Posts Tagged ‘Cholesterol’
Do statins make you immortal?
My blogs over the past week have been concerned about the screening of asymptomatic patients for coronary artery disease and whether we make a difference in their morbidity and mortality if we find it.
That’s really all we are concerned with: Can we, as physicians, change a patient’s outcome by putting in place a medicine or a lifestyle? What good is it to find a problem if you can’t act on it?
To date, what we do when we find a patient who we believe to be at risk is tell them to stop smoking, control their blood pressure and their diabetes. And, we put them on statins. As those that read my blogs know, statins are our first line of defense against progression of coronary artery disease when a patient already has an infarct, angioplasty or coronary artery bypass surgery.
An article was published in Arch Intern Med 2010;170:1024-1031 which addresses this question. It is titled Statins and All-Cause Mortality in High -Risk Primary Prevention: A Meta-Analysis of 11 Randomized Controlled Trials involving 65,229 Participants.
This represents over 244,000 person- years of follow up. The average LDL cholesterol was 138 mg/dl and the results of giving statins yielded an average LDL of 94 mg/dl. An average of 3.7 years of follow up occurred in these studies and there was no evidence of benefit in these findings (7 fewer deaths for every 10,000 person years of treatment).
Although compelling, I believe that this study is flawed by the short follow up. Remember, this is not a randomized clinical trial which is the highest level of significance; it is a Meta-Analysis and only collates the data already collected in like studies.
Statins were approved because they were tested in randomized clinical trials against placebo and there was always a statistically significant reduction in a triple endpoint of unstable angina, myocardial infarction and death. Death however is usually the least affected because we are much better at preventing it if patients who are affected by an acute event present to hospitals. Patients who are found to be “at risk” will continue to be offered statins and the data shows that the lower the LDL is driven, the lower the vent rate. There seems to be no plateau. Every time a study drives the number lower, the event rate follows and some studies have the LDL as low as 50 mg/dl. The study known as TNT, or Treating to new targets,
showed this result in a study with over 10,000 patients.
The real study we want to do can not be done because it is not ethical anymore. Withholding statins from patients would never pass muster. It could be done in patients who refuse statins but the numbers would never be great enough. We will just have to accept the premise for the time being until science moves ahead of need.
This is Really Something
Ever since Star Trek introduced us to the concept of nano particles and technology, we have seen some examples but we are still awaiting the first real use in medicine. It has become the vogue to try and target cells for destruction with chemotherapeutic agents to “spare” healthy cells, something that we do not have control over now but today the success is limited.
A report has appeared of a novel use of nano technology to possibly help in the war on cholesterol deposits in the coronary arteries. We do not have a good model of human atherosclerosis because we are the only species to suffer from it. Researchers can give other species a semblance of coronary disease but it doesn’t do ours justice, just try cracking an atherosclerotic coronary artery plaque with 18 times atmospheric pressure and watch nothing happen to it.
Researchers in Russia and the Netherlands have developed a method of delivering silica- gold nanoparticles to the plaque in coronary arteries and when these particles are exposed to infrared light from outside the body the particles heat up to 50- 150 degrees centigrade and “burn” the plaque while the surrounding tissue is not effected.
The effect is hoped to produce inflammation, which in turn leads to healing. This has already been done in a small group of patients in several different ways. 97% of the plaque was destroyed in a small group when the cells were delivered by circulating progenitor cells, which are similar to stem cells. A laser catheter was then used to deliver the energy. This led to the revascularization of the patient by the opening of the artery much like angioplasty.
One year later the arteries were still open in the patients treated. The field of cardiology continues to test the boundaries of our knowledge. When Dr. Gruentzig started most people believed angioplasty would never work. In multiple ways researchers are looking for better and easier ways to stop the progression of coronary disease. I am hopeful for our future.
The Opportunity We Lost
Healthy People 2010 was launched in 2000. The aim of this project was to reduce the number of cardiovascular deaths by 20%. This is certainly a worthy project. The results were published in the Bulletin of the World Health Organization in February.
