Dec 17, 2006 03:00 AM

Thedrug maker Eli Lilly has engaged in a decade-long effort to play downthe health risks of Zyprexa, its best-selling medication forschizophrenia, according to hundreds of internal Lilly documents ande-mail messages among top company managers.

The documents, givento The Times by a lawyer representing mentally ill patients, show thatLilly executives kept important information from doctors aboutZyprexa’s links to obesity and its tendency to raise blood sugar — bothknown risk factors for diabetes.

Lilly’s own published data,which it told its sales representatives to play down in conversationswith doctors, has shown that 30 percent of patients taking Zyprexa gain22 pounds or more after a year on the drug, and some patients havereported gaining 100 pounds or more. But Lilly was concerned thatZyprexa’s sales would be hurt if the company was more forthright aboutthe fact that the drug might cause unmanageable weight gain ordiabetes, according to the documents, which cover the period 1995 to2004.

Zyprexa has become by far Lilly’s best-selling product,with sales of $4.2 billion last year, when about two million peopleworldwide took the drug.

Critics, including the AmericanDiabetes Association, have argued that Zyprexa, introduced in 1996, ismore likely to cause diabetes than other widely used schizophreniadrugs. Lilly has consistently denied such a link, and did so again onFriday in a written response to questions about the documents. Thecompany defended Zyprexa’s safety, and said the documents had beentaken out of context.

But as early as 1999, the documents showthat Lilly worried that side effects from Zyprexa, whose chemical nameis olanzapine, would hurt sales.

“Olanzapine-associated weightgain and possible hyperglycemia is a major threat to the long-termsuccess of this critically important molecule,” Dr. Alan Breier wrotein a November 1999 e-mail message to two-dozen Lilly employees thatannounced the formation of an “executive steering committee forolanzapine-associated weight changes and hyperglycemia.” Hyperglycemiais high blood sugar.

At the time Dr. Breier, who is now Lilly’s chief medical officer, was the chief scientist on the Zyprexa program.

In2000, a group of diabetes doctors that Lilly had retained to considerpotential links between Zyprexa and diabetes warned the company that“unless we come clean on this, it could get much more serious than wemight anticipate,” according to an e-mail message from one Lillymanager to another.

And in that year and 2001, the documentsshow, Lilly’s own marketing research found that psychiatrists wereconsistently saying that many more of their patients developed highblood sugar or diabetes while taking Zyprexa than other antipsychoticdrugs.

The documents were collected as part of lawsuits onbehalf of mentally ill patients against the company. Last year, Lillyagreed to pay $750 million to settle suits by 8,000 people who claimedthey developed diabetes or other medical problems after taking Zyprexa.Thousands more suits against the company are pending.

On Friday,in its written response, Lilly said that it believed that Zyprexaremained an important treatment for patients with schizophrenia andbipolar disorder. The company said it had given the Food and DrugAdministration all its data from clinical trials and reports of adverseevents, as it is legally required to do. Lilly also said it shared datafrom literature reviews and large studies of Zyprexa’s real-world use.

“In summary, there is no scientific evidence establishing that Zyprexa causes diabetes,” the company said.

Lillyalso said the documents should not have been made public because theymight “cause unwarranted fear among patients that will cause them tostop taking their medication.”

As did similar documentsdisclosed by the drug maker Merck last year in response to lawsuitsover its painkiller Vioxx, the Lilly documents offer an inside look athow a company marketed a drug while seeking to play down its sideeffects. Lilly, based in Indianapolis, is the sixth-largest Americandrug maker, with $14 billion in revenue last year.

The documents— which include e-mail, marketing material, sales projections andscientific reports — are replete with references to Zyprexa’simportance to Lilly’s future and the need to keep concerns aboutdiabetes and obesity from hurting sales. But that effort becameincreasingly difficult as doctors saw Zyprexa’s side effects, thedocuments show.

In 2002, for example, Lilly rejected plans togive psychiatrists guidance about how to treat diabetes, worrying thatdoing so would tarnish Zyprexa’s reputation. “Although M.D.’s likeobjective, educational materials, having our reps provide some withdiabetes would further build its association to Zyprexa,” a Lillymanager wrote in a March 2002 e-mail message.

But Lilly didexpand its marketing to primary care physicians, who its internalstudies showed were less aware of Zyprexa’s side effects. Lilly salesmaterial encouraged representatives to promote Zyprexa as a “safe,gentle psychotropic” suitable for people with mild mental illness.

Sometop psychiatrists say that Zyprexa will continue to be widely useddespite its side effects, because it works better than most otherantipsychotic medicines in severely ill patients. But others say thatZyprexa appears no more effective overall than other medicines.

Andsome doctors who specialize in diabetes care dispute Lilly’s assertionthat Zyprexa does not cause more cases of diabetes than otherpsychiatric drugs. “When somebody gains weight, they need more insulin,they become more insulin resistant,” Dr. Joel Zonszein, the director ofthe clinical diabetes center at Montefiore Medical Center in the Bronx,said when asked about the drug.

