Predicting Optimal Combination LT4 + LT3 Therapy for Hypothyroidism Based on Residual Thyroid Function

To gain insight into the mixed results of reported combination therapy studies conducted with levothyroxine (LT4) and liothyronine (LT3) between 1999 and 2016. 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. Simulation results generated three categories of patients with different RTFs and T3 and T4 levels at trial endpoints. Four trial groups had >20%, four