Treatment of Hypothyroid Patients With L-Thyroxine (L-T4) Plus Triiodothyronine Sulfate (T3S). A Phase II, Open-Label, Single Center, Parallel Groups Study on Therapeutic Efficacy and Tolerability

Abstract

Sodium salt of levothyroxine (L-T4) is the treatment of choice of hypothyroidism. Yet, L-T4 monotherapy produces supoptimal 3,5,3′-triiodothyronine (T3)/T4 ratio in serum, as compared to normal subjects, and a minority of hypothyroid individuals on L-T4 complain for an incomplete well-being. Orally administered 3,5,3′-triiodothyronine sulfate (T3S) can be converted to T3 in humans, resulting in steady-state serum T3 concentrations for up to 48 h. In this study (EudraCT number 2010-018663-42), 36 thyroidectomized hypothyroid patients receiving 100 (group A), 125 (group B), or 150 μg (group C) L-T4 were enrolled in a 75 days study in which 25 μg L-T4 were replaced by 40 μg of T3S. A significant, progressive reduction in mean FT4 values was observed, being the largest in the group A and the smallest in group C, while no relevant variations in FT3 and total T3 serum values were observed in the three groups. TSH serum levels increased in all groups, the highest value being observed in group A. Lipid parameters did not show clinically significant changes in all groups. No T3S-related changes in the safety laboratory tests were recorded. No adverse event was judged as related to experimental treatment, and no patient discontinued the treatment. Twelve patients judged the L-T4+T3S treatment better than L-T4 alone, while no patient reported a preference for L-T4 over the combined treatment.In conclusion, the results of this study indicate that a combination of L-T4+T3S in hypothyroid subjects may allow mainteinance of normal levels of serum T3, with restoration of a physiological FT4/FT3 ratio and no appearance of adverse events. Further studies are required to verify whether the LT4+T3S chronic combined treatment of hypothyroidism is able to produce additional benefits over L-T4 monotherapy.

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

“…For the reasons already given, it is argued that to both monitor T3 dosing and use TSH as a reliable measure of appropriate dosing, a slow-release T3 preparation is required and should be the goal of future trials. Recently, Santini et al [81] demonstrated using T3 sulfate as a slow-release preparation that combination T4/T3 therapy could restore a near-normal fT3:fT4 ratio with reference range TSH levels. Hence, to optimize the pharmacodynamics of LT4/LT3, it is, therefore, proposed that the target for titration in future trials should be to achieve a physiological fT3:fT4 ratio (mean = 0.32, interquartile range 0.27–0.37) in the presence of physiological TSH levels (e.g., 1.4 mU/L).…”

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

“…Of the 14 combination therapy trials that have been completed, 10 employed once-daily LT3 administration (23,46,47,49,51,52,59,71,78,79), 4 employed twice-daily LT3 therapy (17,48,53,60), and none used three times a day LT3 therapy. Assuming that three times daily LT3 administration is too onerous to be used in future trials (75,76), and considering that a sustained-release preparation is not yet available for clinical use (80)(81)(82)(83), twice a day therapy may be the most reasonable option. Given that twice-daily LT3 therapy, although not ideal with respect to the T3 fluctuations produced, is likely to be the best compromise, modeling studies provide information about potential twice-daily LT3 doses that could be utilized (67,77).…”

“…For the reasons already given, it is argued that to both monitor T3 dosing and use TSH as a reliable measure of appropriate dosing, a slow-release T3 preparation is required and should be the goal of future trials. Recently Santini et al demonstrated using T3 sulfate as a slow-release preparation that combination T4/T3 therapy could restore a near-normal fT3:fT4 ratio with reference range TSH levels (81). Hence, to optimize the pharmacodynamics of LT4/LT3, it is, therefore, proposed that the target for titration in future trials should be to achieve a physiological fT3:fT4 ratio (mean = 0.32, interquartile range 0.27-0.37) in the presence of physiological TSH levels (e.g., 1.4 mU/L).…”

“…There should not be a clinically meaningful difference in TSH between groups to be able to make a meaningful comparison of the outcomes between the two therapies. As long as a new sustained-release T3 product is not being utilized (80)(81)(82)(83), the outcome measures do not need to be selected with Food and Drug Administration approval in mind. The most important consideration for choice of outcome measure is whether this outcome is responsive to LT3 therapy within the range of acceptable T3 levels or T3 tissue actions.…”

Levothyroxine: Conventional and Novel Drug Delivery Formulations

“…Even more surprisingly, no adverse events were observed. In 2019, a phase II, open-label, uncontrolled, parallel trial investigating the efficacy and safety of T3S plus T4 was conducted in 36 thyroidectomized individuals ( 178 ). A decreased T4/T3 ratio with no reduction in T3 levels was observed compared with LT4 monotherapy.…”