Discontinuation of levothyroxine in subclinical hypothyroidism Safe, feasible

MONTREAL — Patients who stop levothyroxine for subclinical hypothyroidism may revert to mild hypothyroidism, but, importantly, they show no differences in symptoms and quality of life — and sometimes even show improvement — compared to those who stop the Continue treatment, new research shows.

“Our results demonstrate the feasibility of patient recruitment and the safety of stopping levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the results at the 2022 American Thyroid Association (ATA) Annual Meeting.

Given that widespread overtreatment with levothyroxine has been demonstrated for a variety of reasons, “a discontinuation study like this is important to understand the true need for lifelong thyroxine therapy,” commented James V. Hennessey, MD, director of clinical endocrinology at Beth Israel Deaconess Medical Center in Boston, Massachusetts Medscape Medical News.

Recommendations against levothyroxine in subclinical hypothyroidism

Subclinical hypothyroidism is often overdiagnosed and treatment with a thyroid hormone replacement, levothyroxine, has been shown to provide little or no benefit in terms of quality of life or relief of thyroid symptoms for these patients.

Treatment now comes with burdens, including costs and lifestyle modifications, and a guideline panel recently issued a strong recommendation against the routine use of levothyroxine in most adults with subclinical hypothyroidism.

Nonetheless, levothyroxine treatment has grown in popularity and has become one of the most commonly prescribed medications in the United States.

Lacking research on a key solution to stopping therapy, Maraka, who is part of the Department of Endocrinology and Metabolism at the University of Arkansas Medical Sciences at Little Rock, and colleagues conducted a double-blind, placebo-controlled study by Central Arkansas Veterans Healthcare System. A total of 50 patients being treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 µg daily) or to discontinue treatment and receive placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 who discontinued treatment.

There were no significant differences at baseline between the discontinuation and levothyroxine groups, which were similar in age (66.2 vs 70.8 years) and gender (75% females vs 85% males).

The groups had similar baseline levels of thyroid stimulating hormone (TSH) (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), positivity for thyroid peroxidase antibodies (17% vs .11%) and similar clinical symptoms. All patients had at least one elevated TSH prior to starting levothyroxine treatment.

At 6 to 8 weeks of follow-up, 36.8% of patients in the discontinuation group had subclinical hypothyroidism compared with 10% of patients who continued to receive levothyroxine (P = 0.0648) and TSH levels were 5.5 versus 2.7 mIU/L (P = 0.001) and free T4 levels were 0.8 versus 0.9 ng/dl (P = 0.011).

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation and levothyroxine groups in terms of symptoms and even some improvements upon discontinuation, including the Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms Score ( 4.6 reduction vs. 2.2 increase). , fatigue (2.6 reduction versus 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke or heart failure; osteoporotic fractures; and deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/l after 6 to 8 weeks and switched to open-label levothyroxine 75 µg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 µg daily after 10 weeks due to fatigue, but the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who stopped levothyroxine developed subclinical hypothyroidism was less than expected, Maraka noted.

“That was…unexpected…for us,” she said. “We expected that a larger number of patients would develop hypothyroidism, but to our surprise, that was not the case.”

“But more importantly, there was no difference in quality of life,” she added. “If anything, the placebo group was slightly better, although the [differences] were not statistically significant.”

Makara also noted that in further research and a final 6-month analysis, the authors will examine factors associated with the development of subclinical hypothyroidism after treatment discontinuation, among others.

Discontinuation of levothyroxine is manageable

The results are encouraging as they provide reassurance that levothyroxine withdrawal is manageable.

“This research will pave the way for initiatives to encourage levothyroxine discontinuation and implementation of evidence-based treatment in patients with subclinical hypothyroidism,” she said.

In further comments, Hennessey noted that the dilemma of having patients on levothyroxine who may not benefit from treatment is “significant” because patients are sometimes reluctant to stop treatment for fear of hypothyroidism-associated symptoms such as brain fog and develop weight gain.

However, he noted that “many with slightly elevated TSH actually normalize over time so that they are not truly hypothyroid, [and] If we deprive people with normal thyroid function of thyroxine, they stay normal.”

Makara has no relevant financial relationships reported. Hennessey has reported advising pharmaceutical companies to develop clinical trials for thyroid drugs.

ATA Annual Meeting 2022. Oral Summary #13. Presented October 21, 2022.

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