UKMi Q & A - regarding Armour Thyroid v levothyroxine. The following Q & A prepared by NHS United Kingdoim Medicines Information Pharmacists is being sent out to all NHS healthcare professionals. TPA has responded to those answers that we have found to be misleading, inadequate or incorrect. See link at bottom of UKMi Q & A to see that response.

What is the rationale for using a combination of levothyroxine and liothyronine (such as Armour® Thyroid) to treat hypothyroidism?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

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Published: November 2011

Background

The replacement therapy of choice for hypothyroidism is levothyroxine (T4). Levothyroxine is given once a day and is converted to triiodothyronine in peripheral tissues, providing stable and physiological quantities. Liothyronine (T3) has a much shorter half-life (1 day vs. 6 days) and steady state levels cannot be maintained with once daily dosing (1). Before the 1970s, synthetic combinations of levothyroxine and liothyronine or desiccated animal thyroid containing varying amounts of thyroid hormones were used, but these have now been replaced with the use of levothyroxine monotherapy (2).

Armour® Thyroid tablets are made from desiccated porcine thyroid glands (3). The amount of hormone in the thyroid gland varies from animal to animal but Armour® Thyroid contains standard amounts of levothyroxine and liothyronine according to United States Pharmacopoeia (USP) standards and specifications (4). The US Prescribing Information specifies that one grain of desiccated thyroid (equivalent to a 60mg Armour® Thyroid tablet) provides measurable amounts of approximately 38micrograms of levothyroxine and 9micrograms of liothyronine (3). The basic ‘rule of thumb’ in converting thyroid doses is that 100micrograms of levothyroxine is roughly equivalent to 25micrograms of liothyronine, or 1 grain (60mg) of Armour® Thyroid, based on clinical responses (4). The tablets come in various strengths from 15mg to 300mg. The usual starting dose of Armour® Thyroid is 30mg daily initially, which can be increased by 15mg every 2-3 weeks if necessary, with a usual dose of 60-120mg daily (3).

Armour® Thyroid is licensed in the US; there is no licensed product available in the UK although it can be ordered via importing companies such as IDIS (5). Armour® Thyroid  can be prescribed on an NHS prescription as a specials product (6). What evidence is there to support the use of a combination of the two thyroid hormones?

Answer

The thyroid gland produces about 100micrograms of levothyroxine and 20mcg of liothyronine per day per 70kg bodyweight (7). The goal of treating hypothyroid patients is to restore patients to euthyroid state (8) but some patients still experience a number of symptoms including deficits in cognition and mood, their ability to focus, and their general mental well-being despite biochemical control of their hypothyroidism (9). It has been speculated that liothyronine and levothyroxine combination therapy is a better physiological form of replacement therapy than levothyroxine alone, especially in patients who have no endogenous thyroid hormone or in those who continue to have symptoms of hypothyroidism despite appropriate levothyroxine treatment (2;9).

No study has been found that has specifically used the Armour® Thyroid preparation. A number of trials have been published comparing levothyroxine alone with levothyroxine plus liothyronine at varying ratios (1;10-15). The ratio of levothyroxine to liothyronine secreted by the normal thyroid gland is 14:1 (molar ratio) (2) and only one trial sought to replicate this ratio (13). The doses used in the studies by Clyde et al (1), Walsh et al (12), Sawka et al (11), Saravanan et al (14) and Valizadeh et al (16) were based on those used by Bunevicius et al (10). This trial concluded that combination treatment may improve mood and neuropsychological function better than monotherapy (10) but this effect was not replicated in the other similar trials. Only one other trial, Nygaard et al., found a favourable effect in terms of quality of life measures with combination therapy. However improvements in quality of life and depression scores with monotherapy suggested a placebo effect so questioning the reliability of the study (7).

There are case reports of seven patients with clinical hypothyroidism that was not detected by thyroid function tests who were treated with Armour® Thyroid (17). The patients had a range of symptoms, including depression, fainting, fatigue, hair loss, palpitations, reduced libido and intolerance to cold.  All patients experienced improvements in symptoms within days to weeks of starting treatment.  One patient was changed to levothyroxine, after which her symptoms recurred and she was switched back to Armour® Thyroid.

From the studies found, the evidence generally does not support the use of thyroid combination therapies for hypothyroidism and a meta-analysis of 1216 patients also concluded the same although it should be noted that the trials so far have been largely unsuccessful in mimicking physiological levels of thyroid hormones (18). Current combination products are not ideal as they have an excess liothyronine content which may cause palpitations within a few hours of administration due to rapid absorption. The ideal preparation is thought to contain approximately 100micrograms of levothyroxine and 10micrograms of liothyronine in a sustained released formulation to avoid adverse cardiac effects (8).

