Abstract
KEY POINTS
A 15% preemptive levothyroxine (LT4) dosage increase resulted in similar TSH stability between fasting and nonfasting LT4 intake.
89% of participants preferred taking LT4 with breakfast over fasting ingestion and opted to continue after the trial.
SUMMARY
Background
Levothyroxine (LT4) is the standard treatment for hypothyroidism and is widely prescribed. International guidelines recommend ingestion on an empty stomach, at least 30 minutes before breakfast, to maximize gastrointestinal absorption and maintain stable thyroid-stimulating hormone (TSH) levels.1,2 However, these recommendations have been found to be burdensome for patients and to reduce adherence to therapy, contributing to suboptimal treatment. 3 In this randomized controlled trial, 4 fasting LT4 intake is compared with intake with breakfast together with a 15% dose increase.
Methods
For this open-label randomized clinical trial, conducted at the Zuyderland Medical Center (The Netherlands), adults using a minimum LT4 dose of ≥1.0 µg/kg with well-controlled hypothyroidism, defined as having two consecutive TSH measurements within the assay-specific reference range, were enrolled. Exclusion criteria were rare causes of hypothyroidism, pregnancy, severe conditions with poor prognosis, and comorbidities potentially causing malabsorption. Participants were randomized 1:1 to either standard fasting LT4 ingestion (30–60 minutes before breakfast) or nonfasting LT4 ingestion at the same time as breakfast, with a 15% increase in LT4 dose to compensate for expected reduced absorption, based on a small cohort using a double isotope method to compare fasting LT4 intake versus intake with food. 5 The primary outcome was TSH stability, defined as two consecutive TSH measurements within the reference range (maximum of ±1 mIU/L change from baseline). Patients were followed until TSH stability was achieved or up to 24 weeks and after the fasting group was invited to cross over to nonfasting ingestion with similar monitoring.
Results
There were 88 patients randomly assigned (median age, ∼60 years, ∼80% female). TSH stability was achieved in 74.4% (95% confidence interval [CI], 61.0–88.0) of the fasting group and 73.3% (95% CI, 60.0–87.0%) of the breakfast group (P = not significant). Free thyroxine (FT4) and total triiodothyronine concentrations did not differ significantly between groups. In the nonfasting group, 76% of participants favored the intake with breakfast, and the nonfasting group reported greater improvement in well-being (33% improvement vs. 16% improvement in the fasting group). At the study’s end, 89% opted to continue ingestion of LT4 during breakfast. Similar maintenance of TSH stability was observed after crossover from fasting to nonfasting ingestion.
Conclusions
In adults with well-controlled hypothyroidism, dose-adjusted LT4 ingestion with breakfast maintained TSH stability equivalent to conventional fasting administration. This alternative approach was associated with greater patient preference and improved self-reported well-being, suggesting that it may enhance adherence without compromising thyroid hormone control.
COMMENTARY
International guidelines recommend intake of LT4 in a fasting state to ensure optimal absorption and minimize variability in TSH concentrations.1,2 This is a relevant recommendation, given the small therapeutic window of LT4. However, strict recommendations often lead to a decrease in patient adherence, and LT4 prescriptions are no exception. As reported in a previous study by the same authors, the timing of LT4 intake could decrease patient adherence, with 50% of patients reporting that they found intake before breakfast burdensome and 33% not consistently adhering to intake recommendations, 3 numbers that are similar to those in a previous large study on LT4 prescription adherence. 6
LT4 is absorbed in the small intestine, and absorption is dependent on multiple factors, including solubility, pH, gastric emptying, and binding of other factors to LT4, all of which can be affected by a multitude of foods and medications. 7 Based on previous studies, using the same LT4 dosages per group, LT4 absorption was found to be optimal when taken on an empty stomach, and fasting intake improved TSH stability. Previous solutions to patient adherence problems included intake at bedtime or (relatively expensive) liquid LT4 formulations. 1
In this elegant trial, the authors assessed whether a preemptive 15% dose increase could offset the expected decrease in LT4 absorption. TSH and FT4 were found to be similarly stable between strategies, and the authors concluded that it could be a practical alternative to other forms of ingestion, which could also improve patient adherence. It should be noted that the limited sample size precluded specific subgroup analysis, and patients with varying breakfast regimens might be prone to variability in LT4 absorption. Moreover, certain subgroups, such as pregnant women or patients with malabsorption disorders, were excluded from the study, and it seems prudent not to extend this recommendation to these populations without further data.
In conclusion, while caution is needed in certain cases, taking LT4 with breakfast might provide a practical and feasible alternative to fasting ingestion, especially in situations where improving patient adherence is key to achieving treatment targets.