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).

Place holder to copy figure label and caption

Graphic Jump Location

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.

==============================================================

Read the complete article here.

Beware: new cholesterol lowering drugs coming - Kendrick

Beware: new cholesterol lowering drugs coming

by Dr Malcolm Kendrick

‘…across the gulf of space, minds that are to our minds as ours are to those of the beasts that perish, intellects vast and cool and unsympathetic, regarded this earth with envious eyes, and slowly and surely drew their plans against us.’ War of the Worlds

An era is coming to an end. Statins, the world’s most widely prescribed and profitable drugs, have, with the exception of Crestor (rosuvastatin), all come off patent and their price has plummeted. Good news for NHS accountants: not so good for company profits.

So a supposedly new, improved, much safer and more effective generation of cholesterol lowering drugs will soon be available at a doctor’s surgery near you. At least that will be the general tone of the marketing. With 80% of the population suffering from “high” cholesterol, according to guidelines drawn up by consultants with links to drug companies, there is obviously a huge need. (For an account of how seriously we should take this “need” see Dr John Briffa’s post.)

This is obviously a great opportunity for the companies but it also faces them with a fascinating dilemma. Statins have been relentlessly promoted as the most beneficial l class of drugs ever, protecting not just against cardiovascular disease but also Alzheimer’s and Parkinson’s and being virtually side-effect free into the bargain.

An alarming press release

But if the companies are going to persuade those NHS accountants and cash-strapped GP commissioning bodies to start paying serious prices for the new drugs, they need to persuade them that statins actually had a serious problem all along but it is one that can be avoided by buying the new products.

Recently I received a press release by email that was the first sign that this process is already underway. It was a warning about something called P9 which, had I been a loyal statin believer, I would have found pretty alarming. After explaining how statins worked by targeting an enzyme known as HMG-CoA in the liver, the email went on to tell me this:

“However, statin treatments have been shown to actually stimulate the production of PCSK9, which is counterproductive, possibly damaging to the liver, and ultimately limits the treatment’s ability to lower LDL cholesterol levels.”

Why weren’t we told about this risk before?

What on earth is PCSK9, you and the medical statin believers might well ask. And if it is not only able to damage the liver but also render the whole purpose of taking a statin self-defeating, why haven’t we been told about it before?

Here was a classic marketing ploy; tell you about a problem and immediately offer a solution in the form of a drug that is able to block the production of damaging PCSK9. The full name of these new drugs is proprotein convertase subtilisin/kexin type 9 inhibitors.

And it’s not the only dauntingly high tech-new cholesterol lowering drug that could be coming your way in the not too distant future. For the sake of completeness here is a list of nearly all the new compounds waiting in the wings. Some will undoubtedly founder on the rocks of side effects that are just too dangerous, never to be seen again.

Other new drugs in the race

• Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors)
• Antisense oligonucleotides (ASOs) targeting the production of apolipoprotein B-100 (apoB-100)
• Microsomal triglyceride transfer protein inhibitors
• Squalene synthase inhibitors
• Peroxisome proliferator-activated receptor agonists
• Thyroid hormone receptor agonists

For the moment though my money for the first out of the gate are the PCSK9 inhibitors, which I will call P9 inhibitors. So what exactly are they? Well P9 is an enzyme that is found mainly in the liver. It binds to receptors that remove the “bad” LDL (low density lipoprotein) cholesterol and destroys them after they have taken just one LDL molecule out of circulation, meaning that they can’t be reused to remove more LDL.

But if you block P9, you allow LDL receptors to continue removing LDL merrily from the bloodstream, so LDL levels fall dramatically. In fact P9 inhibitors appear to lower LDL far more effectively than statins which, if you sign up to the belief that the lower your cholesterol goes the more protection you get, this can only be another major benefit.

The new statin combo

What’s clever about this is that it avoids taking on statins directly. Given how familiar doctors are with them, how most believe in them and how cheap they are, a head on attack would be doomed to failure.  The manufacturers know, damn well, that doctors are not just going to stop using statins, so their P9 inhibitors will be positioned to sit alongside statins, allowing them to work, supposedly, even more safely.  At first anyway.

But there is more to this press release and I could pick it apart for hours, marvelling at the ability to say so much – in so few words. But let’s just focus on the phrase…’possibly damaging to the liver’ in relation to statins. Now, I know that statins do damage the liver – to a greater or lesser degree. Liver enzymes in the blood (a sign of liver damage) are often raised to three times normal levels – sometimes more.

But why not focus on the side-effect that is most clearly recognised with statins?  Namely muscle damage and pain. This is the true Achilles heel of statins. Yet the press release talks about liver damage…

Danger to your liver

The most likely reason is that P9 inhibitors have been found to cause liver problems themselves in both animal studies and phase 1 studies on human volunteers. Knowing their mechanism of action, it is more than likely that PCSK9 blocking agents could damage the liver. If you over-ride negative feedback mechanisms, the body doesn’t like it very much, as you will be overloading cells with toxic waste products. Enzymes to break down LDL receptors are there for a reason.