In 2003, after reviewing dataprovided by Lilly and other drug makers, the F.D.A. said that thecurrent class of antipsychotic drugs may cause high blood sugar. It didnot specifically single out Zyprexa, nor did it say that the drugs hadbeen proven to cause diabetes.

The drugs are known as atypicalantipsychotics and include Johnson & Johnson’s Risperdal andAstraZeneca’s Seroquel. When they were introduced in the mid-1990s,psychiatrists hoped they would relieve mental illness without thetremors and facial twitches associated with older drugs. But the newdrugs have not proven significantly better and have their own sideeffects, said Dr. Jeffrey Lieberman, the lead investigator on afederally sponsored clinical trial that compared Zyprexa and other newdrugs with one older one.

The Zyprexa documents were provided tothe Times by James B. Gottstein, a lawyer who represents mentally illpatients and has sued the state of Alaska over its efforts to forcepatients to take psychiatric medicines against their will. Mr.Gottstein said the information in the documents raised public healthissues.

“Patients should be told the truth about drugs like Zyprexa,” Mr. Gottstein said.

Lillyoriginally provided the documents, under seal, to plaintiffs lawyerswho sued the company claiming their clients developed diabetes fromtaking Zyprexa. Mr. Gottstein, who is not subject to theconfidentiality agreement that covers the product liability suits,subpoenaed the documents in early December from a person involved inthe suits.

In its statement, Lilly called the release of thedocuments “illegal.” The company said it could not comment on specificdocuments because of the continuing product liability suits.

Insome ways, the Zyprexa documents are reminiscent of those produced inlitigation over Vioxx, which Merck stopped selling in 2004 after aclinical trial proved it caused heart problems. They treat verydifferent conditions, but Zyprexa and Vioxx are not entirelydissimilar. Both were thought to be safer than older and cheaper drugs,becoming bestsellers as a result, but turned out to have serious sideeffects.

After being pressed by doctors and regulators, Merckeventually did test Vioxx’s cardiovascular risks and withdrew the drugafter finding that Vioxx increased heart attacks and strokes.

Lillyhas never conducted a clinical trial to determine exactly how muchZyprexa raises patients’ diabetes risks. But scientists say conductingsuch a study would be exceedingly difficult, because diabetes takesyears to develop, and it can be hard to keep mentally ill patientsenrolled in a clinical trial.

When it was introduced, Zyprexawas the third and most heralded of the atypical antipsychotics. Withpsychiatrists eager for new treatments for schizophrenia, bipolardisorder, and dementia, Zyprexa’s sales soared.

But as salesgrew, reports rolled in to Lilly and drug regulators that the medicinecaused massive weight gain in many patients and was associated withdiabetes. For example, a California doctor reported that 8 of his 35patients on Zyprexa had developed high blood sugar, including two whorequired hospitalization.

The documents show that Lillyencouraged its sales representatives to play down those effects whentalking to doctors. In one 1998 presentation, for example, Lilly saidits salespeople should be told, “Don’t introduce the issue!!!”Meanwhile, the company researched combinations of Zyprexa with severalother drugs, hoping to alleviate the weight gain. But the combinationsfailed.

To reassure doctors, Lilly also publicly said that whenit followed up with patients who had taken Zyprexa in a clinical trialfor three years, it found that weight gain appeared to plateau afterabout nine months. But the company did not discuss a far lessreassuring finding in early 1999, disclosed in the documents, thatblood sugar levels in the patients increased steadily for three years.

In2000 and 2001, more warning signs emerged, the documents show. In foursurveys conducted by Lilly’s marketing department, the company foundthat 70 percent of psychiatrists polled had seen at least one of theirpatients develop high blood sugar or diabetes while taking Zyprexa,compared with about 20 percent for Risperdal or Seroquel. Lilly neverdisclosed those findings.

By mid-2003, Lilly began to change itsstance somewhat, publicly acknowledging that Zyprexa can cause severeobesity. Marketing documents make clear that by then Lilly believed ithad no choice. On June 23, 2003, an internal committee reported thatZyprexa sales were “below plan” and that doctors were“switching/avoiding Zyprexa.”

Since then, Lilly has acknowledgedZyprexa’s effect on weight but has argued that it does not necessarilycorrelate to diabetes. But Zyprexa’s share of antipsychotic drugprescriptions is falling, and some psychiatrists say they no longerbelieve the information Lilly offers.

“From my personalexperience, at first my concerns about weight gain with this drug werevery significantly downplayed by their field representatives,” said Dr.James Phelps, a psychiatrist in Corvallis, Or. ‘Their continued effortsto downplay that, I think in retrospect, was an embarrassment to thecompany.”

Dr. Phelps says that he tries to avoid Zyprexa becauseof its side effects but sometimes still prescribes it, especially whenpatients are acutely psychotic and considering suicide, because itworks faster than other medicines.

“I wind up using it as anemergency medicine, where it’s superb,” he said. “But I’m trying to getmy patients off of Zyprexa, not put them on.”

– end –

http://www.nytimes.com/2006/12/17/business/17drug.html?ex=1166936400&en=49ecabeacfb44013&ei=5070&emc=eta1

More info on PsychRights see http://www.psychrights.org