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Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design

Open access
Premawardhana, Lakdasa D., Taylor, Peter Nicholas, Okosieme, Onyebuchi E., Adlan, Mohamed A., Obuobie, Emmanuel K., Dayan, Colin Mark·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1282608PMC PMC10687631
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Abstract

Approximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection—(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 μg/day or 100 μg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.

AI snapshot

Written from the paper’s full text.

TL;DR

This perspective argues that prior LT3 + LT4 randomized controlled trials were inconclusive partly because of patient selection, short-acting LT3 preparations, and non-thyroid-specific outcome measures. It recommends future phase 2b/3 trials in symptomatic LT4-treated hypothyroid patients using thyroid-specific PROMs, long-acting LT3 preparations, and a placebo-controlled crossover design.

Key findings

  • Approximately 10%–15% of hypothyroid subjects on LT4 alone have persistent symptoms affecting quality of life; 18 RCTs of LT3 + LT4 have been inconclusive regarding superiority over LT4 alone.
  • Recommended subject selection includes a validated thyroid-specific PROM such as ThyPRO39 or its Composite scale, a recruitment threshold of ThyPRO Composite score 32 or TSQ >4, a minimal important change of 9 points on the ThyPRO Composite score, and LT4 dose ≥1.2 μg/kg/day or 100 μg/day.
  • The D2 Thr92Ala polymorphism is present in about 12%–14% of the UK population; homozygotes have a 3-fold increased symptom burden and may allow a 3-fold smaller study, while non-homozygous individuals on LT4 still had a 22% increase in symptoms.
  • Long-acting LT3 options discussed include poly-zinc-liothyronine (PZL), with a phase 1 trial showing a 6-hour serum T3 plateau, Cmax 30% lower than LT3, and T3 above half Cmax for more than 24 h, and T3 sulfate (T3S), where an 11-week study replacing 25 μg T4 with 40 μg T3S restored a physiological T4/T3 ratio and normal TSH in 89% (n = 36) versus fewer than 45% on LT4 alone.

Methods

  • Narrative review and trial-design proposal; no new primary trial data are reported.
  • The paper synthesizes 18 prior RCTs of LT3 + LT4 (Table 1), mostly in autoimmune thyroid disease, with durations from 5 weeks to 24 months, sample sizes from 13 to 584, and 16 trials using short-acting LT3 preparations.
  • Recommendations are based on cited literature, prior trial results, and pharmacokinetic studies of LT3 preparations; no formal meta-analysis or new statistical analysis is presented.

Limitations

  • Stated: previous RCTs were underpowered, used inappropriate outcome measures, were mainly of short duration, and used short-acting, unphysiological LT3 preparations.
  • Stated: crossover designs risk carryover effects, loss of data, and inability to analyze data if patients drop out; long trial duration may adversely affect enrolment, increase dropout rates, and increase cost.
  • Stated: the 11-week T3S study was uncontrolled and not designed or powered for clinical endpoints. Evident from the text: this is a recommendation paper without new primary data, and the proposed selection criteria and long-acting LT3 efficacy remain to be tested in phase 2b/3 RCTs.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2023.1282608

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 86 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Randomized controlled trials have not established greater efficacy for the LT3 + LT4 combination than for LT4 alone in hypothyroid subjects dissatisfied with LT4.

    “However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone.”
    • Also stated in: § Introduction · hedged
      “Eighteen randomized controlled trials (RCT) of combined liothyronine (LT3) and L-thyroxine (LT4) therapy (LT3 + LT4) have been inconclusive regarding their superiority in improving symptoms and quality of life (QoL) in hypothyroid subjects dissatisfied with LT4 alone (1) ( Table 1 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Millan-Alanis, 2021, Benefits and harms of levothyroxine/L-triiodothyronine versus levothyroxine monotherapy for adult patients with hypothyroidism: systematic review and meta-analysis, Thyroid source

      Not checked in the free run.

  • Findingcitation

    Most studies hitherto have used generic, non-thyroid-specific PROMs such as SF-36, HADS, BDI, and GHQ.

    “Most studies hitherto have used generic, non-thyroid-specific PROMs such as SF-36, HADS, BDI, and GHQ.”
    Quote in the paperSubstantial claim
  • Findingcitation

    In individuals on LT4 alone (n = 573), homozygosity for the Thr92Ala polymorphism was associated with reduced QoL.