So, we can expect P9 inhibitors are going to cause liver damage. However, by attacking statins for causing liver damage, the pharmaceutical companies will be hoping to mask the most serious adverse effect of the new drug. The words used to defuse concerns about this problem will be something along the lines of. ‘With our P9 inhibitor we have seen mild elevations of liver enzymes in clinical studies. However, they are similar to those caused by statins, are reversible and cause no long-term damage.’ Blah, blah….  ‘Move along, nothing to see here.’

This fear is not just based on a vague unease that if you block a feedback mechanism in the body you are probably heading for disaster. It is also based on the fact that, if the companies developing P9 inhibitors are already blaming statins for causing liver damage, they are doing to hide their own problems behind a smokescreen. You heard it here first.

I also predict that severe liver damage problems will take years to emerge. In most people the liver is pretty resilient – it takes a lot of alcohol and a lot of time to destroy it. I fear that clinical studies will not be long enough to demonstrate this effect –before the drugs are launched and widely prescribed. I can say all this because it is what has happened with damaging block buster drugs in the past, such as the anti-inflammatory Vioxx and and the diabetes drugs Avandia.

My predictions for P9 inhibitors:

• They will be widely promoted as the new statins
• Pfizer, or Merck, will buy out the patent to one of the new products (they may have already done this)
• They will be launched without any long-term studies to show they actually cut your chance of dying from a heart attack. They will be approved purely on the basis that they lower cholesterol/LDL cholesterol.
• They will make billions upon billions in the first two years and be hailed around the word as a new generation in cholesterol lowering. The chief executives of the companies selling these drugs will be paid massive bonuses
• Key Opinion Leaders (‘experts’) will promote them ruthlessly at major conferences and press launches
• Reports of a high level of liver damage/deaths will  start to emerge
• The companies will deny there is a problem and attack anyone who says there is one
• They will start to be withdrawn from the market two to three years after launch
• There will be lawsuits
• The companies will be fined a small fraction of the profits they made from hyping the drugs
• It will emerge that the problems with liver damage were known by the companies many years before the drugs were launched but not many people will be interested by then, as the next generation of lipid lowering agents will be arriving
• No-one will be held accountable

Yes, the great Nostrokendrickos has spoken.
In the meantime remember that ‘Something unpleasant this way comes’.
Disclosure: I do not believe that a raised LDL/cholesterol level causes heart disease.
====================================================================
Read the complete article here.

What Causes Elevated LDL Particle Number? - Kresser

What Causes Elevated LDL Particle Number?

By Chris Kresser on May 3, 2013

 

In the last article in this series, I explained that LDL particle number (LDL-P) is a much more accurate predictor of cardiovascular disease risk than either LDL or total cholesterol. In this article, I’m going to briefly outline the five primary causes of elevated LDL-P.

Conventional medicine is primarily focused on suppressing symptoms. If your blood pressure is high, you take a medication to lower it. If your blood sugar is high, you take a medication to lower it. If your cholesterol is high, you take a medication to lower it. In most cases there is rarely any investigation into why these markers are high in the first place, with the possible exception of some basic (but often incorrect) counseling on diet and exercise.

On the other hand, functional medicine—which is what I practice—focuses on treating the underlying cause of health problems instead of just suppressing symptoms. If your blood sugar, blood pressure or cholesterol are high, the first question a functional medicine practitioner will ask is “why?” If we can identify the root cause of the problem, and address it at that level, medication is often unnecessary.

To use a simple analogy, if you have weeds in your garden, what happens if you just cut the weeds from the top? They grow right back—and sometimes faster than before! If you really want to get rid of them once and for all, you have to pull them up by their roots.

With this in mind, let’s look at some of the potential causes of elevated LDL particle number. If your LDL-P is high, it makes sense to test for and treat any of the conditions below (with the exception of the last, which is genetic and thus can’t be treated) before—or at least along with—taking pharmaceutical drugs.

Insulin resistance and metabolic syndrome

LDL particles don’t just carry cholesterol; they also carry triglycerides, fat-soluble vitamins and antioxidants. You can think of LDL as a taxi service that delivers important nutrients to the cells and tissues of the body.

As you might expect, there’s a limit to how much “stuff” that each LDL particle can carry. Each LDL particle has a certain number of cholesterol molecules and a certain number of triglycerides. As the number of triglycerides increases, the amount of cholesterol it can carry decreases, and the liver will have to make more LDL particles to carry a given amount of cholesterol around the body. This person will end up with a higher number of LDL particles.

Consider two hypothetical people. Both have an LDL cholesterol level of 130 mg/dL, but one has high triglycerides and the other has low triglycerides. The one with the high triglyceride level will need more LDL particles to transport that same amount of cholesterol around the body than the one with a low triglyceride level.

