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Rezulin, a type 2 diabetes drug manufactured by Warner-Lambert, has been receiving its fair share of black eyes recently. Many in the diabetes community, however, are standing by Rezulin as an effective agent in treating type 2 diabetes. Others are making plans to treat their type 2 diabetes through other means.
The anti-Rezulin movement began to capture media attention in July 1998 when a United States consumer protection agency known as Public Citizen petitioned the Food and Drug Administration (FDA) to ban Rezulin in the United States. Then, a published report appeared in a journal known as Nature Medicine which mentioned a study conducted at the Salk Institute for Biological Study in which laboratory mice predisposed to intestinal tumors developed colon cancer when given Rezulin.
In the December 1998 issue of Diabetes Care, researchers at Kitasato University School of Medicine in Japan published a study of a 58-year-old Japanese man who contracted severe hepatitis two months after he started taking Rezulin. The man was taking 400 mg of Rezulin, and his blood glucose levels became well controlled after taking the drug, but liver damage progressed gradually even after withdrawal of Rezulin. Within eight weeks, the patient died.
A Long December
In December 1998, however, Rezulin faced its most intense onslaught of negative criticism from the mainstream news media. According to a series of articles that ran in the Los Angeles Times, it was reported that Dr. Richard C. Eastman, who is the top diabetes researcher for the National Institutes of Health (NIH) and a paid consultant for Warner-Lambert, helped oversee the $150 million government study to approve Rezulin. It was also reported that John Gueriguian, a medical officer for the FDA and the chief reviewer of Rezulin, was removed from his position in the fall of 1996 after he opposed Rezulin's approval. The Los Angeles Times then reported that Rezulin has been linked to 33 deaths as a result of liver damage since it was released in March 1997, and on the December 23, 1998 edition of ABC's "Nightline" there was a half-hour feature story that covered all of the quandaries that the Los AngelesTimes reported regarding Rezulin.
In response to the barrage of negative press, Warner-Lambert issued the following statement:
"Warner-Lambert is disappointed with the mischaracterizations of its actions and intentions regarding the development and marketing of Rezulin. The company has always been forthcoming with information regarding the safety and efficacy of this therapy with both the U.S. Food and Drug Administration and health care professionals. The company is particularly disturbed about recent media coverage of the drug that seems to focus primarily on risks, but largely ignores the significant patient benefits that this medication provides."
Warner-Lambert went on to say that the ABC News "Nightline" report was filled with misstatements and omissions of material facts. Warner-Lambert was invited to appear on "Nightline," but chose to submit a written response instead. According to Warner-Lambert, this response, which clarified information regarding Rezulin's safety, the removal of Dr. Gueriguian, and Warner-Lambert's relationship with Eastman, was largely ignored by the broadcast.
"I am clueless as to why there has been so much focus on Rezulin," says Carol Goodrich, director of media relations at Warner-Lambert. "We have said time and time again that the benefits of Rezulin far outweigh its risks. It's really unfortunate that there has been a complete lack of balance in the press coverage."
According to spokespersons at the FDA, there is no intention of pulling Rezulin from the market.
"The FDA continues to believe the benefits of Rezulin outweigh the risks."
Rezulin was given FDA clearance on January 29, 1997. It was considered an instrumental and important agent in diabetes treatment because it was the first drug of its kind to directly attack the underlying causes of type 2 diabetes. Researchers believe that it stimulates a gene to produce more insulin-controlled proteins that remove glucose from the bloodstream. In clinical trials involving 222 type 2 patients a few years ago, Rezulin was proven to reduce insulin dosage in 70 percent of the group. Additionally, Rezulin eliminated the need for insulin shots in 15 percent of the study group.
According to a study conducted by IMS Health that ran in the November 16, 1998 edition of the Wall Street Journal, Rezulin was recognized as one of the ten fastest growing pharmaceutical agents between June 1997 and June 1998. Rezulin had sales of $545 million, which was a 653 percent increase from the previous year.
Withdrawn in the UK
Rezulin, however, was withdrawn from the United Kingdom diabetes drug market on December 1, 1997. At the time, it was reported that six people had died from liver damage after taking the popular diabetes drug, prompting the British government to conclude that "the risks of troglitazone [Rezulin] outweigh the potential benefits." Earlier, on October 29, 1997, Warner-Lambert recommended that people taking Rezulin have their liver enzymes tested five times during the first year (the first one to two months of therapy, and then every three months for the remainder of the first year). After it was withdrawn in the UK, however, the FDA suggested that Warner-Lambert modify the liver monitoring requirements, and add a boxed warning to Rezulin's label. Warner-Lambert complied, and changed the guidelines, suggesting that patients who take Rezulin have their liver enzymes measured 10 times during the first year (at the start of therapy, every month for the first six months of treatment, and then every other month for the remainder of the first year).