    “We observed that in individuals on LT4 alone (n = 573), homozygosity for the Thr92Ala polymorphism was associated with reduced QoL (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Saravanan, 2002, Psychological well-being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based questionnaire study, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • Findingcitation

    We have replicated our findings in the HUNT study in Norway (n = 46,712, n = 1,100 on LT4).

    “We have replicated our findings in the HUNT study in Norway (n = 46,712, n = 1,100 on LT4) (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Taylor, 2022, Individuals on levothyroxine have higher HADS anxiety and depression scores than the general population and this is exacerbated by the Thr92Ala substitution in DIO2, Endocr Abstracts source

      Not checked in the free run.

  • Findingnone given

    There is a shortage of long-acting preparations with clinical utility.

    “There is a shortage of long-acting preparations with clinical utility ( Table 2 , known preparations); however, two preparations have undergone preliminary trials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites ( Table 2 )

      Not checked in the free run.

  • Classified as probably not a substantial claim. 22
  • May combine two claims. 41

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Two long-acting LT3 preparations are currently available.

    “two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Of the 18 RCTs of LT3+LT4, 16 used short-acting LT3 preparations in subjects with primary hypothyroidism, one used natural desiccated thyroid, and one investigated patients with central hypothyroidism.

    “While 16 RCTs used short acting LT3 preparations in subjects with primary hypothyroidism (autoimmune, post-radioiodine, post-thyroidectomy), one used natural desiccated thyroid (NDT) and one investigated patients with central hypothyroidism (2, 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Hoang, 2013, Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [3] Slawik, 2007, Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The Thr92Ala SNP was present in 13% of the population and was not associated with increased HADS scores in subjects not receiving LT4.

    “The Thr92Ala SNP was present in 13% of the population and was not associated with increased HADS scores in subjects not receiving LT4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Taylor, 2022, Individuals on levothyroxine have higher HADS anxiety and depression scores than the general population and this is exacerbated by the Thr92Ala substitution in DIO2, Endocr Abstracts source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Current LT3 preparations last a few hours in the serum and produce "peaks" with persistent T3 levels above the upper limit of the reference range (ULRR) for a significant length of time, the number of peaks depending on the frequency of administration.

    “They last a few hours in the serum and produce “peaks” with persistent T3 levels above the upper limit of the reference range (ULRR) for a significant length of time, the number of peaks depending on the frequency of administration.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingreasoning

    Figure 1 illustrates the variability of serum free T3 at different times before and after oral short-acting LT3, making recommendations about the timing of blood testing for dose adjustment impossible.

    “Figure 1 illustrates the variability of serum free T3 at different times before and after oral short-acting LT3, making recommendations about the timing of blood testing for dose adjustment impossible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 16 RCTs for which information was available, nine used a once/day, four used a twice/day, and one used a three/day LT3 regime.

    “Of the 16 RCTs for which information was available, nine used a once/day, four used a twice/day, and one used a three/day LT3 regime ( Table 1 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites ( Table 1 )

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Non-homozygous individuals also have an excess of psychological morbidity on LT4 compared to the background population, confirming that all subjects with the SNP on LT4 have the potential to benefit from LT3.

    “However, we have confirmed that non-homozygous individuals also have an excess of psychological morbidity on LT4 compared to the background population, confirming that all subjects with the SNP on LT4 have the potential to benefit from LT3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    PZL has not been tested in QoL studies.

    “However, this has not been tested in QoL studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Recruiting a preponderance of subjects with autoimmune thyroiditis increases generalisability.

    “recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Prevalence of hypothyroidism in the USA increased from 9.5% in 2012 to 11.7% in 2019, with over 78% receiving LT4 alone.

    “prevalence in the USA increased from 9.5% (2012) to 11.7% (2019), with over 78% receiving LT4 alone (9)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Wyne, 2023, Hypothyroidism prevalence in the United States: A retrospective study combining national health and nutrition examination survey and claims data, 2009–2019, J Endocr Soc source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    A crossover design is superior in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.

    “The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures may have contributed to the inconclusive results of previous RCTs.

    “While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Subjects with a high symptom load, such as those with the deiodinase 2 polymorphism, have a greater response to combination therapy.