Summary

A combination of levothyroxine and liothyronine, in both non- and physiological proportions, has not consistently been shown to be more beneficial than levothyroxine alone with respect to cognitive function, social functioning and wellbeing.  Use of dried thyroid hormone extracts, such as Armour® Thyroid, is therefore not recommended.  The variation in hormonal content and large amounts of liothyronine may lead to increased serum concentrations of T3 and subsequent thyrotoxic symptoms, such as palpitations and tremor (9;19).

Whilst it is possible that some patients might benefit from the use of combination treatment or Armour® Thyroid, the parameters identifying such a patient group have yet to be clearly identified.

Limitations

The majority of the trials used non-physiological ratios of levothyroxine to liothyronine, which can lead to over-replacement and skew results. 

Study design

Treatment

Outcomes and results

Comments

Randomised, crossover 5 week study in 33 patients with chronic autoimmune thyroiditis (n=16) or thyroid cancer (n=17) (10).

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus liothyronine 12.5micrograms daily. 

 

 

Main outcomes were changes in cognitive, physical and biochemical tests.

  • Scores for the cognitive functions tests were all within normal limits for both groups.  Six out of 17 comparisons showed an advantage with combination treatment (p<0.05).  Performance after the combination was significantly better on parts of 2 of the 3 cognitive performance tests (p<0.05).
  • Patients were less depressed after combination therapy and their global scores on 3 subscales of the Profile of Mood States scale were significantly lower (p<0.05), indicating improvement, compared with levothyroxine alone. 
  • Visual analogue scales pertaining to mood and physical symptoms were scored significantly better after combination treatment than with levothyroxine alone in 7 out of 8 (p<0.04) and 3 out of 7 scales respectively (p<0.02). 

The authors concluded that use of the combination may improve mood and neuropsychological functioning.

 

Comments have been made on this trial.  The patients with cancer had been taking enough levothyroxine beforehand to suppress TSH levels to below the normal limit, which is itself associated with an improvement in well-being and mood (1;11).  In addition, the trial of each therapy was only for 5 weeks, which was not long enough for a steady state to be reached after a change in levothyroxine dose (12;20) .  This trial is quoted in several papers (8;20;21), which all conclude that the results need to be verified and that further research is required to establish if combined treatment has benefits over levothyroxine alone in the treatment of patients with persistent symptoms, despite levothyroxine replacement.

Double-blind, randomised, controlled 4 month study in 46 patients with primary hypothyroidism (1)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus liothyronine (7.5micrograms twice daily.

Main outcomes were tests of neurocognitive function and quality of life.

  • Serum TSH levels were similar in both groups at baseline and endpoint.  In the majority of patients the levels were just below the lower limit of normal; this has been associated with an improved self-assessment of well-being.
  • There were no significant differences in the health-related quality of life scores or neuropsychological tests between the 2 groups.

A longer treatment period was used to allow more time for any beneficial effects to occur. 

 

The authors concluded that levothyroxine monotherapy is most appropriate for patients with primary hypothyroidism

Double-blind, randomised, controlled 15 week study in 40 patients with primary hypothyroidism and depression (11)

Levothyroxine usual daily dose plus placebo

or levothyroxine (usual daily dose reduced by 50%) plus liothyronine 12.5micrograms twice daily. 

 

Main outcomes were changes in mood, social functional status and well-being scales.

  • The effects of the active combination did not significantly affect mood or quality of life compared with levothyroxine/placebo.  No greater change in well-being or social functioning was seen in the combination group.
  • The mean TSH concentrations remained in the normal range in both groups.  In the combination group free T3 rose and free T4 fell.
  •  

These data do not support the routine use of levothyroxine plus liothyronine to maintain euthyroidism in patients with hypothyroidism and depressive symptoms.

Double-blind, randomised, controlled 15 week study in 141 patients with primary autoimmune hypothyroidism of at least 6 months (15)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 25micrograms) plus liothyronine in a ratio of 10:1 or 5:1, in two divided doses.

 

(e.g. levothyroxine 75micrograms plus liothyronine 7.5micrograms or levothyroxine 75micrograms plus liothyronine 15micrograms)

Main endpoint was the subjective appreciation of the study medication by the patient, on a 5-point scale.

  • Endpoint serum TSH and free T4 levels fell, and serum T3 levels rose in the combination groups.  The most prominent changes were in the 5:1 group. 
  • Study medication was preferred by 14/48 patients in the levothyroxine group, 19/46 patients in the 10:1 group and 24/46 patients in the 5:1 group.
  • There were improvements in almost all the secondary outcomes (mood, fatigue, quality of life, neurocognitive tests) but with no significant differences among the treatment groups.  Many of the within-group test results were improved at endpoint, compared with baseline.

The study results do not support the use of combination therapy as subjective preferences were not supported by objective outcomes.

