Abstract
Objective: To gain insight into the mixed results of reported combination therapy studies conducted with levothyroxine (LT4) and liothyronine (LT3) between 1999 and 2016.Methods: We defined trial success as improved clinical outcome measures and/or patient preference for added LT3. We hypothesized that success depends strongly on residual thyroid function (RTF) as well as the LT3 added to sufficient LT4 dosing to normalize serum T4 and TSH, all rendering T3 levels to at least middle-normal range. The THYROSIM app was used to simulate “what-if” experiments in patients and study designs corresponding to the study trials. The app graphically provided serum total (T4) and free (FT4) thyroxine, total (T3) and free (FT3) triiodothyronine, and TSH responses over time, to different simulated LT4 and combination LT4 + LT3 dosage inputs in patients with primary hypothyroidism. We compared simulation results with available study response data, computed RTF values that matched the data, classified and compared them with trial success measures, and also generated nomograms for optimizing dosages based on RTF estimates.Results: Simulation results generated three categories of patients with different RTFs and T3 and T4 levels at trial endpoints. Four trial groups had >20%, four <10%, and five 10–20% RTF. Four trials were predicted to achieve high, seven medium, and two low T3 levels. From these attributes, we were able to correctly predict 12 of 13 trials deemed successful or not. We generated an algorithm for optimizing dosage combinations suitable for different RTF categories, with the goal of achieving mid-range normal T4, T3 and TSH levels. RTF is estimated from TSH, T4 or T3 measurements prior to any hormone therapy treatment, using three new nonlinear nomograms for computing RTFs from these measurements. Recommended once-daily starting doses are: 100 μg LT4 + 10–12.5 μg LT3; 100 μg LT4 + 7.5–10 μg LT3; and 87.5 μg LT4 + 7.5 μg LT3; for <10%, 10–20%, and >20% RTF, respectively.Conclusion: Unmeasured and variable RTF is a complicating factor in assessing effectiveness of combination LT4 + T3 therapy. We have estimated and partially validated RTFs for most existing trial data, using THYROSIM, and provided an algorithm for estimating RTF from accessible data, and optimizing patient dosing of LT4 + LT3 combinations for future combination therapy trials.
Highlights
Combination therapy for hypothyroidism using both levothyroxine (LT4) and liothyronine (LT3) continues to be a topic of much interest to physicians and patients alike (1–4)
When examining outcomes of either quality of life, mood, or neurocognitive function, trials fall into 3 broad categories: those showing substantial clinical benefit of combination therapy (11, 16), those showing partial benefit based on some outcome measures, but not others (10, 13, 18, 21), and those showing no benefit (9, 12, 14, 15, 17, 19, 20, 22)
The goal is to find the best residual thyroid function (RTF) (% secretion rates) that generates starting values that approximate both the initial T4, T3, and TSH concentrations measured prior to dosing therapy, and the approximate final concentrations measured at the end of the study period
Summary
Combination therapy for hypothyroidism using both levothyroxine (LT4) and liothyronine (LT3) continues to be a topic of much interest to physicians and patients alike (1–4) This interest has been spurred, in part, by the welldocumented finding that the ratio of total thyroxine (T4) to total triiodothyronine (T3) increases during LT4 therapy, compared with endogenous euthyroidism (5), and that T3 levels may be lower than in the native state (6). Animal studies suggest T3 deficiency at the tissue level with LT4 therapy alone (7, 8) This interest persists despite the generally mixed results of combination therapy trials, with most results not demonstrating a benefit of such therapy in terms of improvement in quality of life, mood, or neurocognitive function, but some patients expressing preference for therapy containing LT3 (9–22). The seven trials that examined patient preference for combination therapy can be divided into two groups: those in which patients preferred the LT3-containing therapy (9–11, 13, 16), and those in which there was no preference (18, 22)
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