    “those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A significant proportion of endocrinologists (51%) are willing to consider prescribing LT3 for these patients.

    “a significant proportion of endocrinologists (51%) who are willing to consider prescribing LT3 for these patients (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Younes, 2023, Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of UK endocrinologists, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These differences in D2 activity normalize serum TSH whereas peripheral tissues remain unreplenished with T3 converted from the same LT4.

    “These differences in D2 activity normalize serum TSH (the “gold standard” for LT4 dosing), whereas peripheral tissues remain unreplenished with T3 converted from the same LT4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Thyroid-specific PROMs fulfil content validity and responsiveness.

    “These thyroid-specific PROMs fulfil two important criteria: content validity (relevant and acceptable to patients and physicians) and responsiveness (detecting subtle changes over time) (21, 27–29).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [21] Wong, 2016, A systematic review of quality of thyroid-specific health-related quality-of-life instruments recommends ThyPRO for patients with benign thyroid diseases, J Clin Epidemiol source

      Not checked in the free run.

    • cites [27] Watt, 2010, Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO, Eur J Endocrinol source

      Not checked in the free run.

    • cites [28] Watt, 2014, Few items in the thyroid-related quality of life instrument ThyPRO exhibited differential item functioning, Qual Life Res source

      Not checked in the free run.

    • cites [29] Watt, 2014, Confirmatory factor analysis of the thyroid-related quality of life questionnaire ThyPRO, Health Qual Life Outcomes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypothyroid subjects on long-term LT4 alone have a 5% increase in BMI and increased cholesterol.

    “a 5% increase in BMI, increased cholesterol”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [10] Younes, 2023, Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of UK endocrinologists, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [11] Ning, 2017, What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants, BMC Med source

      Not checked in the free run.

    • cites [12] Samuels, 2016, Effects of levothyroxine replacement or suppressive therapy on energy expenditure and body composition, Thyroid source

      Not checked in the free run.

    • cites [13] McAninch, 2018, Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A UK study showed impaired psychological well-being (GHQ) on LT4 alone in homozygotes and a greater response to LT3 + LT4 compared to those with the wild-type allele.

    “A UK study showed impaired psychological well-being (GHQ) on LT4 alone in homozygotes and a greater response to LT3 + LT4 compared to those with the wild-type allele (37).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Panicker, 2009, Common variation in the DIO2 gene predicts baseline psychological wellbeing and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Thr92Ala polymorphism has been shown to be beneficial in the general population: heterozygosity reduces acute lung injury in sepsis by 35% and reduces mortality from COVID-19 by 50%.

    “This polymorphism has been shown to be beneficial in the general population (heterozygosity reduces acute lung injury in sepsis by 35% and reduces mortality from COVID-19 by 50%) (39, 40).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Ma, 2011, Type 2 deiodinase and host responses of sepsis and acute lung injury, Am J Respir Cell Mol Biol source

      Not checked in the free run.

    • cites [40] de Lima Beltrão, 2022, Heterozygote advantage of the type II deiodinase thr92Ala polymorphism on intrahospital mortality of COVID-19, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The D2 SNP affected symptom load, thyroid hormone levels, and response to LT3 + LT4 in both animal and human studies.

    “The D2 SNP affected symptom load, thyroid hormone levels, and response to LT3 + LT4 in both animal and human studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another meta-analysis suggested that there was no consistent evidence of improved preference, except through chance.

    “although another suggested that there was no consistent evidence of improved preference, except through chance (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Akirov, 2019, A systematic review and meta-analysis of patient preferences for combination thyroid hormone treatment for hypothyroidism, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Thr92Ala SNP may cause intracellular organelle dysfunction by abnormal translocation to the Golgi apparatus and disruption of mitochondrial function, apoptosis, and growth factor signalling.

    “However, it may cause intracellular organelle dysfunction by abnormal translocation to the Golgi apparatus and disruption of mitochondrial function, apoptosis, and growth factor signalling (18, 38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Werneck de Castro, 2015, Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine, J Clin Invest source

      Not checked in the free run.

    • cites [38] Jo, 2019, Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The exact mechanism by which the Thr92Ala SNP affects D2 function is unknown because it affects residues distant to the catalytic site, making diminished catalytic activity unlikely.

