Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA

Ezetimibe Prescribing Fails to Keep Up With Evidence     

Mike Mitka, MSJ 

             

JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896

          

 

Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.

 

Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.

 

The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.

 

That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).

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US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.

 

 

The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).

 

So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”

 

In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).

 

Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.

 

“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”

A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.

 

And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.

 

Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.

 

Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”

 

Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.

Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.

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Read the complete article here.

Statin Drugs linked to rise in Diabetes

from Mercola.com

By Suzy Cohen, R.Ph.

Coronary heart disease is a leading cause of death in the United States, killing one in five adults, and doctors are very quick to prescribe statins. In fact, statin drug sales rank in the billions each year globally.

These drugs are so pervasive that they are no longer just indicated for hypercholesterolemia, they are also being prescribed for elevations in C reactive protein, and are promoted for kids as young as eight years old.

Heart disease is so pervasive that some have boldly suggested that we should put statins in our water supply as some kind of protection.

This is very disturbing.

Do You Really Need a Statin Drug?

By far, statin drugs are the most popular cholesterol-lowering drugs available today. They work in your liver by preventing your body from making cholesterol. The drugs block an enzyme called HMG-CoA Reductase. This can be helpful, but only if you are one of those people who happen to produce too much cholesterol.
It doesn’t do a good job at removing it from your clogged arteries, contrary to what most people think.
Physicians and health experts now agree that statins seem to offer more benefit through their ability to reduce dangerous inflammatory chemicals in your body, rather than by reducing production of cholesterol, which usually leads to uncomfortable, unwanted and dangerous side effects. One study found that lowering cholesterol too much actually backfires.
Cholesterol is good for you; it’s one of your body’s most powerful antioxidants, it makes important neurotransmitters and sex hormones so this madness to lower it as much as possible really concerns me. Plus, I believe the indiscriminate use of statins has contributed to the staggering rise in diabetes…

The Statin—Diabetes Connection Few People Know About

I watched this happen to my mom who was given a statin, and then told months later she suddenly had diabetes. All of a sudden? This happened many years ago, and it began my search to understand the connection. It also prompted me to write a book on the subject entitled “Diabetes Without Drugs” (Rodale, 2010).
It typically happens like this:
Many statin users come back to see their physician for a routine visit and after the blood work is drawn, they find their cholesterol ratios may be improved, but now they have high blood glucose.
It’s entirely possible that some physicians then mistakenly diagnose their patients with “Type 2 diabetes” when in fact they just have hyperglycemia—a side effect, and the result of a medication that was prescribed to them months earlier.
Do you think you have type 2 diabetes?
I will provide more information so you can see for yourself that so-called “diabetes” diagnosis might not really be genuine diabetes. It may just be hyperglycemia (high blood sugar)—the result of your cholesterol medication, and for some people, it may be reversible with drug discontinuation. Whether or not you are able to discontinue your medication is between you and your physician.

