Merck’s Cholesterol Drugs—Low Hanging Fruit?

If an expensive, name-brand cholesterol drug costs four times more than a generic but provides no clear clinical benefit, why do insurers—both public and private—continue to pay for it? The answer, in the case of Vytorin, a combination of two drugs designed to lower LDL or bad cholesterol, is that the influence of big Pharma in maintaining the status quo—even when unsupported by evidence—remains a formidable barrier. By suppressing negative studies, relentlessly pursuing positive trial results, and paying academic researchers to promote their therapy, Merck Schering-Plough has managed to hold onto a $4.6 billion market for a drug that has never been proven to be better than cheaper generics in preventing heart attacks or death.

Why is this important? When we talk about reducing health care costs, the discussion eventually turns to cutting waste out of the system—the costly treatments and procedures that don’t provide clear benefits and might even cause harm. Within this group there are “low-hanging fruits;” the treatments and procedures that so clearly meet this criteria that they should be among the first to go. In the nearly $20 billion market for cholesterol-lowering drugs, Vytorin—a combination of simvastin, an off-patent statin and Zetia, a proprietary drug that is designed to inhibit the body’s absorption of cholesterol from food—is one fruit that may be worth plucking.

The case against Vytorin (and Zetia, as well) begins with a large, multi-year trial called ENHANCE that pitted Vytorin against simvastin alone. By at least 2006, executives from Merck and Schering Plough learned of results showing that Vytorin, although more effective in lowering patients’ cholesterol levels, did not reduce plaque in the carotid arteries of patients any better than simvastin alone. Instead of publishing these results, the companies (who at that time were jointly marketing the drug) kept them quiet and launched a massive marketing campaign for Vytorin—featuring upbeat pictures of food and quirky relatives to illustrate the point that to fight heart disease, patients need a drug that controls high cholesterol due to genes and diet. In 2006, the drug brought in $1.5 billion with sales climbing 25% in the first half of 2007 to over $2 billion, according to IMS Health.

In articles for HealthBeat, “The Cholesterol Con—Where Were the Doctors?” and “The Origins of the Cholesterol Con,”  that question whether lowering cholesterol will really help most people ward off heart attacks, Maggie reports that Merck and Schering/Plough, “were shy about reporting the results of the clinical trials. It was only when they were threatened with a Congressional investigation that they made the results public on January 15 [2008]—more than a year and a half after the clinical trials were completed.”

This delay in releasing negative data about Vytorin by Merck and Schering-Plough (which have since merged) has led to legal headaches for the companies. In the last few months the companies have agreed to pay out a combined total of $46 million to state attorney generals and consumers to settle class action lawsuits alleging that the companies violated consumer protection laws by marketing Vytorin and Zetia as being superior to other cholesterol-lowering drugs and selling them at higher prices when, in fact, they were not more effective. Merck continues to deny wrongdoing, and this financial penalty is merely a drop in the multi-billion dollar bucket of profits the company made selling the drugs during the delay.

Investors are also seeking recompense; several large pension funds have now joined a separate class-action lawsuit being filed against Merck/Schering-Plough. This suit alleges that the company knew about the negative results of trials as early as 2005 and continued to make “false and misleading statements that artificially elevated the price of the company’s shares.”

It’s clear that the legal problems surrounding Vytorin and Zetia are not going away anytime soon. And in the meantime, the scientific evidence for the drugs’ benefits continues to be negative—except in merely lowering serum cholesterol levels. Two new studies, presented last week at the American Heart Association meeting in Orlando, have disappointing results that back up the ENHANCE findings:

1) One trial, published in the New England Journal of Medicine, looked at patients who either had coronary artery disease or were at high risk of the disorder and took statins to lower their LDL (bad) cholesterol levels. The participants were given a prescription version of niacin (a b-vitamin) which raises the levels of HDL (good) cholesterol in the body, or alternately, ezetimibe (Merck’s Zetia) which lowers LDL levels even further but has no effect on HDL. The idea was to see which drug regimen worked best in reducing buildup of plaques in the neck artery. When plaque builds up on artery walls it causes them to narrow, leading to heart attack or stroke.

The results were not encouraging. Researchers found that patients in the niacin group saw their HDL cholesterol rise and had a “significant regression in artery wall thickness.” In the group that took Zetia, LDL cholesterol levels fell, but there was no change in the plaque buildup on the artery walls. HDL actually removes LDL from the blood-stream in a process called “reverse cholesterol transport.” Additionally, the researchers found the incidence of heart attacks and strokes to be lower in the group taking niacin.

The results of this trial were not surprising to some experts. According to this article from back in 2007 in the New York Times, niacin has been known to prevent atherosclerosis and to reduce the risk of second heart attacks since 1975.