    “The exact mechanism by which the Thr92Ala SNP affects D2 function is unknown because it affects residues distant to the catalytic site, making diminished catalytic activity unlikely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A subsequent study failed to replicate our findings but was potentially underpowered-had fewer subjects on LT4 (n = 364).

    “A subsequent study failed to replicate our findings but was potentially underpowered—had fewer subjects on LT4 (n = 364) (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Wouters, 2017, No effect of the thr92Ala polymorphism of deiodinase-2 on thyroid hormone parameters, health-related quality of life, and cognitive functioning in a large population-based cohort study, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methimazole worsened these abnormalities and improved the response to LT3 + LT4.

    “Methimazole worsened these abnormalities and improved the response to LT3 + LT4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Jo, 2019, Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain, J Clin Invest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The issue of optimal treatment for hypothyroidism remains unresolved.

    “The issue of “optimal” treatment for hypothyroidism remains unresolved.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Sulfation increases solubility, targets biliary excretion and reabsorption in enterohepatic circulation.

    “Increased solubility targets biliary excretion and reabsorption in enterohepatic circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In hypothyroidism, when T3 levels are low, D1 activity is low in the liver and intestine, and more T3S excreted in the bile can be reabsorbed and desulfated to restore T3 levels.

    “In contrast, in hypothyroidism, when T3 levels are low, D1 activity is low in the liver and intestine, and more T3S excreted in the bile can be reabsorbed and desulfated to restore T3 levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    T3S replacement restores a physiological T4/T3 ratio alongside a normal TSH in 89% (n=36) of patients, compared to fewer than 45% on LT4 alone.

    “This restores a physiological T4/T3 ratio alongside a normal TSH in 89% (n = 36) of patients as compared to fewer than 45% on LT4 alone (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Santini, 2019, Treating hypothyroid patients with L-T4+T3S, Front Endocrinol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Sulfation of the hydroxyl group of T3 generates T3 sulfate (T3S), which is an inactive molecule that is naturally formed during human thyroid hormone metabolism.

    “Sulfation of the hydroxyl group of T3 generates T3 sulfate (T3S), which is an inactive molecule that is naturally formed during human thyroid hormone metabolism.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The disadvantages of a crossover design can be mitigated if a parallel-group design is adopted.

    “These effects can be mitigated if a parallel-group design is adopted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The current recommendation for measuring trough free T3 levels does not consider the previously mentioned peaks and time spent outside the reference range (ULRR), which may adversely affect patients both in the short and long term.

    “The current recommendation for measuring trough free T3 levels does not consider the previously mentioned peaks and time spent outside the reference range (ULRR), which may adversely affect patients both in the short and long term.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    T3S therapy is self-regulating, with excess levels rapidly destroyed and/or excreted, generating a very wide therapeutic index and level of safety.

    “A particularly attractive feature of T3S therapy is that, by exploiting natural physiology, it is self-regulating (as described above), with excess levels being rapidly destroyed and/or excreted, generating a very wide therapeutic index and level of safety.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    A crossover design is attractive to participants because they are certain to receive the intervention during one of the trial phases.

    “Of the various trial designs available, a crossover design is attractive to participants, as they are certain to receive the intervention/drug under investigation during one of the trial phases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PZL slows down its gut transit time and forms a "depot" for slow release of T3 which is then absorbed into the blood stream.

    “This slows down its gut transit time and in essence forms a “depot” for slow release of T3 which is then absorbed into the blood stream (63).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Da Conceicao, 2018, Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Current short-acting LT3 preparations are non-physiological and need to be administered at least two/three times per day to achieve a semblance of a physiological profile.

    “Current short-acting LT3 preparations are non-physiological and need to be administered at least two/three times per day to achieve a semblance of a physiological profile.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A trial of LT3 is recommended in dissatisfied hypothyroid patients by international specialist societies.

    “A trial of LT3 is recommended in them by international specialist societies (30, 47, 68).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Wiersinga, 2012, 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism, Eur Thyroid J source

      Not checked in the free run.

    • cites [47] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement, Thyroid source

      Not checked in the free run.

    • cites [68] Ahluwalia, 2023, Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • Rests on an assumption: LT4 monotherapy leaves a significant minority of hypothyroid patients dissatisfied because of persistent symptoms that impair quality of life.