I’m sure you can guess but we didn’t make it. 400,000 deaths in the U.S. from cardiovascular disease are projected to occur this year. I want to put this into perspective. 416,000 servicemen and women died during World War II. Each year, we lose that many people to heart disease. You would think there would be uproar. The only sound I hear is snacking.
What exactly seems to be the problem? We have had a reduction in improved total cholesterol and in lower blood pressure in men. We have also increased physical activity and decreased smoking. However, this is almost totally offset by an increase in obesity and diabetes.
We must rethink the balance of government and personal responsibility. The government does not make us eat more or make us fat. The government can limit the salt in food and demand that soft drinks be removed from schools. We can develop all sorts of medications, but it seems to come down to what will you do for yourself and most of it seems to revolve around how much you eat. Most diabetes is related to simply being overweight. This is a personal responsibly and until we grasp this future progress may not be made.
The most recent National Health and Nutrition Examination Survey found that most Americans are overweight and one-third are obese. Obesity has overtaken smoking as a major health burden in the United States. This is very apparent if you travel anywhere outside the United States and compare average body size. Don’t go to Disney World, it is truly disheartening.
Let’s all pledge to lose 10 or 15 pounds. We went to the moon. We can understand this problem and solve it. It won’t be solved by drugs, it must be solved by education and the simple understanding that we eat too much. Put down the remote and do something.
The End of Zetia?
We received news that the outcome study of ezetimibe or Zetia ,which is being performed under the name IMPROVE-IT, is slated to end in 2013. Data should then be available by the fall of 2014. Zetia’s patent expires in October 2016. Zetia earned Schering-Plough 1.9 billion dollars in 2006, and they split this money with Merck.
Let me put this in prospective. Two years before a multi-billion dollar drug undergoes patent release to generic, we will finally identify that the drug has some value beyond the lowering of a number. This is truly amazing when you think about it.
As I have blogged before in December 2009, this drug was approved on the basis of just the lowering of a chemical number and not that it reduces hard clinical endpoints. That is what this study is to determine. No one really cares if your LDL cholesterol number is lower just that fewer people die. Let me again point out that the reduction number does not need to be large just statistically significant.
There unfortunately are significant differences in that number and its meaning. Several blogs ago I discussed the new indication for Crestor. In the final analysis you have to treat 1000 patients to prevent two deaths using Crestor under its new indication. The number is significant statistically but is this indication really worth it to patients or just the company?
The issue was further clouded by the “lowering of the bar.” As Dr. Califf pointed out, (Note: I know Dr. Califf and he is one of the finest researchers in cardiology today) “because this study is done on a background of simvastatin the incremental absolute reduction in LDL is expected to be modest and as a result the anticipated absolute reduction in event rates will be modest also,” Am Heart J 2010. DOI: 10.1016
As pointed out in my previous blogs, the ARBITER 6-HALTS study findings were more valuable then these findings will be.
This goes back to the science of LDL cholesterol. It is clear that patients who have peripheral vascular disease, stroke or coronary artery disease should be on maximally tolerated statin doses for the largest effect. This goes for people who have reasonable levels of LDL reduction on small doses of drug because it is felt that some of these effects are “pleiotropic” or to put it another way “magical” and is not fully measurable. These include the decrease of the “inflammation” of the LDL.
We know at least that Zetia is not causing harm because the study was not stopped by the monitoring safety board at half way in the study. Whether it does any good and whether we can afford to pay for it as a society will be left to an answer probably at the American Heart meeting in November 2014. Stay tuned…
Maybe Your Mother Was Right
I’m not making this blog up. An article has been published in Circulation, one of our most difficult journals to get published in. This article in Circulation claims that watching television is killing us. If you want a copy, e-mail me and I will send you a PDF. You can also click on the Circulation word, and it will link you to the article.
The article titled Television Viewing Time and Mortality: The Australian Diabetes, Obesity and Lifestyle Study (AusDiab) evaluated the effect of sedentary behavior with mortality risk. In particular, they examined the relationship of prolonged television viewing and the risk of premature mortality. 8,800 people participated in the study; 3,846 men and 4,954 women. None of the individuals had a history of any cardiovascular disease. The participants entered the study during 1999 to 2000. All participants were examined and had blood tests. The study ended on November 16, 2006.
