Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial

JAMA. 2003 Dec 10;290(22):2952-8. doi: 10.1001/jama.290.22.2952.


Context: Standard therapy for patients with primary hypothyroidism is replacement with synthetic thyroxine, which undergoes peripheral conversion to triiodothyronine, the active form of thyroid hormone. Within the lay population and in some medical communities, there is a perception that adding synthetic triiodothyronine, or liothyronine, to levothyroxine improves the symptoms of hypothyroidism despite insufficient evidence to support this practice.

Objective: To evaluate the benefits of treating primary hypothyroidism with levothyroxine plus liothyronine combination therapy vs levothyroxine monotherapy.

Design, setting, and patients: Randomized, double-blind, placebo-controlled trial conducted from May 2000 to February 2002 at a military treatment facility that serves active duty and retired military personnel and their family members. The trial included a total of 46 patients aged 24 to 65 years with at least a 6-month history of treatment with levothyroxine for primary hypothyroidism.

Intervention: Patients received either their usual dose of levothyroxine (n = 23) or combination therapy (n = 23), in which their usual levothyroxine dose was reduced by 50 micro g/d and substituted with liothyronine, 7.5 micro g, taken twice daily for 4 months.

Main outcome measures: Scores on a hypothyroid-specific health-related quality-of-life (HRQL) questionnaire, body weight, serum lipid levels, and 13 neuropsychological tests measured before and after treatment.

Results: Serum thyrotropin levels remained similar and within the normal range in both treatment groups from baseline to 4 months. Body weight and serum lipid levels did not change. The HRQL questionnaire scores improved significantly in both the control group (23%; P<.001) and the combination therapy group (12%; P =.02), but these changes were statistically similar (P =.54). In 12 of 13 neuropsychological tests, outcomes between groups were not significantly different; the 1 remaining test (Grooved Peg Board) showed better performance in the control group.

Conclusion: Compared with levothyroxine alone, treatment of primary hypothyroidism with combination levothyroxine plus liothyronine demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a HRQL questionnaire, and standard measures of cognitive performance.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Body Weight
  • Cognition
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Hormone Replacement Therapy*
  • Humans
  • Hypothyroidism / drug therapy*
  • Hypothyroidism / physiopathology
  • Lipids / blood
  • Male
  • Middle Aged
  • Quality of Life
  • Thyroxine / administration & dosage
  • Thyroxine / therapeutic use*
  • Treatment Outcome
  • Triiodothyronine / administration & dosage
  • Triiodothyronine / therapeutic use*


  • Lipids
  • Triiodothyronine
  • Thyroxine