  • May combine two claims.

    Premisecitation

    The 11-week study of T3S was uncontrolled and not designed or powered for clinical endpoints.

    “which was uncontrolled and not designed or powered for clinical endpoints (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Santini, 2019, Treating hypothyroid patients with L-T4+T3S, Front Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Orally administered T3S generates a pharmacokinetic profile in which T3S levels peak and return to baseline within 12 hours, while desulfated serum T3 levels rise and remain elevated for over 48 hours.

    “When T3S is administered orally, this system generates a favorable pharmacokinetic profile: T3S levels peak and return to baseline in 12 h, but (desulfated) serum T3 levels rise and remain high for over 48 h”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Santini, 2014, T3 concentrations for 48 hours following T3S, Endocr Pract source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There have been calls from Specialist Societies to investigate long acting LT3 in RCTs in symptomatic hypothyroid subjects on LT4.

    “There have been calls from Specialist Societies to investigate long acting LT3 in RCTs in symptomatic hypothyroid subjects on LT4 (21, 47).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Wong, 2016, A systematic review of quality of thyroid-specific health-related quality-of-life instruments recommends ThyPRO for patients with benign thyroid diseases, J Clin Epidemiol source

      Not checked in the free run.

    • cites [47] Jonklaas, 2014, Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement, Thyroid source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    A long trial may adversely affect enrolment, increase dropout rates, and increase cost.

    “However, a long trial may adversely affect enrolment, increase dropout rates, and increase cost.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Power calculations indicate that studies involving Thr92Ala homozygous subjects allow for a 3-fold smaller study, saving time and money.

    “Power calculations indicate that studies involving Thr92Ala homozygous subjects allow for a 3-fold smaller study, saving time and money.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Taken together, these elements create a self-regulating system to stabilize serum T3 levels: if T3 increases, more is sulfated and excreted via the liver and kidney, and increased D1 levels at these sites result in the irreversible destruction of T3S to inactive metabolites.

    “Taken together, these elements create a self-regulating system to stabilize serum T3 levels: if T3 increases, more is sulfated and excreted via the liver and kidney, and increased D1 levels at these sites result in the irreversible destruction of T3S to inactive metabolites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Recruiting subjects with symptoms who have the potential to respond well to combination therapy will reduce the size (and cost) of the study and increase its power.

    “Recruiting subjects with symptoms who have the potential to respond well to combination therapy will reduce the size (and cost) of the study and increase its power.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    LT3 preparations that deliver profiles mimicking normal human T3 profiles make it easier to adjust the dose and may enhance safety.

    “LT3 preparations that deliver profiles mimicking normal human T3 profiles make it easier to adjust the dose and may enhance safety.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    D1 activity is increased in hyperthyroidism and D2 activity is reduced.

    “D1 activity is increased in hyperthyroidism and D2 activity is reduced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Replacing 25 μg of T4 with 40 μg of T3S in subjects on LT4 monotherapy results in a reduction in serum free T4 without a reduction in free T3.

    “Santini et al. also showed in a continuous dosing study over 11 weeks that replacing 25 μg of T4 with 40 μg of T3S in subjects on LT4 monotherapy results in a reduction in serum free T4 without a reduction in free T3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Santini, 2019, Treating hypothyroid patients with L-T4+T3S, Front Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Crossover design has disadvantages including carryover effects, loss, and inability to analyze data if patients drop out.

    “However, “carryover” of effects of one therapy to a different phase of the study, loss, and inability to analyze data if patients drop out are disadvantages.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    T3S targets T3 for destruction by deiodinase 1 (D1).

    “This targets T3 for destruction by deiodinase 1 (D1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Even those non-homozygous for Thr92Ala have a 22% increase in symptoms and may benefit from LT3.

    “Note, however, that even those non-homozygous for Thr92Ala have a 22% increase in symptoms and may benefit from LT3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The ability to perform paired analyses in a crossover design enhances statistical power, reducing the number of patients needed and costs.

    “Furthermore, the ability to perform paired analyses enhances its statistical power, reducing the number of patients needed to be enrolled, and reducing costs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PZL is a polymeric compound of zinc and LT3 that adheres to the intestinal mucosa following oral administration.

