 50%, which is not even close to being true.

The absolute risk reduction, on the other hand, is always a much more modest number. Using the same example above, the absolute risk reduction in the drug group would have been a paltry one-tenth of a percent, or 0.1% (0.002 – 0.001). That’s not a very catchy headline, is it? “New drug reduces risk of dying by one-tenth of a percent”. It just doesn’t grab you the same way. But this is actually a more realistic view of what happened in the study and what we could expect to happen in the real world.

In fact, one could just as accurately say that in this hypothetical study, a patient has a 1-in-1000 (0.1%) chance of their life being saved by the drug. Said another way, 1,000 patients would have to be treated with this drug in order to save a single life. This measurement is called the Needed Number to Treat, and is another means for interpreting the results of clinical trials.

With that in mind, let’s examine the data from the JUPITER study. The actual numbers were 198 deaths out of 8901 in the statin group and 247 deaths out of 8901 in the placebo group. The relative risk reduction for total mortality (deaths) in the drug group was 19.8% [(247/8901 - 198/8901) / (247/8901)]. That means that the risk of death for people taking Crestor was 19.8% smaller than those taking placebo.

But what happens when we look at the absolute risk reduction numbers? According to the data, 2.77% (0.02774) of people taking the placebo died after two years versus 2.24% (0.02224) of people taking Crestor. This amounts to a difference of 0.55%, or one-half of one percent.

Here’s a graphical illustration of the difference in mortality between the Crestor and placebo group:
jupiter graph

If you’re having trouble making much of a difference, I don’t blame you!

To make this even more clear, let’s use the Needed Number to Treat method of evaluating these results. According to the study data, 182 people would have to be treated with Crestor for two years in order to save a single life.

Now that may not sound like a large number to you, especially if yours was one of the lives saved. However, when evaluating the viability of any potential treatment three considerations (above and beyond the efficacy of the treatment) must be taken into account: cost, side effects, and alternatives.

Let’s look at cost first. The cost of one patient taking Crestor for one year is approximately $1,300. Therefore, to prevent 49 deaths 8,901 people would have to take Crestor for two years at a cost of $23 million dollars. That is an enormously expensive treatment by any measure.

Second, this particular study did not register significant side effects in the statin group. This is very fishy, though, since nearly every other study on statins to date has shown significant side effects and the approval of Crestor itself was delayed by the FDA due to concern about Crestor side effects.

While all statins are associated with rare instances of rhabdomyolysis, a breakdown of muscle cells, Crestor had shown in studies before its approval that the potentially deadly disease had surfaced in seven people. Crestor’s potential muscle- and liver-damaging side effects become more worrisome and difficult to justify in patients who are essentially healthy.

What’s more, the study only lasted two years. That’s not long enough to adequately establish safety for the drug, especially if people are going to use it “preventatively”, which means they could be taking it for several years and even decades. Statins have caused cancer in every single animal study to date. Since cancer can take up to 25 years to develop after initial exposure to the carcinogen, we simply cannot know at this point that statins won’t also significantly increase the risk of cancer in adults.

Finally, before jumping on the statin bandwagon and recommending that we spend billions of dollars treating healthy people with Crestor, we should consider if there isn’t a less costly and risky way of preventing deaths due to inflammation and heart disease.

Wouldn’t you know it, there sure is!

For the last decade medical research has increasingly demonstrated that heart disease is caused not by high cholesterol levels, but by inflammation and oxidative damage. A full explanation of these mechanisms is beyond the scope of this post, but for more details you can read two previous articles: Cholesterol Doesn’t Cause Heart Disease and How To Increase Your Risk of Heart Disease.

So, if we want to prevent and even treat heart disease, we need to address the causes of inflammation and oxidative damage. Again, there’s not room to go into great detail on this here but in general the primary causes of inflammation and oxidative damage are 1) a diet high in polyunsaturated oil (PUFA) and refined flour and sugar, 2) lack of physical activity, 3) stress and 4) smoking.

We can thus prevent heart disease by avoiding PUFA and refined/processed food, getting adequate exercise, reducing stress and not smoking. These simple dietary and lifestyle changes are likely to produce even better results than a statin, for a fraction of the cost and without any side effects. In fact, the only side effects of this approach are improved physiological and psychological health! For more specific recommendations, read my article Preventing Heart Disease Without Drugs.