Numerous studies have found an association between increased LDL particle number, and metabolic syndrome. One study measured ApoB, a marker for LDL particle number, in a group of 1,400 young Finns with no established disease. The participants with the highest LDL particle number were 2.8 times more likely to have metabolic syndrome than those with the lowest levels of LDL-P. (1) A much larger study of over 300,000 men also found a strong association between LDL-P and metabolic syndrome and its components (i.e. insulin resistance, abdominal obesity, high blood pressure, etc.). (2)

Poor thyroid function

Poor thyroid function is another potential cause of elevated particle number. Thyroid hormone has multiple effects on the regulation of lipid production, absorption, and metabolism. It stimulates the expression of HMG-CoA reductase, which is an enzyme in the liver involved in the production of cholesterol. (As a side note, one way that statins work is by inhibiting the HMG-CoA reductase enzyme.) Thyroid hormone also increases the expression of LDL receptors on the surface of cells in the liver and in other tissues. In hypothyroidism, the number of receptors for LDL on cells will be decreased. This leads to reduced clearance of LDL from the blood and thus higher LDL levels. Hypothyroidism may also lead to higher cholesterol by acting on Niemann-Pick C1-like 1 protein, which plays a critical role in the intestinal absorption of cholesterol. (3, 4)

Studies show that LDL particle number is higher even in subclinical hypothyroidism (high TSH with normal T4 and T3), and that LDL particle number will decrease after treatment with thyroid hormone. (5)

Infections

Another cause of high cholesterol profile is infection. Multiple studies have shown associations between bacterial infections like Chlamydia pneumoniae and H. pylori, which is the bacterium causes duodenal ulcers, and viral infections like herpes and cytomegalovirus and elevated lipids. (6) For example, H. pylori leads to elevated levels of total cholesterol, LDL cholesterol, lipoprotein (a), ApoB or LDL particle number, and triglyceride concentrations as well as decreased levels of HDL. (7)

Several mechanisms have been proposed to explain the association between infections and elevated blood lipids. Some evidence suggests that viral and bacterial infections directly alter the lipid metabolism of infected cells, and other evidence suggests that lipids increase as a result of the body’s attempt to fight off infection. Other evidence suggests that LDL has antimicrobial properties and is directly involved in inactivating microbial pathogens. This has been confirmed by studies showing that mice with defective LDL receptors—and thus very high levels of LDL—are protected against infection by gram-negative bacteria like H. pylori. (8)

Leaky gut

One of the primary functions of the intestinal barrier is to make sure that stuff that belongs in the gut stays in the gut. When this barrier fails, endotoxins such as lipopolysaccharide (LPS) produced by certain species of gut bacteria can enter the bloodstream and provoke an immune response. Part of that immune response involves LDL particles, which as I mentioned above, have an anti-microbial effect. A protein called LPS-binding protein, which circulates with LDL particles, has been shown to reduce the toxic properties of LPS by directly binding to it and removing it from the circulation. (9) Studies have also shown significant increases in LPS-binding protein (and thus LDL particles) in cases of endotoxemia—a condition caused by large amounts of circulating endotoxins. (10)

Though more research is needed in this area, the studies above suggest that a leaky gut could increase the level of LPS and other endotoxins in the blood, and thus increase LDL particle number as a result. I have seen this in my practice. I recently had a patient with high LDL-P and no other risk factors. I tested his gut and discovered H. pylori and small intestine bacterial overgrowth (SIBO). After treating his gut, his LDL-P came down to normal levels.

Genetics

The final cause of elevated LDL-P is genetics. Familial hypercholesterolemia, or FH, involves a mutation of a gene that codes for the LDL receptor or the gene that codes for apolipoprotein B (ApoB). The LDL receptor sits on the outside of cells; the LDL particle has to attach to the LDL receptor in order to deliver the nutrients it’s carrying and be removed from the circulation. ApoB is the part of the LDL particle that binds to the receptor. If we use a door lock as an analogy, apolipoprotein B would be the key, and the LDL receptor is the lock. They both need to be working properly for LDL to deliver its cargo and to be removed from the bloodstream.

Homozygous carriers of FH have two copies of the mutated gene. This condition is very rare. It affects approximately 1 in a million people. And people that are homozygous for this mutation have extremely high total cholesterol levels, often as high as 1000 mg/dL. And unfortunately they usually die from severe atherosclerosis and heart disease before the age of 25.

Heterozygous carriers, however, only have a single copy of the mutated gene, and the other copy is functioning normally. This is much more common. The prevalence is between 1 in 300 to 1 in 500 people, depending on which study you look at. These heterozygous carriers of FH have total cholesterol levels that often range between 350 and 550 mg/dL, along with very high LDL particle number. They have about three times higher risk of death from heart disease than people without FH if it goes untreated.

It’s important to note that people with FH have primarily large, buoyant LDL particles, and yet are still at much higher risk for cardiovascular disease. While it’s true that small, dense, oxidized LDL particles are more likely to cause atherosclerosis, large, buoyant particles can also be harmful when their concentration is high enough. This is one reason why LDL particle number is a superior marker to LDL particle size.

In the next article in this series, I will debunk the myth that statins extend lifespan in healthy people with no pre-existing heart disease.
=================================================================
Read the complete article here.