    “PZL is a polymeric compound of zinc and LT3 that adheres to the intestinal mucosa following oral administration (61, 62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Price, 2014, Palmer S metal-coordinated pharmaceuticals, Drug Dev Delivery

      Not checked in the free run.

    • cites [62] Smart, 2005, The basics and underlying mechanisms of mucoadhesion, Adv Drug Delivery Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although theoretical evidence for the recommendation of LT3 trials is convincing, evidence for the efficacy of RCTs is limited.

    “Although the theoretical evidence for this recommendation is convincing, evidence for the efficacy of RCTs is limited.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LT4 monotherapy leaves a significant minority of hypothyroid patients dissatisfied because of persistent symptoms that impair quality of life.

  • May combine two claims.

    Interpretationnone given

    Prior RCTs of combination LT3+LT4 therapy had limitations: they were underpowered, used inappropriate outcome measures, were mainly of short duration, and used short-acting, unphysiological LT3 preparations.

    “However, some limitations of these RCTs should be addressed in future trials: they (i) were underpowered, (ii) used inappropriate outcome measures, (iii) were mainly of short duration, and (iv) used short-acting, unphysiological LT3 preparations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Subjects with the D2 polymorphism (Thr92Ala) would be ideal for trials of combination therapy because they have high symptom burden and propensity to respond better.

    “In this regard, subjects with the D2 polymorphism (Thr92Ala) would be ideal, as they fulfilled both criteria.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The D2 polymorphism (Thr92Ala) determines symptom load and a better response to LT3 + LT4 treatment.
55 of 55

  • The paper relies on this without support.

    LT4 monotherapy leaves a significant minority of hypothyroid patients dissatisfied because of persistent symptoms that impair quality of life.

    “LT4 monotherapy satisfies the majority, but a significant minority remain dissatisfied because of persistent symptoms that impair QoL.”

  • The paper relies on this without support.

    The D2 polymorphism (Thr92Ala) determines symptom load and a better response to LT3 + LT4 treatment.

    “There is a plausible biological role of the D2 polymorphism in determining symptom load and a better response to LT3 + LT4 treatment.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The designs of these trials attracted criticism because they recruited relatively unselected populations with hypothyroidism, with no reason to believe that they might have benefitted specifically from T3 supplementation, such as those with polymorphisms of deiodinases that would predict low fT3.

    “The designs of these trials attracted criticism, however, in that they recruited relatively unselected populations with hypothyroidism, with no reason to believe that they might have benefitted specifically from T3 supplementation, such as those with polymorphisms of deiodinases that would predict low fT3 3,5,23,27 .”

    From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract omits the body-weight basis of the LT4 dose

    Minor

    The abstract specifies a threshold of 1.2 μg/day, whereas the patient-selection criteria specify 1.2 μg/kg/day. These are different eligibility thresholds.

  • PZL is described as both an LT4 and an LT3 polymer

    Minor

    Table 2 expands PZL as an L-thyroxine polymer, but the text describes it as a compound of zinc and LT3.

  • Dosing-frequency counts account for only 14 of 16 trials

    Minor

    The stated counts add to 14, not the 16 trials said to have dosing-frequency information.

    Reported 16 · recomputed 14

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Watt, 2018, Measuring impact of benign thyroid diseases on quality of life
  2. Price, 2014, Palmer S metal-coordinated pharmaceuticals, Drug Dev Delivery, 14

Cited by

Sorted by citations

Related

Authors
Premawardhana, L. D., Taylor, P. N., Okosieme, O. E., Adlan, M. A., Obuobie, E. K., & Dayan, C. M.
Affiliations
  • Cardiff University (GB)
  • Royal Gwent Hospital (GB)
Corresponding author
Premawardhana, Lakdasa D.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2023-11-16
Volume
14
Pages
1282608-1282608
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2023.1282608
PMC
PMC10687631
OpenAlex
W4388728402
Semantic Scholar
901f61b4d70d8624b75428ddfa9feaf6f022686a
Cited by
6
References
66
Citations by year
2026: 1 · 2025: 2 · 2024: 3
FWCI
0.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
liothyronine, levothyroxine, combination thyroid hormone therapy, quality of life, patient-reported outcome measures, autoimmune thyroiditis, crossover design
MeSH terms
Humans, Hypothyroidism, Thyroid Hormones, Thyroxine, Triiodothyronine, Patient Selection

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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