Three categories of time where created <2, >2 to<4 and>4h/d and were assessed for a period of a week. This was a combination of television or video and you had to be watching. It wasn’t that the television was on but you were doing other things.
Over the 6.6 years, a total of 284 deaths occurred. 87 or 31% were due to cardiovascular disease, 125 or 44% were due to cancer and 72% or 25% were “other”. Each 1-hour increment was found to be associated with an 11% increase in all cause mortality and an 18% increase in cardiovascular mortality. Here’s the bottom line, if you watched more than 4 hours a day you had a 46% increased risk of all cause mortality and a whopping 80% risk of cardiovascular mortality, which was independent of the traditional risk factors such as smoking, blood pressure, cholesterol and diet.
Don’t tell NBC, they are having enough trouble figuring out what to do with Jay Leno.
Why this is so? Maybe the association of eating “snacks” when we watch television, but the data is well done and points out a further reason that we need to change our habits. Further, television watching is only one sedentary activity we do. The total time of sedentary work and computer use adds considerably to the problem.
The solution is simple but often ignored. Get up and do something, anything.
Will Cardiac Diagnostics Work?
We, as physicians, are used to measuring things. We measure temperature, blood pressure, height and weight. We measure your blood counts and the level of cholesterol in your blood. We are used to measuring things and part of this derives from the science of medicine.
In general, we believe that it you can measure something you will understand something better and possibly begin to change it. With the development of blood glucose monitors, we are able to be more precise in our control of diabetes. Those of you who are old enough will remember when glucose control was measured by urine test strips. Glucose monitors are now an essential part of diabetic care and are approved by Medicare and Insurance companies. There is some debate as to whether this glucose control does any real good but it is accepted by both physicians and the public.
How do you measure a hearts function. It is not blood pressure because a normal heart can have a blood pressure of 90/60; a failing heart can have a blood pressure of 200/110. The physical signs are rapid weight gain and special sounds we hear in the lungs called rales, which is derived from the French word rattle. A Frenchman Rene Laennec in 1816 developed the first stethoscope, again to measure something.
We measure heart function by measuring the pressure in the heart and lungs. I do this daily at cardiac cath and we have exquisite knowledge about these dynamics. We can also measure the pressures non-invasively by echocardiogram.
In the late 1960’s, two physicians at Cedars-Sinai in Los Angeles developed a catheter that could be placed in a vein and threaded into the heart to measure the pressures in the lungs. Initially known as a Swan-Ganz catheter after its inventors, Jeremy Swan and William Ganz, it eventually became known as a Swan. (Don’t ever be the second name on an invention.) These catheters saved millions of lives and led to an era of improved intensive care. The seminal article was published in the New England Journal of Medicine in August 1970.
We now have two ways that I know of to measure the status of the heart on a day to day basis. The science of these measurements is well understood. FDA before approval of the devices and the measurements demanded proof that the obtaining of the measurements led to good clinical outcomes such as staying out of the hospital with heart failure. We at the Jim Moran Heart and Vascular Institute participated in one of the device approval trials.
Next…the devices and why they may help us better care for patients.
Novel Future Treatments for Cholesterol
There are other novel and promising agents, which are being tested for the treatment of elevated cholesterol. One of the challenges I face on a weekly basis is that of patients who have coronary atherosclerosis and are on the maximum dose of statin and still have serious elevations of LDL cholesterol. We have no good treatment options at this time. These individuals try even strict diets to no avail. Many have a genetic condition referred to as heterozygous familial hypercholesterolemia which produces exceptionally high levels of LDL cholesterol.
One novel agent almost finished with testing is Mipomersen. This is a compound in development by Genzyme. Genzyme purchased the drug from ISIS Pharmaceuticals for $325 million and will pay a further $825 million if the annual revenue tops $5 billion in two consecutive years. To put that in perspective Lipitor had revenue of $16 billion last year and Plavix provides $11 billion in revenue to Bristol-Myers and Sanofi combined.
This compound is an antisense therapeutic agent. It is administered as a weekly injection and concentrates in the liver where the action occurs. It competes with the patient’s native compound and fools the messenger RNA which then decreases the production of apolipoprotein B thereby decreasing the level of LDL cholesterol.
