A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism

There remains considerable interest in the therapeutic use of combinations of levothyroxine (LT4) and triiodothyronine (liothyronine, T3) in the management of hypothyroidism, especially where hypothyroid-like symptoms persist on optimised LT4 monotherapy. This interest appears to be increasing, despite the lack of consistent identification of clinical benefit in people with hypothyroidism in randomised trials going back two decades. Guidelines support an individualised trial of addition of T3 to LT4 for symptomatic patients on optimised LT4. A new generation of clinical trials seeks to address this issue, using thyroid-specific instruments to measure patient-reported outcomes, among other innovations. Safety is the other critical element of the therapeutic profile of a drug. In this article, we review the safety of treatment LT4 + T3, with an emphasis on side-effects suggestive of thyrotoxicosis (overtreatment with thyroid hormones). Randomised trials that evaluated LT4 + T3 did not raise clear or consistent safety issues with this treatment. This was despite the use of regimens with a lower ratio of LT4:T3 (usually 4–10:1) than recommended currently by clinical experts in the field. In addition, a real-world analysis of side-effects of a commercial LT4 + T3 treatment (LT4:T3 ratio 5:1) that were reported spontaneously to a pharmacovigilance database revealed a low rate of reports, both overall and with regard to symptoms possible reminiscent of thyrotoxicosis. Safety concerns regarding the possibility of iatrogenic thyrotoxicosis appear unlikely to limit the future guideline-driven therapeutic use of LT4:T3 combinations with a ratio of these ingredients of around 15:1.