Taking a statin to “prevent” inflammation and heart disease is rather like bailing water with a pail to prevent a boat from sinking instead of simply plugging the leak. Unfortunately, our entire health care system is oriented around “bailing water with a pail”, which is to say treating the symptoms of disease, instead of “plugging the leak”, or addressing the causes of disease before it develops. The reason this is the case is because there’s a lot more money to be made from drugs, surgery and other costly interventions than there is from encouraging people to eat well, exercise and reduce stress.

Even if we ignore all of the issues I’ve pointed out above, the best thing we can say about this study is that a small group of unusual patients – those with low LDL-cholesterol AND high C-reactive protein – may slightly decrease their risk for all-cause mortality by taking a drug that costs them almost $1,300 per year and slightly increases their risk for developing diabetes.

That’s the best spin possible given the data from this study. Compare that to the mainstream media headlines, and you’ll have a clear understanding of how financial conflicts of interest are seriously damaging the integrity and value of clinical research.

At least the media wasn’t completely fooled. They did manage to at least include the perspective of sane doctors who questioned the desirability of millions of relatively healthy people taking drugs for the rest of their lives. According to the Wall Street Journal:

Moreover, despite large relative benefits, the actual number of patients helped was small. Those on the drug suffered 142 major cardiovascular events compared with 251 on placebo, a difference of 109. Dr. Hlatky said that raises questions about the cost-effectiveness of CRP screening and the value of putting millions of low-risk patients on medication for the rest of their lives.

From the New York Times:

Some consumer advocates and doctors raised concerns about the expense of putting relatively healthy patients on statins, which would cost the health system billions of dollars.

From Fox News:

About 120 people would have to take Crestor for two years to prevent a single heart attack, stroke or death, said Stanford University cardiologist Dr. Mark Hlatky. He wrote an editorial accompanying the study published online by the New England Journal of Medicine.

“Everybody likes the idea of prevention. We need to slow down and ask how many people are we going to be treating with drugs for the rest of their lives to prevent heart disease, versus a lot of other things we’re not doing” to improve health, Hlatky said.

If you know of someone who is considering a statin after reading about the JUPITER study, please do them a favor and send them a link to this article first. They should hear both sides of the story before making such a significant decision.
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Read the full article here.

Wednesday, March 14, 2012

Genetic studies lay the foundations for anti-inflammatory drugs to prevent heart disease

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

IL6R Genetics Consortium Emerging Risk Factors Collaboration

Summary

Background

Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.

Methods

In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.

Findings

The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4—38·2) and of interleukin 6 by 14·6% (10·7—18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9—9·1) and of fibrinogen by 1·0% (0·7—1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8—5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.

Interpretation

Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

Funding

British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

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View the article here.
See also this article in theheart.org.

Thursday, January 19, 2012

There Is No Scientific Basis to Support Treating to LDL Targets

First, no major randomized clinical trial (RCT) has tested the benefits of treating patients according to LDL targets.⁵ The clinical trials tested fixed doses of drugs that lower lipid levels in specific patient populations. In some of these trials, drugs were shown to reduce risk (eg, statins), but in others, this reduction in risk was not demonstrated (eg, clofibrate and torcetrapib). Other drugs, such as ezetimibe, remain to be tested. The trials do not demonstrate that all drugs that reduce lipid levels reduce patient risk. Thus, the dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy.

As noted above, trials show that not all drugs that improve lipid profiles reduce patient risk. In fact, almost all the trial evidence for patient benefit is for a single medication class—statins—that is known to have multiple biological activities that are often referred to as “pleiotropic” effects. Standard doses of the first generation of statins, such as simvastatin, dramatically reduce cardiovascular events and mortality. High-potency statins, such as atorvastatin, reduce nonfatal events by an additional 15–20%. Thus, the trial evidence indicates that the use of statins, and not treatment to target, can reduce risk. Although the mechanism(s) by which statins exert their benefit is controversial, one does not need to impugn the cholesterol hypothesis to recognize that different lipid-lowering drugs could possibly have deleterious effects that offset their potential benefit. Further, it is quite possible that a surrogate measure, such as LDL, may appear to be a single entity even though clinically important subcomponents (such as heterogeneity in particle size) or interactions (such as total cholesterol/high-density lipoprotein [HDL] ratio) may exist. Thus, we cannot assume that lowering LDL, by any means, will improve patient outcomes.

