Methimazole for Graves Disease Linked to Acute Pancreatitis

Nancy A. Melville

November 04, 2019

CHICAGO — The treatment of Graves disease with the antithyroid drug methimazole is associated with a significantly increased risk of acute pancreatitis, and although cases are rare, the risk justifies warnings about this potential adverse event, according to a nationwide controlled study in Denmark spanning more than 20 years.

"The data are very strong and convincing, (showing) that the risk of pancreatitis is of the same order as that of agranulocytosis, which we have warned against and informed about for decades," first author Laszlo Hegedus, MD, president of the European Thyroid Association, told Medscape Medical News.

"So not taking this seriously would be extremely arrogant," he said after presenting his findings at the 89th American Thyroid Association (ATA) Annual Meeting.

With six notable case reports of acute pancreatitis associated with methimazole therapy, the European Medicines Agency (EMA) issued a warning about the risk in January 2019, prompting a change in product labeling to include acute pancreatitis as a serious side effect.

However, similar action has not been taken in the United States.

With methimazole among the most commonly used drugs in the United States, the findings underscore the need to communicate this information to patients, Hegedus said.

"Not informing an individual about this potential serious side effect would be incorrect, in my view," he said. "We do so in Denmark, both orally and in writing."

Program committee cochair Mona M. Sabra, MD, noted that these new Danish findings were considered noteworthy enough to make an additional effort to include in the ATA program.

"This is really new information that is very important," Sabra, who is professor of clinical medicine, Endocrine Service, Department of Medicine at Memorial Sloan Kettering and Weill Cornell School of Medicine, New York City, told Medscape Medical News.

"These data were presented at the European Thyroid Association last week, and we made an exception and accepted to put it on the program this week due to the importance of the results," she said.

Risk of Acute Pancreatitis Real With Methimazole

To further investigate the risk in a large population of methimazole users and the other most commonly used antithyroid drug, propylthiouracil (PTU), Hegedus and colleagues identified 118,649 antithyroid drug users (defined as having at least one prescription of either agent) in national registries in Denmark from 1995 to 2018, including 103,825 methimazole users and 14,824 PTU users.

During the same period, there were 43,580 cases of acute pancreatitis in the overall population, including 226 cases (0.5%) among methimazole users and 19 cases (0.04%) among PTU users, with a case-crossover analysis showing an odds ratio (OR) of 1.51 (95% CI, 1.12 - 2.02) for acute pancreatitis among methimazole users and an OR of 1.16 (95% CI, 0.46 - 2.93) among PTU users, respectively.

Matching each case with four controls, there was no increased risk of acute pancreatitis for the highest vs lowest quartiles of the cumulative drug doses for methimazole (OR, 0.98) or PTU (OR, 0.86).

Nor was there any association between a cumulative dose effect (low, intermediate, or high) of either drug with the risk of acute pancreatitis (OR, 1.00 for both drugs).

"Ongoing methimazole but not PTU use seems associated with an increased risk of acute pancreatitis; however, we found no evidence of a cumulative dose effect of methimazole or PTU in the risk of acute pancreatitis," said Hegedus, who is with the Department of Endocrinology and Metabolism at Odense University Hospital, Denmark.

During a discussion of the findings, an audience member raised the question of whether hyperthyroidism, itself, could play a role in the risk; however, Hegedus told Medscape Medical News he knew of no reports linking acute pancreatitis with hyperthyroidism.

Furthermore, if hyperthyroidism had a causative role, one might expect the increased risk not to be limited to methimazole, he said.

"However," he acknowledged, "the strength of the findings with PTU are weakened by lack of power — too few were treated with [it] to rule out an effect of PTU in relation to increased risk of pancreatitis," Hegedus said.

And Hegedus noted a previous population-based case-control study of methimazole users in Taiwan showed no significant association with acute pancreatitis (Indian J Pharmacol. 2016;48:192-195).

He added that limitations of the current study were a lack of biochemical data, including the severity of hyperthyroidism, and a lack of power, which prevented distinguishing between Graves disease and nodular toxic goiter.

But with strengths including the large scale, long-term investigation and validated pharmaco-epidemiological methods, Hegedus called for "verification in an independent cohort...with efforts to investigate the potential mechanisms behind this adverse effect."

"Although I hoped to disprove this, the warning by the EMA seems justified. The frequency of acute pancreatitis in ongoing methimazole users is of a similar magnitude as reported for agranulocytosis," he concluded.

New and Rarely Described Complication Needs to Be Examined in US

Kepal Patel, MD, chief of endocrine surgery and associate professor of surgery, otolaryngology, and biochemistry at NYU Langone Medical Center, agreed that the new findings are noteworthy.

"I think it is fascinating because it's a new and rarely described complication," Patel told Medscape Medical News.

"It would be nice to look at it in [the US] population...I think it seems it may be a true complication of antithyroid drugs. It's a small number and a rare complication, but nonetheless, if it's been reported and exists, it's something we absolutely should be aware of when we treat patients with antithyroid drugs."

89th ATA Annual Meeting. Abstract #6. Presented November 2, 2019.

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