Liver Monitoring Tests
In July 1998, it was then revealed that 21 people had died from taking Rezulin, prompting United States consumer protection agency Public Citizen to petition the FDA for Rezulin's removal from the United States drug market. On July 27, 1998, Warner-Lambert modified its labeling requirements once again, suggesting that patients who take Rezulin have their liver enzymes measured 11 times during the first year (at the start of therapy, monthly for the first eight months of therapy, and then every two months for the remainder of the first year).
Since the petition was submitted to the FDA last July, the Los Angeles Times reported in December that 33 people have died as a result of liver damage associated with Rezulin use. Dr. Sidney Wolfe of Public Citizen feels that these additional 12 deaths are further reason why Rezulin should be banned.
"When we first sent in the petition [last July], there were only 21 deaths, and now there are 33," says Wolfe. "This is even worse, because at the time of our petition to ban Rezulin, the medical officer assigned to the drug [Dr. Gueriguian] had already warned the FDA that it should not be approved."
Wolfe goes on to say that Warner-Lambert's liver monitoring modifications between December 1997 and July 1998 did little to prevent additional deaths associated with Rezulin use.
"Those [liver monitoring] guidelines are interesting, but they don't work," says Wolfe. "All they did with the new guidelines was change the requirement from 10 tests a year to 11. If 10 tests a year didn't stop people from being injured by Rezulin, what made them think that 11 would?"
One endocrinologist disagrees with Public Citizen's claim.
"If you look at the statistics, the incidence of elevated liver enzymes in other medications on the market are astronomical in comparison to Rezulin," says Richard Bernstein, MD, FACE, FACN of the Diabetes Center in Mamoreneck, New York. Bernstein contends that the number of deaths related to liver damage in individuals taking Rezulin is very small. He emphasizes that deaths as a result of high blood sugars are much higher in people with diabetes, and that organizations like Public Citizen should be focusing on that instead. "I have over 60 patients on Rezulin. The first person to show elevation of liver enzymes just came in the other day. Aside from that, I have had three people whose liver enzymes have gone down while taking Rezulin, which is the opposite effect of what Public Citizen is claiming."
According to Bernstein, there are three liver enzyme tests: the ALT, which has a normal range of 0 to 38; the AST, which has a normal range of 0 to 42; and the GGTP, which has a normal range of 0 to 65.
"Anything above these numbers constitutes a high liver enzyme reading, and it is recommended that usage of any pharmaceutical agent be discontinued if numbers get this high during the drug's administration," says Bernstein.
Bernstein goes on to say that having to perform the mandatory liver enzyme tests is a bit of an inconvenience in that it leaves the physician liable for any complications that might arise from taking Rezulin or any other drug.
"The test means that if someone taking Rezulin develops viral hepatitis, and the doctor has not been checking him or her for enzymes, then the doctor could be held liable," says Bernstein. "What I have been doing is leaving the decision to use Rezulin or insulin up to the patient."
Bernstein does perform the liver enzyme test for his patients taking Rezulin.
"As a result, I have paper work piling up all over the place," says Bernstein.
Others in the diabetes community feel that liver problems are very hard to predict, and are dependent upon liver function of the patient, age and other medications the patient might be taking.
"Let's put things in perspective though," says R. Keith Campbell, RPh, CDE, professor of the pharmacy department at Washington State University. "Tylenol, an over-the-counter medication, causes over 70 deaths each year due to liver problems. Yet, it is over-the-counter, and no recommendations for liver function tests are required."
Campbell extols the merits of Rezulin in the treatment of type 2 diabetes.
"I rate Rezulin as a major breakthrough in the treatment of type 2 diabetes," he says. "I predict that some day, it will be given to people with impaired glucose tolerance to reduce insulin resistance and the devastating consequences of high blood sugar, high blood pressure and high lipid levels on the heart."
Debra Singer, RPh, CDE, from Kalamazoo, Michigan, does not recommend that her patients take Rezulin. She explains that reducing insulin resistance can be accomplished without the drug.
"I know that a wellness protocol based on diet, nutrition, exercise and lifestyle modification can be successful in normalizing blood glucose control," says Singer. "I would recommend that patients who currently take Rezulin become informed and seek to work closely with their health care providers to determine the advisability and design of other treatment options and goals."
Peter Lodewick, MD, medical director at the Diabetes Care Center in Birmingham, Alabama, heralds Rezulin as a great advance in the improvement of blood sugar control that has not been possible with the sulfonylurea drugs that work mainly to stimulate insulin release.
"Rezulin has a unique effect on protein-glucose transport, which improves the transport of glucose into muscle, fat and even liver cells," says Lodewick. "In my experience with patients who use Rezulin, it has had such a dramatic effect that is totally different from the other oral agents."
Mixed Reactions about Rezulin
Other people in the diabetes community have developed apprehensions about Rezulin since the recent circus of media events.