Several studies have been performed and the pivotal trials are done. It is expecting approval late this year. It has been tested alone and in combination with statins and has been shown to be safe and effective. It is not clear whether the FDA will require clinical efficacy testing before release or after.
If effective this would become a useful compound in those patients who have not achieved goal with statins and in those patients who cannot take statins at all because of side effects. Novel treatments like this and ApoA-1 Milano may become the treatment of atherosclerosis in this decade.
The Truth about Diet and Heart Disease
When I talk with families after an angioplasty, the most common comment is “will you tell him (it’s usually him) to eat better.” Unfortunately people have long memories when it comes to some things, and we as physicians failed in our early attempts to inform patients about how to avoid heart disease. Diet was held out as a way to avoid the illness and alternatively, if you eat terribly, you would get it. Neither is true. Frankly, if diet really caused heart disease, then we would all be dead. Those “billions and billions” served have to count for something. Diet makes you fat and being fat leads to diabetes. The Diabetes Life Style study showed that strict diet and exercise can lead to a halting of the diabetic process and allows patients to stop medications. It unfortunately has little or nothing to do with heart disease.
Genetics is the root cause of this illness and unquestionably cigarette smoking accelerates the process. If your father or mother had coronary disease in their 30’s or 40’s then watch out. If they lived to be 90, then the high likelihood is you will not be afflicted with it. This is not exact but in general it fits. Much of this is related to cholesterol and its metabolism. 90% of your cholesterol level is created by you on a daily basis to serve as the building blocks of cells and proteins. 10% is consumed. In general you cannot lower your cholesterol by diet because of a “feedback loop” in the liver, which senses the amount of cholesterol and then increases the production of it to make up for the loss. This is where statins come in as they terminate the feedback loop.
We are now in the middle of the holidays and it is a time where we often gain weight and then on New Year’s Day resolve to lose it. The day after New Year’s the gym is full and it usually remains that way for two or three days. Then we are just heavier.
Please do not take this as a pass. People should attempt to do what’s right. People should weigh as close to their ideal weight as possible, and study after study has shown that if you weigh less you live longer. The seminal studies on mice show that if you feed them 30% less than “required” the study mice live significantly longer than control mice. This is difficult to do with humans but provocative none the less. You will be much less likely to develop diabetes and have hypertension that is difficult to control. This is where exercise comes in since it “burns” some of those excess calories.
We now have perhaps the ultimate example of fat doesn’t equal heart disease and that will be the subject of my next blog.
Statins 101
The statin drugs, such as Zocor and Lipitor to name a few, have revolutionized the practice of cardiology. These drugs discovered by Akira Endo and Masao Kuroda in Japan in 1971 when investigating inhibitors known as HMG-CoA reductase. The first agent isolated was mevastatin followed by the isolation of lovastatin from the mold Aspergillus terrus.
For over 75 years an effect known as the Shoenheim effect was observed but not understood. If you fed mice low cholesterol diets their livers manufactured more cholesterol and they had levels higher than when they started. This same effect occurs in humans. This concept of receptor mediation was discovered and explained by Michael Brown and Joseph Goldstein. Their work was rewarded with the 1985 Nobel Prize for Medicine and stands as some of the most important work of the 20th century.
The statins are divided into those which are synthetic and have had their molecular structure altered and those which are natural and fermentation derived. Red rice yeast has the substance mevastatin in it and that is it’s mechanism of action. Pravastatin known as Pravachol is also naturally derived. Simvastatin is an altered molecule from a fermentation derived source. The most potent statins are Lipitor and Crestor. Crestor and all statin drugs provide a dose dependant response. The large number of trials of the drugs have provided us with average dose reductions per dose. If your LDL or bad cholesterol is 150 you can lower it on average 45% by taking 5 mg of Crestor. This rises to 63% for the 40mg dose.
Goals have been set by the various groups associated with atherosclerotic disease whether it is in your heart vessels, head vessels or your peripheral vessels. If you are at risk the goal is less than 100mg/dl. If you have disease your goal is 70 mg/dl. Adjusting the dose becomes easy at that point.
Next up: why we use the statins.
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