Rezulin (troglitazone) — the Diabetes Pill Withdrawn in 2000 After 63 Liver-Failure Deaths

When the U.S. Food and Drug Administration asked Warner-Lambert to pull Rezulin from the market on 21 March 2000, it ended a three-year arc in which a celebrated first-in-class diabetes pill killed at least 63 people through liver failure while the warning that should have stopped it had been visible from before launch. Rezulin (troglitazone), the first thiazolidinedione — an oral “insulin sensitizer” acting on the PPAR-gamma receptor — was approved on 29 January 1997 and marketed as a breakthrough that let type 2 diabetics use their own insulin more effectively. The gap between that promise and the harm was not subtle: the drug produced idiosyncratic, sometimes fulminant hepatotoxicity, and Britain’s Glaxo Wellcome withdrew it from the U.K. market on 1 December 1997 — barely ten months after the U.S. approval — while the FDA kept it on American shelves for another twenty-eight months.

The signal was institutional, not merely clinical. The FDA medical officer originally assigned to the application, Dr. John Gueriguian, had recommended against approval over cardiac and liver concerns; he was removed from the review on 4 November 1996, and his negative analysis was purged from the official record before the drug was cleared on an expedited timeline. Within the first year of marketing, serious hepatotoxicity reports accumulated, and an internal FDA memorandum cited 135 reports of serious liver injury by late 1997. Public Citizen’s Health Research Group, led by Dr. Sidney Wolfe, petitioned for withdrawal in July 1998, asking the agency how many more Americans would have to die or need transplants.

The verdict is therefore plain at the outset: a profitable, regulator-blessed, heavily prescribed medicine reached nearly two million Americans while the evidence that condemned it — a foreign withdrawal, a buried internal review, mounting death reports, and an outside petition — sat fully legible in the record. The FDA’s response was incrementalism: four label changes between 1997 and 1999 adding ever-stricter liver-monitoring instructions that real-world prescribing could not reliably execute, rather than removal.

What finally forced the withdrawal was arithmetic the labels could not fix. Once two safer thiazolidinediones — rosiglitazone and pioglitazone — reached the market in 1999 without the same fatal liver signal, Rezulin’s risk-benefit case collapsed, and the FDA requested its removal on 21 March 2000. Litigation followed: Warner-Lambert, absorbed by Pfizer in 2000, ultimately resolved roughly 35,000 claims for an estimated $750 million, and “Rezulin” became a byword for how a buried safety review and an ignored foreign recall can keep a lethal drug on the market for years.

Phenformin (DBI) — the “Imminent Hazard” Diabetes Pill Banned in 1977, Half Its Victims Dead

When Joseph Califano, Secretary of Health, Education and Welfare, signed the order suspending phenformin on 25 July 1977, he was invoking a power Congress had granted the Food and Drug Administration fifteen years earlier and which no official had ever used: the declaration that an approved medicine was an “imminent hazard to the public health.” Phenformin (phenethylbiguanide), synthesized in 1957 by a team including Seymour Shapiro at the U.S. Vitamin Corporation and marketed in the United States from 1959 by Ciba-Geigy as DBI, had been prescribed to control adult-onset diabetes for nearly two decades. It was withdrawn not because it failed to lower blood sugar — it did that adequately — but because it could quietly poison the body with lactic acid, a complication that killed roughly one of every two patients it reached.

The gap between the promise and the harm was the gap between a surrogate benefit and a survival outcome. Phenformin reliably reduced glycemia, the number physicians could see on a chart; what it did not reliably do was keep patients alive. The biguanide’s mechanism — pushing cellular metabolism toward anaerobic glycolysis — produced excess lactate, and in patients with even modest kidney or heart impairment that lactate could accumulate into a metabolic catastrophe. Phenformin-associated lactic acidosis ran at roughly 40 to 64 cases per 100,000 patient-years, and once it occurred it was fatal in approximately half of cases. The drug treated a chronic disease by trading a visible, manageable problem for an occasional, lethal one.

The verdict was therefore plain long before the suspension. As early as 1959 — the same year U.S. marketing began — the literature linked biguanides to lactic acidosis. In 1971 the federally funded University Group Diabetes Program (UGDP) terminated its phenformin arm after finding excess total and cardiovascular mortality, roughly double that of the placebo and insulin groups combined. By October 1976 the FDA’s own Endocrinology and Metabolism Advisory Committee had recommended removal. The harm sat in the published record for years while ~385,000 Americans were still taking the drug in 1977.

What forced the cord was not the agency but a consumer group and a lawyer’s petition. Ralph Nader’s Health Research Group petitioned for suspension on 22 April 1977; Califano acted in July; the drug was off the U.S. market by 15 November 1978. The episode became the founding precedent for emergency drug suspension, the cautionary prologue to its safer sister biguanide metformin, and the textbook case of how a medicine can be effective on the metric it was sold on and still be a net killer.