Research Suggesting Raised Blood Sugar is a Side Effect of Statin Use

Several studies have indicated that statins can cause high blood sugar, which can be mistaken for “diabetes.” For example, researchers in Glasgow, Scotland conducted a meta analysis, known as the JUPITER trial, which took into account 13 statin trials that each included 1,000 patients or more. The participants were followed for over than a year. The conclusion was there was indeed an increase, albeit small, in the development of Type 2 diabetes.
It should be considered that some of the patients in this meta analysis already had symptoms of insulin resistance or metabolic syndrome, so it could be said that they were on their way to diabetes anyway.
Now consider another meta-analysis published in the Lancet Here, the researchers reviewed randomized controlled trials beginning in 1994 and ending in 2009, for a total of 91,140 participants who took either a statin or a placebo.
They found that people treated with statin drugs showed a nine percent increase for diabetes. They did not evaluate other factors however, which would be considered pre-diabetes, so I suspect their nine percent number to be on the low side.
Insulin is a pancreatic hormone that reduces blood sugar. You want some insulin to maintain blood glucose levels, but too much of it is bad—it’s an inflammatory compound in your body when it is elevated. And guess what? The use of statin drugs appears to INCREASE your insulin levels! High insulin is extremely harmful to your health.
For starters, elevated insulin levels lead to heart disease, and isn’t that the reason cholesterol drugs are prescribed in the first place?
The ratio of glucose to insulin should be less than 10:1, this ratio is far more important than the levels of glucose or insulin alone. Keep that in mind if you seek a complete recovery. For more information about the harmful effects of elevated insulin levels, see my article on dearpharmacist.com, or my book Diabetes Without Drugs.
You want to keep insulin normal, to protect yourself from heart disease and high blood pressure. Chronically elevated insulin causes a cascade of inflammatory chemicals and high cortisol which lead to belly fat, high blood pressure, heart attacks, chronic fatigue, thyroid disruption, plus major diseases like Parkinson’s, Alzheimer’s and cancer.
Unfortunately, the most popular cholesterol drugs in the world seem to increase insulin levels. However, that’s just one mechanism by which these drugs can raise your risk for diabetes.

How Statins Raise Your Insulin

Keeping things simple, you might imagine it like this: When you eat a meal that contains starches and sugar, some of the excess sugar goes to your liver, which then stores it away as cholesterol and triglycerides. Now stay with me — when you have a statin on board, it’s like a message to your liver saying, “No! Don’t make any more cholesterol, please stop.”
So your liver sends the sugar back OUT to your bloodstream. As a result, your blood sugar goes up.
In 2009, it was proven that statins could directly raise blood sugar, whether or not you have diabetes. Over 340,000 people were included before this conclusion was made. The people who did not have diabetes but took statins experienced a rise in blood glucose from 98 mg/dl to 105 mg/dl. Those who already had diabetes and also took statins experienced a rise from 102 mg/dl to 141 mg/dl.
After adjustments for age and medication use were considered, researchers concluded that both diabetic and non-diabetic statin users showed a statistically significant rise in blood sugar.
Why take all these risks, just to get the convenience of taking a pill instead of eating a better diet and exercising?
It’s been scientifically discussed and even published in JAMA that eating a better diet could lower cholesterol as well as the statin drug lovastatin.
And of course, there are so many other benefits to eating a healthier diet that consists of fruits, vegetables, nuts, seeds, and lean meats. Besides feeling better and increasing lifespan, you can squeeze into those skinny jeans you’re hiding in your closet.
Another way statins can affect your blood sugar is via their “drug mugging” effect. A drug mugger is my term, and the title of my newest book, which describes how a drug can rob your body’s warehouse of a valuable nutrient. In the case of statins, they rob your body of two different nutrients, both of which are needed to maintain ideal blood sugar.

