SCOTTSDALE, AZ — In patients with Graves disease, prescribing a lower maintenance dose of methimazole (MMI) before discontinuing the drug is associated with significantly higher rates of remission, compared with a higher dose, according to a new study presented at the 2025 American Thyroid Association Annual Meeting.

“If further research confirms this association, these findings could contribute to revisions in clinical guidelines and encourage the broader adoption of tailored tapering strategies in clinical practice,” the researchers wrote in the study, which was published online in the Journal of Clinical Endocrinology and Metabolism. “These strategies could substantially reduce the number of relapsed cases, considering the global prevalence of Graves’ disease.”

Relapse of Graves disease after standard antithyroid treatment with MMI and other antithyroid drugs is common, ranging from 20% up to 70%, with risk factors including the total duration of time on antithyroid medication and the length of time patients remain on a minimum dose, the authors noted.

Recent studies have indicated that a minimum maintenance dose prior to discontinuation has emerged as “a critical, modifiable factor under the control of physicians,” wrote senior author Takashi Akamizu, MD, of the Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan, and colleagues.

In Japan, a lower dose is easier to achieve with a 2.5-mg tablet formulation that was made available there in February 2021. The current lowest dose available in tablet form in the United States is 5 mg.

Because evidence regarding the optimal maintenance dose before discontinuation was lacking, the researchers conducted a retrospective cohort study to determine whether a lower dose than 2.5 mg would reduce relapse rates.

As Dose Decreases, Relapse Risks Falls

The researchers identified 4352 patients at Kuma Hospital who were newly diagnosed with Graves disease between 2008 and 2024 and who had discontinued MMI after receiving a minimal maintenance dose of 2.5 mg per day or less.

The patients were categorized into four groups according to their final maintenance dose prior to discontinuing MMI: 2.5 mg/day (n = 3523); > 1.25 to < 2.5 mg/day (n = 526); 1.25 mg/day (n = 227); and < 1.25 mg/day (n = 76). Those who had doses below 2.5 mg received the pill every other day.

The rates of relapse at 1 year in the four groups were 13.8% for a maintenance dose of 2.5 mg/day; 13.1% with > 1.25 to < 2.5 mg/day; 7.1% with 1.25 mg/day; and 2.6% in the < 1.25 mg group.

Of note, 85.5% of those in the 1.25 mg/day group had thyrotropin receptor antibody (TRAb) titers below the detection limit at baseline, compared with approximately 55% in the < 1.25 and > 1.25 to < 2.5 mg/day groups and 45.8% in the 2.5 mg/day group.

After adjusting for factors — including age, sex, thyroid volume, smoking status, total duration of MMI treatment, duration of maintenance dose, and TRAb titer at the time of discontinuation — the associations were unchanged.

Compared with those tapered at 2.5 mg/day, the adjusted risk ratios (RRs) for relapse were 0.92 for the > 1.25 to < 2.5 mg/day group, 0.46 for the 1.25 mg/day group, and 0.18 for the < 1.25 mg/day group.

“A statistically significant trend was observed across dose categories (P for trend <.05), suggesting a dose-response relationship where lower MMI doses prior to discontinuation were associated with a reduced risk of relapse,” the authors reported.

Propensity Score Analysis

In a propensity score analysis in which patients were matched into two groups of 172 patients with similar characteristics, those receiving 1.25 mg/day of MMI had a significantly lower 1-year relapse risk compared with those receiving 2.5 mg/day (RR, 0.44).

In propensity score comparisons of patients receiving ≤ 1.25 mg/day vs those receiving > 1.25 to ≤ 2.5 mg/day of MMI prior to discontinuation (with 271 patients in each group), the 1-year risk of relapse was significantly lower in the ≤ 1.25 mg/day group compared with the > 1.25 to ≤ 2.5 mg/day group (RR, 0.46).

The findings underscore that “a lower minimal MMI dose before discontinuation is associated with lower relapse,” Akamizu told Medscape Medical News. 

“A less than 2.5 mg per day tapering strategy may be useful, [and] the final MMI dose should be considered before discontinuation,” he said.

Possible Mechanisms

Previous studies have indicated that the duration of the maintenance period, and not necessarily the minimum maintenance dose itself, may be associated with the risk of relapse.

“The minimum dose has received less attention in discussions, partly because it is often determined by the available tablet strengths,” the researchers wrote.

The authors noted that treatment duration has been suggested to contribute to TRAb negativity, suggesting that the lower minimum maintenance dose prolonged the treatment period and resulted in the reduced risk of relapse.

However, the current study showed an association between the lowest dose and lower relapse risk, even after adjusting for both treatment duration and the duration of maintenance at the minimum dose.

“This suggests that the minimum dose itself, as well as the gradual tapering process, may independently reduce the risk of relapse,” the authors wrote.

The specific mechanism could involve “stabilizing the immune state or minimizing immune reactivation,” they added. “However, these remain speculative hypotheses, and further research is needed to elucidate the underlying immunological and physiological mechanisms of these observations.”

In the meantime, lower-dose tablet formulations should be considered for broader availability, the authors noted.

“Dissemination and development of lower-dose formulations, such as 2.5 mg and 1.25 mg, may be more cost-effective compared with new drug development,” Akamizu told Medscape Medical News.

Clinical Implications

While TRAb negativity can guide discontinuation, relapse rates can still vary, and — particularly in older populations — longer-duration low-dose MMI can be beneficial, James Hennessey, MD, an associate professor of medicine, at Beth Israel Deaconess Medical Center in Boston, told Medscape Medical News.

“I've got a lot of patients, especially older patients, who have been reduced to 1.25 mg per day or 2.5 mg per day, and others might say ‘that's such a small dose, what good is it doing?’ But when they discontinue, the hyperthyroidism comes back,” added Hennessey, who was not involved in the study. “So, a lot of people get by on very low doses, and it can be just enough to keep them in balance and keep their thyroid function normal.”

Akamizu said that he continues patients on the low dose, even if their TRAb levels are negative.

“Patients are generally more satisfied with the 1.25 dose, probably because they feel [they are] getting better or approaching the remission,” he added.

The study findings show that “dose reduction is feasible in daily practice,” Akamizu said.

“The take-home message from this for clinicians should be to try the lower dose of MMI if your aim is the remission of Grave’ disease,” he said.

Akamizu and Hennessey had no disclosures to report related to the study.