Acute Effects of Liothyronine Administration on Cardiovascular System and Energy Metabolism in Healthy Volunteers

Abstract

Context: The pharmacokinetics of liothyronine causes concerns for cardiovascular toxicity. While the effects of sustained increase in serum T3 concentrations are well described, little is known on the effects of acute changes in T3 concentrations due to rapid action of thyroid hormone.

Objective: To assess the clinical relevance of transient increase of T3 levels on cardiovascular system and energy metabolism.

Setting: Double-blind, three arms, placebo controlled, cross-over study (ClinicalTrials.gov Identifier: NCT03098433).

Study participants: Twelve volunteers (3 females, 9 males), age 27.7 ± 5.1 years.

Intervention: Oral administration of liothyronine 0.7 mcg/kg, equimolar dose of levothyroxine (0.86 mcg/kg), or placebo in three identical study visits. Blood samples for total T3, free T4 were collected at times 0', 60' 120' 180' 240'. Continuous recording of heart rate, blood pressure, and hemodynamic data was performed using the volume clamp method. Resting energy expenditure was measured by indirect calorimetry. An echocardiogram was performed on each study visit at baseline and after the last blood sampling.

Main outcome measures: Changes in cardiovascular function and energy expenditure.

Results: Following the administration of liothyronine, serum T3 reached a Cmax of 421 ± 57 ng/dL with an estimated Tmax of 120 ± 26 minutes. No differences between study arms were observed in heart rate, blood pressure, hemodynamics parameters, energy expenditure, and in echocardiogram parameters.

Conclusions: The absence of measurable rapid effects on the cardiovascular system following a high dose of liothyronine supports the rationale to perform long-term studies to assess its safety and effectiveness in patients affected by hypothyroidism.

Keywords: cardiovascular function; energy expenditure; liothyronine; pharmacodynamics; pharmacokinetics; rapid effects of thyroid hormone.

Conflict of interest statement

The Division of Endocrinology, Diabetes and Metabolism of Virginia Commonwealth University has received an unrestricted grant from IBSA Institut Biochimique, Lugano Switzerland. Liquid formulations of LT3, LT4, and placebo were a kind gift of IBSA Institut Biochimique Lugano (Switzerland). IBSA was not part of the study design and had no access to the data prior to the publication. FC has served as consultant for IBSA, Acella and Kashiv (now merged with Amneal). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Chen, Wohlford, Vecchie’, Carbone, Yavuz, Van Tassell, Abbate and Celi.

Figures

Figure 1

Study hypothesis. (A) If clinically relevant, rapid action of LT3 (dashed red line), would be measurable following a pharmacological dose at or immediately after Cmax. (B) Conversely, if the thyroid action is entirely attributable to genomic signaling (continuous red line) one would expect minimal measurable effects during the distribution phase with a gradual and delayed onset. Black continuous line: pharmacokinetics of single dose LT3. The shaded area represents the reference range for serum T3.

Figure 2

Study design. Top panel: timeline of the study. After enrollment, study volunteers underwent three identical visits each separated by at least 48 hours. Bottom panel: study procedures. An echocardiogram was performed upon arrival to the Clinical Research Services Unit and after completion of the stay in the whole room indirect calorimeter. Energy expenditure was recorded for at least 30’ before the administration of the study drug or placebo. Five blood samples were collected to record the LT4 and LT3 pharmacokinetics. Blood pressure, heart rate, and hemodynamics data were collected throughout the stay in the whole room calorimeter.

Figure 3

CONSORT chart.

Figure 4

Thyroid hormone and TSH kinetics following study drugs administration. (A) changes in total T3 concentration from baseline following LT3 administration. (B) changes in free T4 concentration from baseline following LT4 administration. (C) TSH concentrations at baseline and 240’ following administration of LT3, LT4, and placebo. Data are presented as mean ± SEM. ns, not significant.