Razvi S

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 1 Cardiac Safety and Efficacy of Combination LT4 and LT3 in patients with Athyreotic 1 Hypothyroidism: Reassuring Initial Data but More is Needed. 2  3 Salman Razvi, MD 4  5  6  7 Correspondence: 8 Dr. Salman Razvi 9 Senior Lecturer and Honorary Consultant Endocrinologist 10 Translational and Clinical Research Institute 11 Newcastle University 12 Central Parkway, Newcastle upon Tyne NE1 3BZ 13 United Kingdom 14  15 Ph: +44 191 4456052 16 Email: salman.razvi@ncl.ac.uk 17  18 Word count: 1100 words 19  20 Ethics statement: No ethical review was required for this work 21  22 Data access statement: There is no original data reported in this manuscript. 23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  2 Thyroid hormones (TH) play an important role in regulating the development and function 47 of almost all tissues including the cardiovascular system (1). Levothyroxine (LT4), a synthetic 48 L form of tetraiodothyronine, has been the mainstay of treatment for hypothyroidism since 49 the 1970s when it superseded thyroid extract (2). While LT4 therapy normalizes serum TSH 50 levels in the majority of patients with primary hypothyroidism, several metabolic 51 parameters remain abnormal suggesting that tissue euthyroidism hasn’t been fully achieved 52 (3). Furthermore. some patients treated with LT4 monotherapy display evidence of impaired 53 psychological well-being and this led to trials of combination therapy with both LT4 and 54 liothyronine (LT3, the synthetic form of triiodothyronine or T3) (4).  55  56 Fourteen randomized trials have evaluated the effect of combination LT4 and LT3 to date on 57 various parameters including symptoms, quality of life and cardiovascular signs (5). A major 58 concern of clinicians with regards to combination therapy with LT4 and LT3 is the potential 59 for adverse effects with the long-term use of the active and more potent T3 on heart rate, 60 risk of supraventricular arrhythmias and high-output heart failure. A real-world 61 observational study from Scotland suggested that long-term LT3 use was not associated 62 with increased observed risk of atrial fibrillation or cardiovascular disease (6). Results from 63 previous randomized controlled trials have shown variable results. Resting heart rate was 64 increased in the combination therapy group in two trials, decreased in another two trials, 65 and no change was observed in the remaining trials in which it was assessed (5). In a 66 randomized cross-over trial of 8 women with near-total thyroidectomy for Graves’ disease, 67 combination therapy with LT4 and LT3 for 5 weeks was suggestive of an improvement in 68 diastolic function on echocardiographic assessment (7). A meta-analysis of 18 trials 69 assessing combined LT4 and LT3 therapy versus LT4 monotherapy concluded that similar 70 proportion of participants reported adverse events and reactions in both groups (8). The 71 lack of long-term outcome data, in addition to inconsistent proof of benefit, has led the 72 American and European Thyroid Associations to recommend that LT4 and LT3 combination 73 therapy should not be used routinely or only to be used as an experimental therapy in some 74 selected patients with close clinical and biochemical monitoring (9, 10). 75  76 In this issue of Thyroid, Biondi and colleagues report the results of a randomized double-77 blind placebo-controlled trial of combination LT4 and LT3 therapy compared to LT4 and 78 placebo (11). The primary objective of this trial was to assess the cardiac effects of 79 combination therapy using electrocardiography and echocardiography. Thirty-eight 80 participants with hypothyroidism due to previous thyroidectomy for low-risk thyroid cancer 81 were recruited and, of these, twenty-four participants had assessments at baseline after 6 82 and 12 months. An additional control arm of fifty euthyroid volunteers were also studied 83 once. The LT3 and placebo was provided by a pharmaceutical company in the form of 84 identical oral drops and participants were instructed to be consumed in the morning and 85 after 12 hours. All participants continued their pre-existing LT4 therapy one-hour before 86 breakfast. Thyroid function and metabolic parameters were assessed at baseline, 3, 8 and 87 12 months of therapy. The main investigator was aware of thyroid function test results and 88 adjusted the dose of the LT4 to achieve an LT4:LT3 ratio of 17:1. Subsequently, doses of 89 both LT4 and LT3 were further adjusted at 3 and 6 months to aim for a serum TSH level 90 within the reference range and FT4 and FT3 concentrations in the middle of their respective 91 reference ranges. The electrocardiographic and echocardiographic examinations were 92  3 performed by two cardiologists who were unaware of participants’ allocated treatment 93 group.  94  95 Participants allocated to the combined LT4 and LT3 group demonstrated a significant 96 increase in serum FT3 levels and diastolic function at 12 months, as evaluated by a 97 reduction in E/e’ ratio on Doppler echocardiography. The improved E/e’ ratio after 12 98 months of LT4 and LT3 therapy was similar to the ratio observed in the euthyroid control 99 group. There were no significant differences observed in body weight, systolic and diastolic 100 blood pressure values, total and LDL-cholesterol or heart rate between the combination 101 therapy or LT4 and placebo group after 12 months. Furthermore, no serious adverse events 102 including arrhythmias were reported during the duration of the trial.   