SCOTTSDALE, AZ — Among patients with hypothyroidism, administering a higher dose of levothyroxine with breakfast preserved thyroid-stimulating hormone (TSH) stability and was favored by patients compared to taking the usual dose followed by a 1-hour fasting period, a new study has found.

“A 15% dose-adjusted levothyroxine regimen taken with breakfast maintains TSH stability comparable to standard fasting levothyroxine in well-controlled hypothyroidism,” said first author Jeresa Willems, MD, of the Department of Internal Medicine at Zuyd Thyroid Center, Sittard, and the Zuyderland Medical Center, Heerlen, Netherlands, in presenting the findings at the American Thyroid Association 2025 Meeting in Scottsdale, Arizona. “In these new findings, we have shown that non-fasting ingestion is a viable alternative to the standard fasting ingestion.”

“Almost 90% of participants chose to continue the approach after the study,” she added.

Levothyroxine has an absorption time, or gastric dissolution phase, that can last 30-60 minutes. Taking the medication with a meal can reduce absorption by about 15%, with a potential subsequent increase in TSH between 1 million and 1.9 million units per liter, Willems and her colleagues noted

However, the fasting approach can be burdensome, particularly for those who have had a thyroidectomy and require levothyroxine for the rest of their lives, and could hinder medication adherence, potentially leading to poor control of thyroid function.

To address these concerns, Willems and colleagues conducted a randomized, controlled trial to evaluate whether a small dose adjustment designed to compensate for the absorption could allow patients to avoid fasting without compromising thyroid function stability.

The INFINITY Trial

For the INFINITY trial, the researchers enrolled 88 adult patients with well-controlled hypothyroidism who were on at least 1 mcg/kg of levothyroxine and randomly assigned them to receive levothyroxine either at their usual dose and with the recommended fasting (n = 43) or at a dose 15% higher than their regular dose taken with breakfast (n = 45).

To achieve the 15% dose increase, patients were instructed to take one extra tablet per week. Patients were followed for up to 24 weeks, and their TSH, free T4, and total T3 were measured every 6 weeks. 

At the end of the study period, those in the fasting levothyroxine group were invited to cross over to the nonfasting regimen and had similar follow-up. The primary outcome was TSH stability, defined as two consecutive values within the reference range and a maximum ± 1 mIU/L change from baseline. 

Regarding patients, 80.7% were female, the median age was 62 years, and there were no significant differences in patient characteristics between the groups.

At a mean follow-up of 24 weeks, there were no significant differences between the groups in TSH stability, which was achieved in 74.4% in the fasting group vs 73.3% in the nonfasting group.

Those on the higher dose at breakfast reported a significantly stronger preference for nonfasting intake (76.2% vs 44.2%; P < .001). They also self-reported greater improvement in well-being, although the difference did not reach statistical significance.

At the end of the study, 88.9% of patients chose to continue with the nonfasting regimen, and similar findings were reported in the crossover group.

“We think that the engagement of levothyroxine has to be tailored to patients’ individual lifestyles and to improve therapy adherence,” Willems said.

Fasting Requirement Seen as a Burden

In a previous study, Willems and colleagues surveyed 410 patients treated with levothyroxine at Zuyderland Medical Center. They found that 30% of patients did not adhere to the fasting rule, 24.9% regularly omitted their breakfast during the week because of the requirement, and 13.4% reported forgetting to take their pill due to the rule.

Overall, 49.5% of respondents said the fasting requirement was a burden that caused delays in their breakfast every day, and 61% expressed a preference for nonfasting ingestion.

Despite important requirements that patients take interfering drugs and supplements at least 4 hours from levothyroxine, only 27 (31.8%) of the 85 patients who used interfering medications said they had received instruction regarding the need for the separation, and only 40.7% of those adhered to the instruction.

“Our findings raise the question whether the benefit of fasting ingestion outweighs its burden,” the authors wrote.

Some studies have suggested that taking levothyroxine at night can be equally as effective as morning dosing, and — asked during her talk about that alternative — Willems noted that patients on that regimen are advised to take the pill 3-4 hours after dinner.

“So, if patients want to have a late-night snack or something, it isn’t possible,” she said.

Other formulations of levothyroxine, such as a soft gel or liquid, may be taken with breakfast; however, since those formulations are often not reimbursed in the Netherlands, Willems could not address those options, she added.

‘Chasing the Dose’

Commenting on the study, James Hennessey, MD, an associate professor of medicine at Beth Israel Deaconess Medical Center in Boston, noted that when patients’ TSH levels are fluctuating, management can become a frustrating cycle of “chasing the dose” to try to normalize levels.

“What typically isn’t asked [by the clinician] is ‘are you now taking the pill with breakfast, or are you still fasting for 60 minutes following ingestion of the levothyroxine?’”

The approach of increasing the dose with an extra tablet a week to compensate for the lower drug absorption of ingestion with breakfast could be acceptable because levothyroxine has a half-life of about 7 days, Hennessey said.

However, even with that strategy, fluctuations can still occur based on the broad definition of what constitutes breakfast, he told Medscape Medical News.

Nearly 70% in each group in the current study reported having generally the same breakfast every day, Hennessey noted. For patients whose diets aren’t as consistent, a very small breakfast could feasibly increase the amount of medication that’s absorbed, while a very large breakfast could have the opposite effect, he said.

In addition, Hennessey said, certain food types such as high-fiber and calcium-rich foods, as well as supplements, can interfere with levothyroxine absorption, which could lead to further frustrations in “chasing the dose.”

The authors had no disclosures to report. Hennessey has consulted for AbbVie and Acella Pharmaceuticals.