Double-blind, randomised, controlled 12 month study in 697 patients with hypothyroidism (14)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus liothyronine 10micrograms daily.

 

Psychological well-being, mood, cognitive function, physical symptoms and treatment satisfaction were assessed.

  • After 12 months no difference in psychological well-being was detected using depression scores, cognitive behaviour, physical symptoms and satisfaction questionnaires.  If any benefit had been seen it would have been overwhelmed by the size of the placebo effect.
  • Using a fixed combination of 50 micrograms of levothyroxine plus 10micrograms liothyronine resulted in a rise in TSH and fall in T4, indicating under-replacement with levothyroxine.

Data did not provide conclusive evidence of benefits for using levothyroxine with liothyronine.

Double-blind, randomised, controlled, cross-over trial in 110 patients with primary hypothyroidism of at least 6 months (12)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus liothyronine 10micrograms daily.

 

Treatment periods lasted for 10 weeks, separated by a 4 week period during which patients took their usual levothyroxine dose.

 

General health, psychological function, cognitive function and treatment preference were assessed.

  • The results of the quality of life measures were not significantly different between the two groups.  Some measures were worse in the combination group (e.g. psychological wellbeing, anxiety scores, sickness/nausea).
  • There were no significant differences in the cognitive function tests between the groups.
  • Mean TSH levels rose during combined treatment compared with levothyroxine alone.  Serum free T4 was significantly lower with combination treatment than with levothyroxine alone, with no significant differences in the serum free T3 levels.
  • Out of 101 patients completing the study, 36 preferred combination treatment, 46 preferred levothyroxine alone and 18 had no preference (p=0.32).

 

No benefit of combined therapy over levothyroxine was demonstrated on quality of life, hypothyroid symptoms, cognitive function, subjective satisfaction with replacement therapy or treatment preference.

Double-blind, randomised, crossover study in 28 women with overt primary hypothyroidism taking 100micrograms levothyroxine for at least one year (13)

Levothyroxine 100micrograms daily

or levothyroxine 75micrograms plus liothyronine 5micrograms daily (14:1 ratio), given for 8 weeks each, with a final 8 week add-on period of 87.5micrograms levothyroxine plus 7.5micrograms liothyronine, in case the trial combination doses resulted in under treatment. 

There were a number of main outcomes including quality of life and neuro-cognitive function tests.

  • No improvement after the combination therapy was seen in the Profile of Mood State, Digit Symbol Substitution Test or Visual Scanning Test. 
  • No statistically significant differences between the groups were seen in the quality of life, psychometric function or visual analogue mood scale scores.
  • Patients were over-treated during the add-on period:  TSH levels fell to below the lower limit of normal, and T3 levels rose, compared with standard treatment.

 

No clear advantages of giving combination therapy over standard levothyroxine therapy were found.

 

Despite the lack of objective advantages 12 patients preferred the combination therapy.  [Six preferred the add-on therapy, 2 preferred standard treatment and 6 had no preference.]

Double-blind, randomised controlled 4 month study in 71 patients with primary hypothyroidism for at least 6 months and taking a stable dose of levothyroxine for at least 3 months (16)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus liothyronine 6.25micrograms twice daily.

General health and psycho-social status were assessed.

  • Serum T3 levels increased and T4 levels fell in the combined group; within range of normal limit. Serum TSH did not significantly change in both groups.
  • No statistically significant differences between the groups in overall scores of the Goldberg’s General Health Questionnaire-28 (self-reported) were seen.
  • No change in somatic symptoms, social dysfunction and depression were noted between the groups. Significant differences were only noted in the anxiety/insomnia subscale (p<0.05), with a reduction in score for the combination group, indicating some improvement.

 

There was no clinical advantage of giving combination therapy over standard monotherapy in improving psychosocial outcomes.

Randomised, controlled 6 month trial in 36 premenopausal women with untreated overt hypothyroidism (22)

Levothyroxine 1.6microgram/kg daily

or levothyroxine (1.6microgram/kg reduced by 25micrograms) plus liothyronine 12.5microgram.

Outcomes measures were changes in lipid profiles, bone metabolism markers, bone density and ECG monitoring.

  • No significant differences in TSH levels, ECG monitoring, bone densitometry or thyroid symptom scores between the groups were noted.
  • Total cholesterol and LDL decreased significantly (p<0.05 for both) in the combination group.
  • Out of the 36 patients, 10 (28%) preferred combination treatment, 8 (22%) preferred levothyroxine alone and 18 (50%) had no preference.

Combination therapy showed favourable changes in serum lipid levels. A slightly greater activation of bone resorption was seen with combination therapy although not statistically significant. No particular preference for either therapeutic regimen was expressed by the patient.