A closer look at the evidence demonstrates further reasons against basing treatment decisions on LDL levels. In considering recommendations, it is useful to recognize that there are only 2 factors that determine the benefit of a treatment for an individual patient: (1) the risks of morbidity or mortality in the absence of treatment and (2) the degree to which the treatment reduces or increases these risks.⁶ LDL levels are not useful in either of these areas. The LDL level contributes little to estimating cardiovascular risk overall and especially compared with non-HDL⁹ or total cholesterol/HDL ratio.^10–12 Moreover, clinical trials demonstrate that the relative effects of statin therapy are not substantially related to a patient's pretreatment LDL.^13,14 It should be noted that although C-reactive protein has been demonstrated to be an independent predictor of cardiovascular risk, it is not strongly related to the relative risk reduction of statins, although the evidence is not entirely consistent.^13,15,16 Thus, there is strong scientific evidence that LDL is not a very useful factor in determining who is at risk for cardiovascular disease or how much that risk will be reduced by a statin.

The conclusion that the evidence does not support a target-based approach may seem counterintuitive to those whose work has been focused on the biology of cardiovascular disease mechanisms, but the science of clinical decision-making requires a different approach. The critical component of good clinical decision-making is not the scientific evidence regarding disease pathogenesis or treatment mechanisms but rather the best empirical predictors of patient risk and factors that reduce risk, the 2 elements that help determine the risks and benefits of a treatment in individual patients.^6,7 As has been demonstrated conclusively, it does not matter whether LDL is the sole biological mechanism mediating the treatment benefits of statins. What matters is that LDL does not appreciably help predict a patient's cardiovascular risk or a statin's relative risk reduction and therefore provides a poor premise on which to base treatment recommendations. Beyond statins, we must extend our concern to the question of whether treatments might be harmful and not just whether they may or may not be effective.
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Read the complete article HERE.

Wednesday, November 17, 2010

Dr. Briffa on statins and cholesterol reduction

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

http://www.drbriffa.com/blog/ November 15, 2010

Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

Big cholesterol news emerged last week on the publication (much publicised) of a massive meta-analysis of statin treatment in those at relatively high risk of cardiovascular disease. The idea of this meta-analysis was to assess whether aggressive lowering of cholesterol (specifically LDL-cholesterol) brings additional benefits in terms of cardiovascular disease protection. The meta-analysis included results from a total of 26 trials (involving a total of about 170,000 individuals) [1].

What this meta-analysis found was that more intensive lowering of cholesterol was associated with a reduced risk of ‘vascular events’ such as heart attacks, fatal heart attacks and the most common form of stroke (ischaemic stroke). The authors state that for each 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol, risk of vascular events was reduced by about a fifth. They go on to say “reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50 per cent.”

Perhaps not surprisingly, this meta-analysis is being used to ram home the conventional view that cholesterol causes cardiovascular disease, and that lower levels of LDL-cholesterol are better. However, there are a number of reasons why this study fails to tell the whole story about statins and cholesterol reduction.

Statin drugs have a number of different mechanisms which might allow them to reduce cardiovascular disease risk in a way which has nothing to do with cholesterol reduction. For example, statins have anti-inflammatory effects, which we would expect to lead to reduced risk of cardiovascular disease. Now, when we intensively lower cholesterol with these drugs, non-cholesterol-related effects (e.g. anti-inflammatory action) will generally be increased too. So, we cannot assume that any additional benefits from more intensive statin therapy have come from more intensive lowering of cholesterol.

In this meta-analysis, the results of a large number of studies was pooled. The problem is, these studies used a range of different drugs at different doses. Sometimes, the drugs were being tested against placebos, and sometimes they were being tested against other drugs. Rarely, two doses of the same drug were tested. Basically, the studies represent a huge hotchpotch of ‘methodologies’ and ‘variables’.

