By Evan Levine, M.D.

In 2002, Merck labs received FDA approval for the use of their soon-to–be blockbuster drug; a drug that has since given Merck more than $40,000,000,000 (40 billion dollars in sales). But with all the hype, and billions in profit, Ezitamide (brand name of Zetia) has failed to show it helped any patient in every published trial, and likely has done nothing for the scores of patients who dutifully paid for and swallowed this pill.

Zetia, a novel drug that does lower cholesterol and can be taken with the statin drugs, got its approval from the FDA even when Merck could not produce a trial showing it lowered heart attack rate or improved survival. Perhaps naively or possibly because some members of this expert panel were interested in helping Merck, members of the FDA panel assumed that since statins lowered cholesterol and statins reduced heart attacks that Zetia should do the same. Both drugs clearly lowered cholesterol and so, both drugs should lower cardiac event rates, they reasoned. But Zetia works differently than statins. Statins reduce production of cholesterol in the liver; Zetia works by inhibiting absorption of cholesterol in the small intestine. That difference in mechanism, coupled with the very short clinical trials (3 months instead of the usual 6 to 12 months) makes the likelihood of unknown risks with Zetia use higher.

By 2008, and with billions already in sales, Merck got the bad news -- a randomized trial, known as ENHANCE ( Hypercholesterolemia Enhances Atherosclerosis Regression) showed that Zetia helped lower cholesterol but did not reduce the progression of arterial plaque. In fact, there were suggestions that patients who took Zetia actually develop more plaque.

I was a pessimist from the day the drug was marketed, since it did not have any outcome data, other than lowering cholesterol and it was quite expensive, so I stuck with the statin drugs for therapy in my patients. But my first-hand experience with how Merck saturated doctors with pharmaceutical reps and free dinners angered me. So much that I banned the Merck Reps who marketed the drug from my office, and when they still continued to walk into my office, without an invitation, I placed a sign for all my patients and the reps to see, saying “I do not prescribe Zetia” and that”anyone marketing the drug should not come to this office.“

While too many physicians continued to give dinner talks for Zetia, with a pay-out of over a $1,000 dollars for an hour talk, I enjoyed stopping Zetia in patients I saw in consultation. Approached in the parking area of our office by a Merck Rep I was asked why I acted like I do and if I knew how much I was hurting her career and sales numbers. There seemed to be very few people worried that a teaspoon of water was as good as Zetia in reducing heart disease. And if you were irreverent enough to disagree with hundreds of experts, Merck, and many of your colleagues, you were looked upon as some quixotic pest.

Call me irresponsible, call me irreverent, or call me someone with a foolish conscience, but I enjoyed bucking the trend. I just didn’t enjoy watching some very good people, good physicians, ignore what was clear to me -- Zetia didn’t work.

To be fair, many physicians just listened to what many of the experts professed, some who prostituted themselves for healthy sums of money. There were and are too many experts far more knowledgeable in the pathophysiology of lipid disorders and far smarter than I, who had to know that Ezetimide did not work . I liken them to a bunch of gangsters who happened to be educated in the best schools but might have been a drug lord had they been born under different circumstances. And these hooligans sold their souls and a heck of a lot of Zetia. To his credit, Yale University Cardiologist Harlan Krumholz , a well-respected cardiologist, was quoted a few years ago saying that Zetia should not be a first or even second option for doctors treating lipid disorders. And yet zetia continued to rack up billions of profits for Merck.

When a drug is proven not to work we might expect that doctors would finally stop prescribing it. And while a review of prescptions of Zetia, published in the American Heart Journal, found prescription rates falling by over 47% after studies showed the drug did not work, it still meant that Ezitamide sales were in the billions. In 2008 alone Merck reported sales of 4.9 billion dollars in drugs that contained Ezitamide.

In 2009 a trial called ARBITER-HALTS showed that patients who took Niacin with a statin had regression of their atherosclerotic disease while patients who took Zetia with a statin had no benefit. Another trial would show that the addition of a Niacin to a statin was no better than just taking a statin alone raising the most alarming question that perhaps Zetia may be harmful, since in the ARBITER-HALTS trial Niacin plus Statin was better than Zetia and Statin. But the drug still kept selling, either as a combination with Merck’s generic Zocor, a generic Lipitor combination, or by itself. In 2010 the outspoken cardiologist Dr. Steven Nissen finally said something many of us were saying for years: “We’ve spent billions on a drug that may turn out to be a placebo.” And yet Zetia sales kept on chugging along , with 4.3 billion in sales in 2009. Merck smartly combined their generic Zocor with Zetia, named it Vytorin, and created another multibillion dollar drug.

No matter how bad the news was the drug kept on making money, and Merck kept on selling their Zetia and Vytorin brands. In 2011 and 2012, Merck sold over 4.3 billion dollars of drugs that contained Zetia, and in 2013, two of their top five drugs contained Zetia. In just over ten years, Merck has sold over 40 billion dollars of nothing!

There is one better way of knowing that Zetia is a 40 billion-dollar dud, a loser that may have left patients dead and Merck shareholders rich, something even more important than every negative study published on Zetia. There are no copycats! IF this drug worked, if big Pharma thought they could get a Zetia-like copycat past the FDA, we would have lots of other Zetia-like pills on the market. When Mevaor was a success, Pharma followed with Zocor, and Pravachol, and Lipitor, and Baycol (Baycol killed a bunch of people and was withdrawn from the market) and Crestor, and those copycats made billions for their respective companies. When Prilosec was a success, out came Protonix, Aciphex, Dexilant, and the greatest of them all, the purple pill Nexium that stands as the top selling drug in our pathetic healthcare system.

I can go on with this but you get it; if a drugs works, if even only marginally, and if Pharma knows they can get it past the FDA, Pharma will produce a copycat and make billions by slightly altering the molecular structure of the original drug and packaging it nicely, say, in a purple pill. Yet… there is no purple Zetia, is there?

About the author: Evan S. Levine, MD FACC, is Director of the Cardiovascular Center at Saint Joseph’s Hospital and a Clinical Assistant Professor of Medicine at Montefiore Medical Center – Albert Einstein College of Medicine. He is also the author of the book “What Your Doctor Won’t (or can’t) Tell You”. He lives in Connecticut with his wife and children.