In a randomised trial, combination treatment was not superior to treatment with levothyroxine alone.

Some patients with hypothyroidism report feeling better when they take both levothyroxine (T4) and triiodothyronine (T3) than when they take T4 alone, but published evidence supporting combination therapy is mixed. For this trial, Italian researchers enrolled 141 patients who had undergone total thyroidectomy for benign or malignant disease and who had been on stable T4 replacement therapy. They were randomised to receive either daily T4 alone or daily T4 plus twice-daily T3 – with appropriate placebos to preserve blinding. Doses were adjusted (by clinicians not involved with the participants) to maintain normal thyroid-stimulating hormone (TSH) levels; for patients who received combination treatment, additional adjustments targeted a physiological ratio of blood free T3/free T4 levels.

During six months of treatment, changes in scores on a thyroid-specific questionnaire that addresses symptoms and quality of life did not differ significantly in the two groups. Additionally, measurements of several tissue markers of peripheral thyroid hormone activity were similar in the two groups. 

Comment: In my anecdotal experience, clinicians vary in their willingness to prescribe T4/T3 combination therapy for patients with ongoing symptoms despite seemingly adequate T4 dosing. This trial’s findings do not support combination therapy, but a caveat is that these participants were not selected specifically for having persistent hypothyroid symptoms during T4 treatment. According to the American Thyroid Association’s guideline on hypothyroidism, evidence is insufficient to support routine combination therapy in patients with primary hypothyroidism who feel unwell on T4 alone). However, the guideline authors suggest that additional research might identify subgroups of patients with laboratory markers that could predict benefit from combination treatment.

Allan S. Brett, MD, Clinical Professor of Medicine, University of Colorado School of Medicine, Aurora, USA.

Brigante G, et al. Randomized double-blind placebo-controlled trial on levothyroxine and liothyronine combination therapy in totally thyroidectomized subjects: the LEVOLIO study. Eur J Endocrinol 2024; 190: 12-22.

This summary is taken from the following Journal Watch titles: General Medicine, Ambulatory Medicine.