103  104 Does this trial allay concerns about the safety of combination LT4 and LT3 therapy in 105 patients with hypothyroidism? Before this question is answered, it is important to highlight 106 the strengths and limitations of this trial. It was rigorously conducted and is the first trial to 107 have assessed effect of combined LT4 and LT3 on cardiac parameters over 12 months. In 108 addition, the doses of both LT4 and LT3 were adjusted at regular intervals to aim for thyroid 109 function within the reference range. Also, a group of matched euthyroid volunteers 110 provided control data against which cardiac and metabolic parameters could be compared 111 against. However, this trial has several limitations with the most important being the lack of 112 a priori sample size estimation. The number of participants providing data at both baseline 113 and at 12 months was relatively small (14 in the combination and 10 in the LT4 and placebo 114 groups, respectively), predominantly due to recruitment difficulties as a consequence of the 115 COVID-19 pandemic. The other limitation is that this trial was conducted in a highly selected 116 group: young to middle-aged (18-55 years) and relatively healthy (on no other medication 117 except LT4) athyreotic patients due to previous thyroid surgery. Therefore, the results 118 obtained may not be generalizable to the majority of patients with hypothyroidism. Finally, 119 the clinical relevance of a statistical improvement in E/e’ ratio is unclear. An E/e’ ratio of <8 120 is considered to be normal, a ratio >15 is considered to be indicative of increased left 121 ventricular filling pressure (diastolic dysfunction) and values between 8 and 15 may indicate 122 possible diastolic dysfunction. Furthermore, using the E/e’ ratio alone may not provide a 123 complete assessment of diastolic function (12). This trial provides data regarding safety of 124 combination therapy that supports other trials of T3 alone in high-risk cardiac patients (13). 125  126 Should the results of this trial change clinical practice? This trial mainly provides reassurance 127 that combination therapy with LT4 and LT3 is safe over 12 months in younger patients 128 without increased cardiovascular risk. This trial also provides preliminary evidence that 129 combination therapy could improve some echocardiographic markers of diastolic function. 130 Trials in larger group of patients with diverse characteristics including older patients, those 131 with hypothyroidism due to other causes, those with comorbidities, and patients with 132 known diastolic dysfunction are needed to confirm these findings. Until this time clinicians 133 managing patients on combination LT4 and LT3 should continue to monitor for any adverse 134 clinical effects. 135  136  137 Author Contribution: The author confirms sole responsibility for the writing of this 138 manuscript. 139  4 Disclosure statements: Dr. Razvi has received speaker fees from Merck KGaA, IBSA Institut 140 Biochimique SA, and Abbott Pharmaceuticals Ltd. 141  142 Funding statement: No funding related to this work to declare.  143  144 References: 145  146 1. Jabbar A, Pingitore A, Pearce SH, et al. Thyroid hormones and cardiovascular disease. 147 Nat Rev Cardiol 2017;14:39-55. 148 2. McAninch EA, Bianco AC. The history and future of treatment of hypothyroidism. 149 Ann Intern Med 2016;164:50-56. 150 3. McAninch EA, Rajan KB, Miller CH, et al. Systematic thyroid hormone status during 151 levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis. J 152 Clin Endocrinol Metab 2018;103:4533-4542. 153 4. Saravanan P, Chau W-F, Roberts N, et al. Psychological well-being in patients on 154 ‘adequate’ doses of l-thyroxine” results of a large, controlled community-based 155 questionnaire study. Clin Endocrinol 2002;57:577-585. 156 5. Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-based use of 157 levothyroxine/liothyronine combinations in treating hypothyroidism: a consensus 158 document. Thyroid 2021;31:156-182. 159 6. Leese GP, Soto-Pedro E, Donnelly L. Liothyronine use in a 17 year observational 160 population-based study – the tears study. Clin Endocrinol 2016;85:918-925. 161 7. Bunevicius R, Jakuboniene N, Jurkevicius R, et al. Thyroxine vs thyroxine plus 162 triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ 163 disease. Endocrine 2002;18:129-133. 164 8. Millan-Alanis JM, Gonzalez-Gonzalez JG, Flores-Rodriguez A, et al. Benefits and 165 harms of Levothyroxine/L-triiodothyronine versus levothyroxine monotherapy for 166 adult patients with hypothyroidism: systematic review and meta-analysis. Thyroid 167 2021;31:1613-1625. 168 9. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of 169 hypothyroidism: prepared by the American thyroid association task force on thyroid 170 hormone replacement. Thyroid 2014;24:1670-1751. 171 10. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: the use of L-T4+L-T3 172 in the treatment of hypothyroidism. Eur Thyroid J 2012;1:55-71. 173 11. Biondi B, Pucci M, Pontieri G, et al. Preliminary results of a double-blind randomized 174 controlled trial evaluating the cardio-metabolic effects of levothyroxine and 175 liothyronine compared to levothyroxine with placebo in athyreotic low risk thyroid 176 cancer patients. Thyroid 2023. doi: 10.1089/thy.2023.0135. 177 12. Sunderji I, Singh V, Fraser AG. When does the E/e’ index not work? The pitfalls of 178 oversimplifying diastolic function. Echocardiography 2020;37:1897-1907. 179 13. Tharmapoopathy M, Thavarajah A, Kenny RPW, et al. Efficacy and safety of 180 triiodothyronine treatment in cardiac surgery or cardiovascular diseases: a 181 systematic review and meta-analysis of randomized controlled trials. Thyroid 182 2022;32:879-896. 183 

Cardiac Safety and Efficacy of Combination Levothyroxine and L-Triiodothyronine in Patients with Athyreotic Hypothyroidism: Reassuring Initial Data but More Is Needed

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Cardiac Safety and Efficacy of Combination Levothyroxine and L-Triiodothyronine in Patients with Athyreotic Hypothyroidism: Reassuring Initial Data but More Is Needed

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