“Here you have a drug that was about as effective as the early statins, and it just never caught on,” Dr. B. Greg Brown, professor of medicine at the University of Washington in Seattle told the Times. “It’s a mystery to me. But if you’re a drug company, I guess you can’t make money on a vitamin.”

2) In another study, also presented in Orlando, researchers with UnitedHealth Group Inc.’s pharmacy benefits unit Prescription Solutions analyzed medical claims of 30,000 patients taking either Vytorin, Lipitor (a statin made by Pfizer) or simvastatin, the cheaper generic. They found no difference in rates of heart attacks or strokes among the three groups. Although this analysis comes from a pharmacy benefit manager and hasn’t been published in a medical journal, it has major implications. Vytorin costs more than four times more per dose than simvastin—and again, hasn’t shown any clear benefits other than lowering cholesterol.

In the face of all this negative data, Merck continues to insist that Vytorin and Zetia have real benefits worthy of their high price tags—merely by lowering cholesterol levels somewhat lower than generic statins.  At the Orlando conference, the company went on “a public relations offensive,” according to an article in Forbes. Merck sent research chief Peter Kim and marketing head Kenneth Frazier to Orlando to defend Zetia and even trotted out the inventor of the drug to talk to analysts and doctors.

In their defense of Zetia and Vytorin, the Merck researchers continue to stress that the drugs reduce cholesterol levels some 20% more than generic statins. This is not a huge benefit to begin with. And many experts question the wisdom of putting so many otherwise-healthy people on prescription drugs to reduce their cholesterol levels when this seems to have modest or no benefit in preventing heart attacks and strokes.

Merck is continuing to pursue this elusive evidence that its drugs will prevent heart attacks. It started enrolling people in a study looking at the benefits of Zetia versus a placebo in preventing heart attacks in 2005 and has yet to meet its goal of enrolling 18,000 patients. Results are not expected until 2012 at the earliest, and critics wonder if the study will ever be completed—especially as patients drop out due to bad press about Zetia’s benefits.

Merck has also enlisted some of the top names in cardiovascular medicine to help in its public relations offensive. An article last month in the Chronicle of Higher Education provides details of how Merck Schering-Plough is using prominent doctors to convince their colleagues of Vytorin’s benefits:

“Fourteen university-affiliated physicians collected more than $400,000 from the makers of the anti-cholesterol drug Vytorin as part of a campaign to encourage the use of the medication. The 2008 campaign went on after an internal company study showed that the drug, with several billion dollars in sales, had little or no overall value for most patients.

“The physicians, many of them prominent in the field of cardiovascular disease, accepted the money from the manufacturers Merck & Company and the Schering-Plough Corporation for delivering speeches to health practitioners and attending advisory meetings. Sergio Fazio, a professor of medicine at Vanderbilt University, was paid $82,260, for example. Michael H. Davidson, a professor of medicine at the University of Chicago, was paid $71,150, and Antonio M. Gotto Jr., dean of the Weill Cornell Medical College, collected $27,146.”

So far insurers continue to buy the pitch. According to Merck, 81% of managed care customers have access to Vytorin at the “lowest branded copay.” Medicare continues to list Vytorin as a “Tier 2” drug, the best spot for a branded drug—Tier 1 drugs are generics and require the lowest co-pays from subscribers. Once a drug moves in Tier 3 in Medicare or managed care plans, the co-pays become much larger and the drug is prescribed far less.

How will the government, which stands to save billions over the years in removing these expensive drugs from their formularies, respond to this new evidence? The New York Times
reports that “Senator Charles E. Grassley, Republican of Iowa, wrote to the Department of Health and Human Services, asking its director, Kathleen Sebelius, what action she intended to take in light of the study results. Mr. Grassley sits on the Senate Finance Committee which has jurisdiction over Medicare and its drug spending. In 2006 and 2007, the drug makers made more than $300 million through Medicare Part D in sales of Vytorin, a drug that combines Zetia and a statin, Mr. Grassley wrote.”

Secretary Sebelius has not yet responded publicly. But the issue begs her consideration—if only because refusing to pay for expensive medications with no clear benefit over cheaper alternatives seems to be at the heart of efforts to drive down sky-rocketing health care costs. It will also provide a good test case for how successful the government can be in using evidence-based medicine as a defense against Big Pharma’s lobbying machine.

Comments

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Can cholesterol drugs/statins cause psychological side effects?
I've been taking cholesterol drugs for a while, and they've been making me feel strange to a slight degree, but nothing too bad; however I can't help but notice how I just feel so...agitated/anxious/depressed as of late, and am trying to figure out what it can be.