Avandia, Rezulin and Actos: Same Chemical Family; Similar Benefits, and Unfortunately, Quite Similar Risks

Armand Rossetti

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I happened to read Tom Lamb’s article (Drug Injury Watch) this morning about Avandia. I learned that Public Citizen’s Health Research Group’s (HRG) has requested that the FDA ban GlaxoSmithKline’s diabetes drug, Avandia (rosiglitazone). HRG made the request because of Avandia’s serious side effects, which now include episodes of liver failure similar to incidents that resulted in the withdrawal of Rezulin from the market in 2000.

HRG has reported 14 cases of Avandia-induced liver failure, including 12 deaths. (Here are some additional examples presented as case studies: Case 1, Case 2, and Case3)

Chemical Structural Relationships:

Nearly a decade ago, Avandia was one of three structurally related diabetes drugs, belonging to a class of substances known as thiazolidinediones (TZDs) became available to consumers. To begin with, let’s take a look at the structures of those compounds:

• Thiazolidinedione (TZD) (the starting compound for the following three diabetes drugs);
• Rosiglitazone (Avandia);
• Pioglitazone (Actos); and
• Troglitazone (Rezulin, for which the FDA issued a recall notice in 2000 because it caused several incidents of liver failure resulting in several deaths)

After a brief review, it is evident that all three diabetes drugs contain TZD with similar aliphatic compound structures bonded to it. This usually occurs when different manufacturers design around each other's compounds to avoid intellectual property litigation.

Therefore, close structural relationships between several drugs in a family are common in the industry. To illustrate, let's review a group of psychoactive drugs belonging to the benzodiazepine family; Librium, Valium, and Dalmane. Each has a similar family structure and they all react with the body in a similar fashion. The same holds true for barbiturates, aminoglycosides, and a host of other groups of drugs that are currently on the market.

Although it is not always the rule, it is reasonable to suspect that drugs in the same family biologically react in a similar fashion to provide certain like benefits. Therefore, it is not unreasonable to suspect that that those same structurally related drugs might also present similar risks to many of the patients who use them.

Avandia’s Effectiveness:

Recently, the Cochrane Systematic Review analyzed data from 18 trials that involved a total of 8432 people and found no evidence that rosiglitazone led to better patient outcomes when compared with other therapies. Diabetic control (as measured by levels of HbA1c) was no better in patients given rosiglitazone when in comparison to other antidiabetic drugs.

As a result, if Avandia’s benefits do not outweigh unacceptable risk of consumers contracting cardiac, liver, or skeletal problems, then the FDA should request that GlaxoSmithKline recall Avandia and withdraw it from the market.

Recently, the American Diabetes Association and the European Association for the Study of Diabetes have concluded that, “given that other [treatment] options are now recommended, the consensus group members unanimously advised against using rosiglitazone” for treating Type 2 diabetes.

A History of Liver Problems with TZDs:

On April 13, 1999, the FDA corresponded with SmithKline Beecham about delaying Avandia’s approval for pediatric use because Rezulin was causing liver failure, and that it would be wise to first review post market safety performance:

“As you are aware, Avandia was granted a priority review by the Division primarily based on an improved hepatic safety profile as compared with the only marketed thiazolidinedione, Rezulin™ (troglitazone) [Parke-Davis/Warner-Lambert]. Troglitazone has been demonstrated to cause rare cases of liver failure in adults, the magnitude of which only became fully apparent with post marketing experience. As outlined in the final pediatric rule, in certain cases, studies should not begin in pediatric patients until after the safety profile of the drug is well established through post marketing experience. Although there is no evidence for hepatotoxicity with Avandia in clinical trials in over 4600 treated patients, we believe that it is appropriate to delay the initiation of pediatric studies with Avandia until after it has been approved and marketed.” [Pages 9-10 of letter from Solomon Sobel, MD, Center for Drug Evaluation and Research (CDER) Food and Drug Administration dated April 13, 1999].

At least the FDA had expressed caution. However, a subsequent letter from SmithKline Beecham to the FDA dated May 5, 1999 shows that SmithKline was less interested in conducting further long term studies with Avandia, than it was in avoiding the expense of conducting those trials and quickly bringing Avandia to market. Here is the text of the communication:

“Also provided is the proposed phase IV post marketing plan. For the past several months, SB has been debating the design of longer term outcomes trials with the new thiazolidinedione, rosiglitazone, and has been in discussions with external advisors to this end. Preventing disease progression is an area that would be most interesting to investigate. Such trials could also address additional areas of interest. However, given the scope, complexity, and expense of such trials, SB (Smithkline Beecham) is not currently in a position to make any commitment about a long term outcomes trial. We are, however, able to offer the current post-marketing plan (Phase IV) which is attached. We look forward to agreement with the FDA team.” [Cover letter dated May 5, 1999 from Claire Khan, PhD at SmithKline Beecham to Jena Weber (HFD-510) regarding Phase IV commitments, Page 3].

The March 2000 Rezulin Recall:

On March 21, 2000, less than a year after Avandia had received its approval, the FDA issued a Release Withdrawal Notice for Rezulin:

“FDA today asked the manufacturer of Rezulin (troglitazone) -- a drug used to treat type 2 diabetes mellitus-- to remove the product from the market. The drug's manufacturer, Parke-Davis/Warner-Lambert, has agreed to FDA's request.

FDA took this action after its review of recent safety data on Rezulin and two similar drugs, rosiglitazone (Avandia) and pioglitazone (Actos), showed that Rezulin is more toxic to the liver than the other two drugs. Data to date show that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk.”

Moving on several years to March 2007, the FDA notified Takeda Pharmaceuticals of North America, Inc. that its diabetes drug, Actos was responsible for increased incidents of bone fractures in women using the drug. That same month, Takeda issued a “dear doctor” letter, which alerted physicians about increased incidents of bone fracture in women taking the drug, and the letter also contained the following warning about liver damage:

“Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in post marketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS.”

Perhaps the message behind all of this is that it should not have taken the FDA or Manufacturers seven years to figure out that when drugs in the same class provide similar therapeutic benefits, those drugs might also pose similar safety risks.