Examining T4/T3 Combination Therapy in Hypothyroidism

CHICAGO — Levothyroxine (LT4) monotherapy remains the standard treatment for hypothyroidism, although a subset of patients continue to have hypothyroidism despite normal thyroid-stimulating hormone (TSH) and serum-free thyroxine levels. LT4 and liothyronine (LT3) combination therapy to improve hypothyroidism remains a topic of interest.
A clinical session at the recent American Thyroid Association (ATA) 2024 Meeting explored LT4/LT3 combination therapy. Speakers addressed the biochemical and clinical differences between monotherapy and combination therapy. Take-home messages included that combination treatment is both safe and effective and is preferred by many patients. Additionally, attendees heard an update on the Joint British Thyroid Association guidelines on the use of LT3 in hypothyroidism.
The Physical Basis of Using Triiodothyronine (T3)
The thyroid system is “wired” to defend serum T3 and in the absence of a fully functional thyroid gland, patients rely only on the deiodinases, Antonio C. Bianco, MD, PhD, of The University of Texas Medical Branch in Galveston, Texas, told attendees. 
Bianco referred attendees to his recent article in The Journal of Clinical Endocrinology & Metabolism, which examined data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brazil) study. Bianco and his coauthors analyzed data from 186 participants who started treatment with LT4 during the study and 243 subjects continuously treated with LT4 therapy. The more recent LT4 participants experienced an 11%-19% decrease in TSH, an approximately 19% increase in free T4 (FT4), and a 7% reduction in free T3 (FT3) serum levels.
Approximately 40% of the recent LT4 patients had declines of FT3 > 10%, said Bianco. “This was associated with an increase in triglyceride levels and the use of hypolipidemic and antidiabetic medications,” he said. “Participants continuously treated with LT4 showed a stable elevation in serum FT4 and a reduction in serum FT3 and TSH levels.”
Bianco suggested using a shared decision-making model when treating patients with hypothyroidism. “Twice as many patients prefer treatment with combination therapy compared to LT4 alone,” he said.
Quality of Life Considerations
Patients may seem to prefer combination therapy for hypothyroidism, but why? That was the question Jacqueline Jonklaas, MD, PhD, of Georgetown University in Washington, DC, posed to attendees.
Patients taking LT4 monotherapy report reduced health-related quality of life, mood, and neurocognitive function, said Jonklaas. Possible causes of what she called the clinical shortcomings of monotherapy include that LT4 does not recapitulate normal thyroid physiology, genetic issues could cause impaired conversion of T4 to T3, or even seemingly unrelated causes like awareness of a chronic condition or that autoimmune status separate from thyroid status could harm quality of life.
Health-related quality of life was studied in 14 trials, Jonklaas said. “Two trials showed the superiority of combination therapy on multiple measures and two trials showed the superiority of combination therapy on a minority of measures,” she said. “That means 10 trials showed no superiority of combination therapy.”
Jonklaas called these findings discordant: “Comparing combination therapy with monotherapy, we’re not able to show a difference in quality of life, but there clearly seems to be a preference for the combination therapy when we look at it in meta-analysis,” she said. “It is possible that there’s some parameter of quality of life that we’re not capturing with our current instruments or some other intangible benefit of combination therapy.”
Joint British T3 Guidelines
Kristien Boelaert, MD, PhD, of the University of Birmingham, Birmingham, United Kingdom, provided an overview of the Joint British Thyroid Association guideline on the use of T3 in hypothyroidism. Key provisions of the guidelines, published in 2023, include:
Before considering a trial of LT3, confirm a diagnosis of primary hypothyroidism, with a TSH level ≥ 10 and/or low FT4 level. Additionally, exclude comorbidities as the cause of persistent symptoms.
Before starting combination therapy, TSH levels should be detectable and within reference range. Consider LT4 dose reduction before starting LT3 in patients with undetectable TSH levels.
To start combination therapy, substitute LT3 at about 1:17th of the current LT4 dose and reduce LT4 by three times the LT3 dose.
Plan on a 3- to 6-month trial of combination therapy while maintaining a TSH level within reference range before assessing response.
Monitor with serum TSH only to assess response. Interpret measured serum F3T levels in the context of dosage, timing and frequency of LT3 therapy.
Additionally, the guideline recommends that physicians should not routinely remove patients from LT3 who feel well on combination therapy and have an appropriate serum TSH level. LT3 should not be used as monotherapy nor in pregnancy. The guideline does not recommend the use of desiccated pig thyroid extract, which is not licensed in the United Kingdom, said Boelaert.
Boelaert also added context as a clinician practicing in a country with a national health system. “In the UK, care is always shared with the patient’s GP [general practitioner], so I start appropriate patients on a trial of combined therapy for 6 months,” she said. “After that, if they are benefiting and their thyroid function is within the desired range, then the GP will take over prescribing and monitoring.” 
Boelaert emphasized that the guideline is optional: “As we wrote the guideline, we strongly felt we should make clear that there is no compulsion for National Health Service clinicians to prescribe combination therapy,” she said. “If that clinician feels it is not in the patient’s best interest or they have significant concerns about it, they absolutely do not have to prescribe LT3.”
Jonklaas and Boelaert disclosed no relevant financial relationships. Bianco’s disclosures included relationships with AbbVie, Acella, Aligos, and Synthonics.
 
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