Randomised, double-blind cross-over trial in 59 patients with hypothyroidism and on stable levothyroxine substitution (7)

Levothyroxine usual daily dose

or levothyroxine (usual daily dose reduced by 50micrograms) plus

liothyronine 20micrograms or levothyroxine 50micrograms over a 12 week period, followed by cross-over for another period of 12 weeks.

 

The levothyroxine dose was regulated to maintain serum TSH levels.

Quality of life and depression scores (SF-36, Beck Depression Inventory and SCL-90-R) were measured.

  • Significant differences in quality of life and psychological well-being were seen in 7 out of 11 scores (p<0.02), indicating a positive effect  for the combination group compared to  monotherapy.
  • Open-label levothyroxine was reduced due to decreasing TSH levels in 10 patients (seven during combination period and three during monotherapy) and increased in three patients (all during monotherapy period).
  • Out of the 59 patients, 49% preferred combination therapy, 15% monotherapy and 35% had no preference.
  • No significant differences in adverse effects were noted between the two groups.

In this study TSH levels were maintained throughout and it found that combination therapy was superior to monotherapy in both quality of life measures and patient preference.

 

However there was also statistically significant improvement in quality of life and depression scores for 10 out of 11 scores in patients that received levothyroxine monotherapy from baseline and throughout study. This suggests a placebo effect and questions the reliability of the results.

 
 

References

     (1)   Clyde PW, Harari AE, Getka EJ et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism. The Journal of the American Medical Association 2003; 290(22):2952-2958.

     (2)   Cooper DS. Combined T4 and T3 therapy - back to the drawing board. The Journal of the American Medical Association 2003; 290(22):3002-3004.

     (3)   Forest Pharmaceuticals Inc. Armour® Thyroid (thyroid tablets, USP). Revision January 2010.  http://www.frx.com/pi/armourthyroid_pi.pdf

     (4)   Forest Pharmaceuticals Inc. Armour® Thyroid. Frequently Asked Questions (FAQs).  www.armourthyroid.com

     (5)   IDIS world medicines. Personal Communication. November 2011.

     (6)   Prescription pricing authority. Personal communication. November 2011.

     (7)   Nygaard B, Jensen EW, Kvetny J et al. Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. European Journal of Endocrinology 2009; 161:895-902.

     (8)   Toft AD. Thyroid hormone replacement - one hormone or two? The New England Journal of Medicine 1999; 340(6):469-470.

     (9)   Kansagra SM, McCudden CR, Willis MS. The challenges and complexities of thyroid hormone replacement. Labmedicine 2010; 41(6):338-348.

    (10)   Bunevicius R, Kažanavicius G, Žalinkevicius R et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. The New England Journal of Medicine 1999; 1999(340):424-429.

    (11)   Sawka AM, Gerstein HC, Marriott MJ et al. Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomised, controlled trial. The Journal of Clinical Endocrinology & Metabolism 2003; 88(10):4551-4555.

    (12)   Walsh JP, Shiels L, Lim EM et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomised controlled trial in patients with primary hypothyroidism. The Journal of Clinical Endocrinology & Metabolism 2003; 88(10):4543-4550.

    (13)   Escobar-Morreale HF, Botella-Carretero JI, Gómez-bueno M et al. Thyroid hormone replacement therapy in primary hypothyroidism: a randomised trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Annals of Internal Medicine 2005; 142:412-424.

    (14)   Saravanan P, Simmons DJ, Greenwood R et al. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. The Journal of Clinical Endocrinology & Metabolism 2005; 90(2):805-812.

    (15)   Appelhof BC, Fliers E, Wekking EM et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled trial. The Journal of Clinical Endocrinology & Metabolism 2005; 90(5):2666-2674.

    (16)   Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H et al. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomised controlled trial. Endocrine Research 2009; 34(3):80-89.

    (17)   Gaby AR. "Sub-laboratory" hypothyroidism and the empirical use of Armour® Thyroid. Alternative Medicine Review 2004; 9(2):157-179.

    (18)   Wiersinga WM. Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? European Journal of Endocrinology 2009; 161:955-959.

    (19)   Hypothyroidism. Sweetman, SC. Martindale: The complete drug reference, 3rd quarter 2011 update. Pharmaceutical Press.  www.medicinescomplete.com

    (20)   Walsh JP, Stuckey BGA. What is the optimal treatment for hypothyroidism? The Medical Journal of Australia 2001; 174:141-143.

    (21)   Hueston WJ. Treatment of hypothroidism. American Family Physician 2001; 64(10):1717-1724.

    (22)   Fadeyev VV, orgunova TB, elnichenko GA et al. Combined therapy with L-thyronine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Hormones 2010; 9(3):245-252.

 

Quality Assurance

Prepared by

Varinder Rai, [based on earlier work by Alexandra Denby], London Medicines Information Service (Northwick Park Hospital).

Contact

[email protected]

Date Prepared

November 2011