"My opinion of Rezulin has changed," says Brenda Overall of Woodbridge, Virginia. "I was skeptical in the beginning, but now I feel justified. I'm glad my doctor was skeptical too."
Jacki Barineau, on the other hand, is one of the people who swears by what Rezulin has done for her in her treatment of type 2 diabetes.
"I personally feel that Rezulin has been somewhat of a 'miracle drug' as far as getting my insulin requirements down," says Barineau, who says that she has been taking Rezulin for over a year. Prior to starting Rezulin, she required 50 units of Regular insulin before each meal, and said that her postmeal blood sugars still ran around 180 to 200, and sometimes higher. After starting 400 milligrams of Rezulin per day, her insulin requirements dropped to 30 units before meals. Eventually, her insulin dosage decreased to 10 to 15 units per day, and her postmeal blood sugar readings have been between 120 and 150 for almost a year now. "I would be extremely upset if Rezulin were removed from the market."
Barbara Sklar of Eugene, Oregon, considers Rezulin to be anything but a miracle drug.
"My blood sugars did begin to come down after about six weeks, however, unbeknownst to me, my liver was beginning to be poisoned by the medication," says Sklar. "I had a chronic case of diarrhea, as well as severe fatigue, and my doctor did not relate these symptoms to a possible adverse drug reaction. He was also not testing me for liver enzymes, although he was aware of the guidelines to do so. After the test, he could not believe the results. My liver enzymes were 30 times the normal at their peak, and I was taken off Rezulin. It took an additional three months for my liver enzymes to normalize."
Byron Atkinson of Lake Zurich, Illinois, argues that Rezulin should not be blamed for the deaths if it is not known whether the 33 people who died had histories of drinking, drug abuse or liver damage.
"My druggist told me that aspirin causes more liver damage than Rezulin," says Atkinson. "All I know is that once I started Rezulin, my insulin usage dropped back 66 percent. I have had no problems with it, and my liver tests have all come back normal."
Bill McLarty of Mobile, Alabama, says that he started using Rezulin, but it didn't do much in the way of controlling his blood sugars. Then he heard about the 33 deaths, and was convinced.
"With no apparent benefit, and the risk of liver damage, I discontinued using Rezulin," says McLarty.
George Carpenter of Pinckney, Minnesota, feels that poor blood sugar control, not Rezulin, is what really kills people with diabetes.
"I have decided to see my doctor and urge him to prescribe Rezulin for me," says Carpenter. "I am convinced that with the monthly liver tests, I can reduce my BGs, do less damage to my body and even lose weight."
Donald Bump, PhD, of Miami, Florida, says that he took Rezulin for nine months and was very pleased with how it reduced his insulin needs to 40 units a day. Bump then developed problems with his liver enzymes, and tests indicated that his liver had started to malfunction.
"I had to go off Rezulin, even though the problem was borderline," says Bump. "The liver problems did reverse, and since that time, I have had to increase my insulin use to 60 units a day."
The Media: Gatekeeper or Bloodhound?
Debra Singer says that if the reports in the Los Angeles Times about Rezulin are true, then she considers the actions of Warner-Lambert to be reprehensible.
"I now not only question Rezulin, but other Warner-Lambert products as well," says Singer.
Richard Velten of Harbor City, California, says that when you compare the number of Rezulin deaths to the size of the diabetes population, it does not warrant the type of coverage that the Los Angeles Times and "Nightline" afforded it.
"The negative reports in the press tend to do more harm than good to the extent that they make people nervous and concerned as to whether they will become the next victims," says Velten, who will consider discontinuing Rezulin only if his endocrinologist recommends that he do so.
John D. Miller of Fairmont, Minnesota, says that he is grateful to the press for exposing the problems surrounding Rezulin.
"They have pointed out questions that need to be answered. I do believe there is a conflict of interest when the employee of a drug company was involved in the decision-making process of the company's drug," says Miller, who takes 600 milligrams of Rezulin each day to control his type 2 diabetes. "My doctor has tried to reassure me that Rezulin is a safe drug, but I am still not sure."
Some people in the diabetes community feel that while Public Citizen tries to contaminate Rezulin's reputation, Public Citizen is not giving endocrinologists and people with diabetes the benefit of the doubt.
"I oppose Public Citizen's efforts to have Rezulin removed," says Mark Davis of Lafayette, Indiana. "While there is clearly some health risk, that risk is well documented and it is reasonably easy to test for any liver problems. Public Citizen appears to be assuming that the doctor and patient are not capable of understanding the risks of taking Rezulin."
Davis goes on to say that even insulin itself is a very dangerous drug if not taken properly.
Despite Rezulin's popularity as a type 2 medication, Sidney Wolfe says that Public Citizen will continue with its efforts to have Rezulin removed from the American pharmaceutical market.
"It will be banned soon," says Wolfe. "How many more people are going to have to die in this country before this drug comes off the market?"