BACKGROUND
Graves’ disease is the most common cause of hyperthyroidism in the United States. Graves’ disease is caused by the body making antibodies that attack the thyroid and turn it on, causing the thyroid gland to make too much thyroid hormone. There are three main treatment options for Graves’ disease. Two of these, surgery and radioactive iodine therapy, are referred to as definitive therapy as they destroy the thyroid and permanently stop the overactive thyroid function. Antithyroid drugs, such as methimazole, control thyroid hormone production while keeping the thyroid gland functioning. The goal with antithyroid drug therapy is to have the Graves’ disease go into remission. Most guidelines recommend treating with methimazole for at least 12 – 18 months before stopping and assessing for a remission. If thyroid function doesn’t stay normal, patients often proceed to radioactive iodine therapy or surgery.

Past research has shown that relapse of Graves’ disease is more likely in patients who are younger, smoke tobacco, have large thyroid glands, severe hyperthyroidism, or high levels of thyroid-stimulating antibodies. Some recent studies suggest that longer treatment with methimazole may be associated with longer-term remission, but it has been unclear whether the dose of methimazole at the time of stopping affects relapse risk. The goal of this study was to determine if the final dose of methimazole before stopping had any effect on the rate of remission of Graves’ disease.

THE FULL ARTICLE TITLE
Miyamura K et al. Impact of minimal dose strategy before anti-thyroid drug discontinuation on relapse risk in Graves’ disease. J Clin Endocrinol Metab. Epub 2025 Aug 1:dgaf433. doi: 10.1210/clinem/dgaf433. PMID: 40746193.

SUMMARY OF THE STUDY
This large study was done in Japan, where doctors often continue low-dose methimazole for several years. Japan also has 1.25 mg methimazole tablets, allowing for a more gradual taper (the lowest available tablet strength elsewhere is typically 2.5 mg). Researchers reviewed records from more than 4000 people treated with methimazole for Graves’ disease at a single institution between 2008 and 2024. They included patients who had reached a stable low dose of methimazole, 2.5 mg or less per day, for at least 3 months before stopping treatment, and who were followed for at least 6 months afterward. Patients whose thyroid was removed or who had radioactive iodine or pregnancy were excluded.

Relapse was defined as a need to restart methimazole within 12 months after stopping it. Researchers also collected information on patient age, sex, smoking status, thyroid size, total duration of methimazole treatment, duration on minimal dose of methimazole, and thyroid stimulating antibody levels at treatment end.

They found 5081 patients who had started methimazole for Graves’ disease between 2008 and 2024. In the final analysis, 4352 patients were eligible for the study, 82% were female, 67% were older than 40 years, and 16% were tobacco smokers. On average, patients were treated with methimazole for 2.7 years. Most patients (82%) were taking the least amount of methimazole they could take to keep the thyroid hormone levels normal for at least 6 months before stopping the medication. Patients who were taking lower final dose of methimazole had been on treatment longer – about 3.8-4.8 years for those on 1.25 mg/day or less, compared with 2.5 years for those on 2.5 mg/day. Thyroid stimulating antibody levels were undetectable in 49% of patients when they stopped the medication. One year after stopping methimazole, 13% of patients had relapsed. People whose antibodies became undetectable before stopping the medication were less likely to relapse. Those who maintained normal thyroid levels on smaller final doses also had lower relapse rates.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
The researchers concluded that patients who had normal thyroid function on stable, very low doses of methimazole before stopping treatment may have a better chance of long-term remission, and that the maintenance dose may be considered when deciding to stop the medication. However, the study does not prove that lowering the dose itself or continuing treatment longer directly prevents relapse.

For some patients, especially those who want to delay or avoid radioactive iodine or surgery, continuing methimazole at a small daily dose for a longer time under medical supervision might be a good option. Serious side effects are rare with low doses and usually happen earlier in treatment. Patients should discuss with their healthcare team whether this approach is right for them and how to balance benefits and risks. Having smaller-dose tablets available everywhere could also help physicians safely adjust treatment for each patient. In the meantime, future studies and new guidelines will help clarify whether the length of treatment, the final dose, or other factors matter most in keeping thyroid hormone levels normal after treatment.

— Ebru Sulanc, MD

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