If you really want to take a scientific approach to assessing the role of cholesterol reduction on health, you would ‘control your variables’. This basically means changing only one thing. So, for instance, you could give two groups of people differing doses of the same statin. You could then see if the group on the higher dose had additional benefits, and also see if this appeared to be related to cholesterol reduction or something else. You’d be surprised how rarely such studies are done.

One example of such a study is the so-called TNT study [2]. Here, individuals with heart disease (very high risk of future vascular events) were given either 10 or 80 mg of atorvastatin for an average of about 5 years. The higher dose did lead to lower LDL levels and lower risk of death due to heart-related disease. The absolute reduce in risk was 0.5 per cent, by the way, so nothing to get too excited about. Plus, this study did not report on the non-cholesterol-related effects of the two different dosages, and so it’s impossible to gauge if the relative benefit of the higher dosage was down to LDL reduction and/or something else.

It should also be borne in mind, by the way, that the higher dose of statin in this study (eight times the lower dose, remember) did not lead to a reduction in overall risk of death. In other words, taking 8 times the dose of this drug for five years did not, overall, extend life by a single day, even in individuals at high risk of heart attacks and stroke.

The idea that the anti-inflammatory effects of statins (and not their cholesterol-reducing effects) may be at the heart of their benefits has been bolstered by work focusing on an inflammatory marker known as C-reactive protein (CRP). Statins are known to have the capacity to reduce CRP levels.

In one study [3] assessing the relationship between statin therapy and cholesterol and CRP levels, it was discovered that “Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol.” (emphasis mine).

In another study [4] published in the same edition of the journal, statin therapy and cardiovascular disease risk assessed using ultrasound scanning of the inside of the coronary arteries. It was found that “atherosclerosis regressed in the patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels.”

In yet another study [5] it was found that when treating with statins, those with the highest levels of inflammatory markers at the start of the study derived the most benefit, irrespective of initial cholesterol
levels.

Evidence that statins don’t work through their cholesterol-reducing effect comes from other evidence, including the findings that:

•Statins substantially reduce the risk of stroke, despite the fact that raised cholesterol levels are a weak or non-existent risk factor for stroke [6,7].

•Statins are claimed to reduce CVD risk in individuals who have ‘normal’ or even ‘low’ cholesterol levels [8].

•More intensive cholesterol reduction does not necessarily lead to improved outcomes [9].

Despite what the authors of the recent Lancet review would have us believe, there is considerable evidence that statins primarily work through mechanism that are independent of their cholesterol-reducing effects.

Stepping aside from the science for a moment, let’s also perhaps inject some common sense. Let us not forget that cholesterol is a natural constituent of the body that is a major component in cell membranes, the brain, steroid hormones (including sex hormones) and vitamin D (which appears to have major disease-protective properties). It simply does not make sense to me that driving levels of this key substance to lower and lower levels if, in and of itself, beneficial to health. We would not make the case for driving levels of, say, sodium to lower and lower levels, would we? Or blood sugar levels?

All rationality and common sense seems to fly out of the window when certain doctors and scientists start talking about cholesterol. And when it comes to the science, it’s clear that many are ignorant of or choose to ignore the stacks of evidence that clearly contradict their stance.

References:

1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 9 November 2010 [epub ahead of print]

2. La Rosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35

3. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20-8

4. Nissen SE, et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352(1):29-38

5. Ridker PM, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98(9):839-44

6. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346(8991-8992):1647-53.

7. Imamura T, et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009;40(2):382-8

8. Ridker PM, et al, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207

9. Kastelein JJ, et al, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358(14):1431-1443

Credible Evidence

FB-TW

Thursday, March 6, 2014

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Early atherogenesis and visceral fat in obese adolescents

Abstract

Saturday, March 30, 2013

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About Dr Mark Hyman

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Coronary artery calcium bests other risk markers.. - O'Riordan

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Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors.

Source

Abstract

Thursday, May 31, 2012

More statin shenanigans

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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Summary

Background

Methods

Findings

Interpretation

Funding

Thursday, January 19, 2012

There Is No Scientific Basis to Support Treating to LDL Targets

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Wednesday, November 17, 2010

Dr. Briffa on statins and cholesterol reduction