The Troglitazone story

I am a diabetes specialist based in Bristol in the UK. I first became interested in the troglitazone story when invited to give a talk on this class of agents at the meeting of the European Association for the Study of Diabetes (EASD) in Jerusalem.

I was asked to present the evidence for the use of two sister drugs, rosiglitazone and pioglitazone, which were just about to enter the European market.

I initially declined the invitation, on the grounds that others were more qualified to give this talk, but was told that it was difficult to identify an expert in the area who did not have a major conflict of interest.

When I set out to learn more about these agents, it very soon became apparent that there was little information about them in the published literature—partly because they had been rushed through the regulatory process to fill the gap left by troglitazone—a drug that had been introduced in 1997 and withdrawn from the US market in 2000.

But what gap was there left to fill? Astonishingly, there was no evidence that troglitazone was better than existing medication. Its main competitor was metformin, a drug which has been widely and safely used around the world for almost forty years, and is still considered the drug of choice for type 2 diabetes. It had however been banned from the USA in 1977 when its sister drug, phenformin, was withdrawn because of the danger of an often fatal complication called lactic acidosis. As it happens, my very first clinical paper in 1976 had advocated the withdrawal of phenformin [1]. Metformin, as later emerged, is a safe drug in this respect if used according to standard guidelines. It was the ultraconservative stance of the US Food and Drug Administration (FDA) which had kept metformin out of the US for nearly 20 years, until it came on the market in 1995. Meanwhile, political interference at the behest of the pharmaceutical industry had resulted in greatly expedited approval of new drugs in the 1990s. This sharp swing between over-caution on the one hand and unseemly haste on the other was the root cause of the deaths that were to follow; metformin had been kept out unnecessarily, and troglitazone was allowed in too soon.

My talk in Jerusalem was well received by the delegates, less so by the industry. It was subsequently published in the Lancet, and I was soon contacted by a US Attorney and gave testimony along the lines of the paper I had written. This brought me into much closer touch with the reality of what had happened. It is one thing to read a list of side-effects, and another to learn about the name and details of the person who had died.

One of the most remarkable aspects of this whole story, in my view, is the extraordinary passivity of the medical profession in the face of what may have been several hundred deaths. If an airliner goes down, everyone wants to know why, and how a repeat might be avoided. Not so with troglitazone, which killed just as many people. Instead there was a curious collective amnesia, with a subtext that it was perhaps a pity but could not have been otherwise. Shoulders were shrugged and no-one, it seems, was really to blame. And what of my fellow-physicians, who all learn in medical school that the first principle of medicine is to do no harm?

This is why I wanted to research and publish the story of troglitazone. Read it, and judge for yourself.

EAM Gale
Diabetes and Metabolism
Medical School Unit
Southmead Hospital
Bristol
BS10 5NB

Email: Edwin.Gale@bristol.ac.uk