Two Important Nutrients Decimated by Statins

The first nutrient that is mugged is vitamin D. There have been mixed studies regarding the D-depletion effect of statins, but statins reduce your body’s natural ability to create active vitamin D called 1,25-dihydroxycholecalciferol, shortened to “calcitriol” when it is eventually converted to its active hormone form.
This happens because statins reduce cholesterol, and you need cholesterol to make vitamin D! It is the raw material that exposure to UVB from sunlight will convert to vitamin D.
It is well documented that D improves insulin resistance, so needless to say, when you take a drug mugger of vitamin D (like statins), then you increase your risk for diabetes.
More specifically, a 2004 study published in the American Journal of Clinical Nutrition determined that raising a person’s serum vitamin D levels (from 25 to 75 nmol/l) could improve insulin sensitivity by a whopping 60 percent.
Compare that to the blockbuster diabetes drug metformin, one of our pharmaceutical gold-standards, which can dispose of blood sugar by a meager 13 percent according to the New England Journal of Medicine.
Now, statins also suppresses your natural coenzyme Q10— also called “ubiquinol” in its active form; it makes energy for every cell in your body, and it’s produced mainly in your liver.
This powerful antioxidant just so happens to also play a role in maintaining blood glucose. When you deplete levels of CoQ10 by taking a drug mugger of it, like a statin drug, then you lose that benefit. You also raise your risk for heart failure, high blood pressure and heart disease as CoQ10 deficiencies can contribute to those conditions. A study by Hodgson et al, published in 2002 found that 200mg CoQ10 taken daily caused a 0.4 percent reduction in hemoglobin A1c.
Moreover, CoQ10 protects your body from oxidative stress, a strong contributing factor in the development of diabetes, metabolic syndrome and heart attacks. You want to make sure you have enough CoQ10 (or ubiquinol) on board to protect every cell in your body. The take home point is that statins annihilate this compound and you need it for good health.
In summary, if you take a statin medication and you’ve been told that you have diabetes, it may be drug-induced, and it’s possible that it can be reversed over the course of time. However, you will have to eat right, exercise, and take supplements that help to lower your risk for heart disease naturally.
About the Author
Suzy Cohen, R.Ph., has been a licensed pharmacist for 22 years, and has had a weekly syndicated health column for the past 13 years which you can get for free by signing up at her website Widely recognized as “America’s most trusted pharmacist,” she has appeared on The Dr OZ Show, The View, Good Morning America Health and The 700 Club.
Cohen is also the author of three books: The 24-Hour Pharmacist, Diabetes Without Drugs, and Drug Muggers: Keep Your Medicine from Stealing the Life Out of You.
For more information, see www.SuzyCohen.com.

Sources:
Journal of the Federation of American Societies for Experimental Biology May 1, 2004; 18(7): 805-815
Journal of Investigative Medicine March 2009; 57(3): 495-499
About.com February 20, 2010
The Lancet February 2010; 375(9716): 735 – 742
The Lancet February 27, 2010; 375(9716): 700 – 701
Reuters March 10, 2011
International Journal of Obesity February 8, 2011 [Epub ahed of print]
American Heart Journal (ENHANCE trial) February 2005; 149(2): 234-239
Lancet February 27, 2010; 375(9716): 735-42
Journal of Investigative Medicine March 2009; 57(3): 495-499
JAMA 2003;290(4):502-510
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Read article with comments here  http://articles.mercola.com/sites/articles/archive/2011/03/28/the-stealth-drug-cause-of-diabetes.aspx

Bad Cholesterol is now Good

Bad Cholesterol is now Good  - Dec092009


Wednesday, December 9, 2009 at 04:59PM

People take cholesterol-lowering statin drugs to reduce ‘bad’ cholesterol (LDL ‘cholesterol’), however ‘bad’ cholesterol may not be as bad as we think. A study published in the American Heart Journal looked at the cholesterol levels of people who had been admitted to hospital in America with heart disease. The study included 136,905 people – all of these people had their LDL level measured within 24 hours of arrival in hospital.

The graph below is taken directly from the study. I have marked on the graph the suggested ideal LDL level of 3 mmol/l (or 120 mg/dl). We are constantly told that our risk for heart disease is reduced below this level and above this level our risk increases.



We can immediately see that the majority of these people with existing heart disease had an LDL level below the suggested ideal level – LOWER levels of so called 'bad' cholesterol were much more likely to be associated with heart disease than higher levels. This of course is the opposite of what we are expected to believe.

The average LDL level for this group of people was 2.7 mmol/l (or 104 mg/dl). However, the average LDL level for the general population around the same time was 3.2 mmol/l (124 mg/dl).




If people with heart disease have lower LDL levels than the general population, then perhaps we need to rethink the policy of spending hundreds of millions of pounds on reducing LDL levels in the general population.

References:


Carroll MD et al (2005) Trends in serum lipids and lipoproteins of adults, 1960–2002. Journal of the American Medical Association 294 pp1773–1781.

Sachdeva A et al (2009) Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. American Heart Journal 157 111–117