Recommendation ID

What is the clinical and cost effectiveness of levothyroxine (T4) and liothyronine (T3) combination therapy compared with T4 alone for people with hypothyroidism whose symptoms have not responded sufficiently to T4 alone? Does DiO2 polymorphism affect the response to combination therapy with T4 and T3?

Any explanatory notes
(if applicable)

Why the committee made the recommendations
Thyroid hormone replacement
The committee agreed that hypothyroidism needs thyroid hormone replacement. Potential treatments are levothyroxine, usually prescribed to everyone, liothyronine, which is sometimes prescribed when levothyroxine fails, and natural thyroid extracts (which is currently unlicensed for use in the UK). Overall the evidence from 7 randomised controlled trials suggested that combination treatment with levothyroxine and liothyronine did not offer any important health benefits compared with levothyroxine monotherapy and was significantly more expensive. However, the committee noted that some of the trials did show some small benefits in specific quality of life domains and anecdotal evidence from some committee members suggested beneficial effects of combination treatment with levothyroxine and liothyronine in small subgroups of patients. The committee were aware that some people reported still feeling unwell with levothyroxine monotherapy and agreed that in this group adding liothyronine could potentially have greater benefit than in the general population with hypothyroidism, although there are no trials in this population. Some evidence suggested that combination therapy with levothyroxine and liothyronine could be harmful because it may suppress the production of TSH and its long-term adverse effects are uncertain. The committee was aware that the use of combination therapy is a critical issue in hypothyroidism. They could not recommend liothyronine either alone or in combination treatment based on the evidence available and its current list price but agreed a research recommendation to help inform future guidance in this important area[5].
The committee agreed that the evidence for natural thyroid extracts showed no benefit over levothyroxine. The committee also noted that the proportion of T3 to T4 is higher in natural thyroid extracts than produced in the human body and the adverse effects are uncertain. Natural thyroid extracts are an unlicensed medication in the UK and overall the committee agreed they should not be offered.

Levothyroxine starting dose
Some evidence showed that a high starting dose of levothyroxine produced more rapid improvements in quality of life than a lower starting dose followed by titration. The committee agreed that this was also their experience and therefore recommended a high starting dose (1.6 micrograms per kilogram body weight per day) in adults unless contraindicated (adults over 65 or with a history of cardiovascular disease). Although evidence about dosing was very limited, the committee agreed that adults over 65 years are more likely to have cardiovascular comorbidities. Most studies of hypothyroidism and subclinical hypothyroidism use 65 as a cut-off when defining older adults. The committee agreed to recommend a lower starting dose with titration for people over 65.
The committee were unable to make recommendations on iodine or selenium supplements because of a lack of evidence.

How the recommendations might affect practice
The recommendations on thyroid hormone replacement and natural thyroid extract reinforce current practice and are not expected to have a significant cost impact. Currently everyone is offered levothyroxine as thyroid hormone replacement and small subgroups of people who do not feel well on levothyroxine are sometimes offered liothyronine.
Full details of the evidence and the committee's discussion are in evidence review E: managing hypothyroidism.

Source guidance details

Comes from guidance
Thyroid disease: assessment and management
Date issued
November 2019

Other details

Is this a recommendation for the use of a technology only in the context of research? No  
Is it a recommendation that suggests collection of data or the establishment of a register?   No  
Last Reviewed 30/11/2019