Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism

Mohamed K.M. Shakir; Daniel I. Brooks; Elizabeth A. McAninch; Tatiana L. Fonseca; Vinh Q. Mai; Antonio C. Bianco; Thanh D. Hoang


J Clin Endocrinol Metab. 2021;106(11):e4400-e4413. 

In This Article

Abstract and Introduction


Introduction: Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.

Methodology: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.

Results: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component).

Conclusions: As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.


Hypothyroidism, or underactive thyroid function, is a common condition characterized by cognitive and metabolic impairments.[1] It is estimated that 3.7% of the general US population is affected by hypothyroidism based on The National Health and Nutrition Examination Survey (1999–2002).[2]

Various forms of thyroid extracts were originally developed in the 1880s, with desiccated thyroid extract (DTE) becoming the dominant form and commercially available in the early 1900s. During the 1970s, there was a switch to therapy with levothyroxine (LT4), which to this day is the standard of care, considered safe and effective.[3] The switch occurred rapidly, but some anecdotal evidence emerged that a few patients did not feel well on LT4 and asked to return to DTE.[4] The existence of residual symptoms in LT4-treated patients was first documented through a patient survey[5] and later through questionnaires that evaluated thyroid-specific symptoms and quality of life (QoL),[6] as well as sophisticated cognitive tests.[7] Several clinical trials addressed the question of whether residual symptoms could be resolved through the use of combination therapy with LT4 and liothyronine (LT3), but evidence of consistent superiority of combination therapy was not obtained.[8,9] A case could be made that, in some instances, patients prefer the combination approach.[10,11] Indeed, in a recent randomized, double-blind, crossover study,[12] we confirmed that QoL of hypothyroid patients was similarly improved with LT4 or DTE, but the latter was associated with modest weight loss (~4 pounds); nearly 50% of the study patients preferred treatment with DTE over LT4.

Most professional medical guidelines[3] recommend LT4 monotherapy "as the preparation of choice" for thyroid hormone replacement, and against the "routine use" of combination treatment with LT4 and LT3 or DTE because of uncertainty about long term efficacy and potential safety concerns. A recent consensus statement by the American, European, and British Thyroid Associations reasoned that previous clinical trials did not focus sufficiently on patients who were symptomatic while on therapy with LT4.[9] The statement recommends that studies should be appropriately powered to study clinical outcomes, the potential interference of gene polymorphisms affecting thyroid hormone signaling, and include patients dissatisfied with their current therapy. Patient preference should be considered as a secondary outcome.

The current investigation involves the prospective crossover study of 75 hypothyroid patients while on 3 different forms of thyroid hormone replacement therapy. In addition to studying outcomes for each treatment arm, we also performed a subanalysis for those patients who were most symptomatic while on the LT4 treatment arm.