Triiodothyronine alongside levothyroxine in the management of hypothyroidism?

Figures & data

Table 1. Overview of recommendations regarding the application of combinations of levothyroxine (LT4) + triiodothyronine (T3) in a guideline for the management of hypothyroidism issued by the European Thyroid Association²².

Who might receive LT4 + T3 combination therapy?	Consider “solely as an experimental treatment modality” for compliant patients with hypothyroid symptoms despite optimized LT4 therapy who are free of other conditions that might explain these symptoms
Genotype-guided therapy?	The possibility of genotyping for deiodinase polymorphisms in guiding therapy is discussed, but no recommendation was made
Who should definitely not receive LT4 + T3?	Pregnant women
	Patients with cardiac arrhythmias
Duration of treatment	Discontinue after 3 months if no clear benefit
Important information for patients receiving LT4 + T3	Counsel them on the experimental nature of this treatment
How to administer?	Several methods for calculating starting dosages are presented
	Start with ratio of LT4:T3 between 13:1 and 20:1
	Give LT4 once daily and T3 twice daily (before breakfast and last thing at night)
	Use separate LT4 and T3 preparations if combination tablets in the above ratios are not available
	Adjust the T3 dose before the LT4 dose if dose titration is needed for normalization of thyroid hormones (see below)
Who should administer?	LT4-T3 combination therapy should be supervised by a specialist physician with suitable experience
How to monitor?	Aim to normalize thyrotropin, FT4, FT3 and FT4:FT3 ratio
	Use a blood sample taken in the morning before the patient takes thyroid hormones

Recommendations have been paraphrased for conciseness: always consult the full guideline before prescribing.

Table 2. Randomized trials that have compared monotherapy with levothyroxine (LT4) with combinations of LT4 and triiodothyronine (T3) in patients with hypothyroidism.

Ref	Design (weeks^a)	Year^b	N^c	LT4/T3 doses (µg)/ratio^d	Précis of main findings
34	DB, PG (52)	2005	697	77/10 (8:1)	Transient improvement in some psychological function questionnaires at 3 months, which were not sustained to 12 months (primary endpoint = change in General Health Questionnaire–12 score).
35	DB, PG (15)	2005	141	75/7.5 or 15 (10:1 or 5:1)	Primary outcome: more patients preferred LT4 + T3 (41–52.2%) vs. LT4 (29%; ptrend=0.024). No differences for mood, fatigue, psychological, or neurocognitive symptoms. Weight loss was greater on the combination, and this (but not changes in TSH) correlated with patient satisfaction.
36	DB, PG (10)	2003	110	86/10 (9:1)	No benefit for LT4 + T3 on questionnaire scores/VAS measurements for cognitive function, QoL, treatment satisfaction, or most hypothyroid symptoms; more anxiety and nausea on the combination.
37	DB, XO (8)	1970	99	80/20 (4:1)	No preference for the combination, associated with more severe side effects.
38	DB, PG (16)	2009	71	104/12.5 (4:1)^e	No changes in psychosocial scores, weight, vital signs, and lipid; small but statistically significant reduction in anxiety/insomnia on the combination.
39	DB, XO (12)	2009	68	75/15 (5:1)	Significant benefit for QoL and depression scores for combination vs. LT4 alone; 49% preferred combination vs. 15% for monotherapy (p = .002).
21	DB, PG (24)	2005	58	50–100/12.5 (4–8:1)	Combination resulted in lower FT4 vs. the monotherapy group, with no difference in FT3.
40	DB, PG (16)	2003	46	86/15 (6:1)	No benefit for combination on weight, lipids, hypothyroid symptoms (health-related QoL questionnaire), or cognitive function.
41	DB, PG (15)	2003	40	67/19 (4:1)	No difference for self-reported mood or well-being from three validated questionnaire instruments.
42, 43	SB, XO (5)	1999, 2000	33	125/12.5 (10:1)	Benefit for combination on 6/17 cognitive function scales and 10/15 mood or physical status scales; no difference for blood pressure or lipids.
44	DB, XO (15)	2005	28	75/5 (15:1)	No benefit for combination for most QoL psychometric tests, or patient preference (benefit for combination on Digit Span Test). FT3 was reduced on the combination, with no change in FT3.
45	DB, XO (8)	2016	32	75/15 (5:1)	Combination therapy increased heart rate and reduced FT4 with no change in T3 vs. monotherapy; no differences for BP, lipids, weight or QoL.
46	DB, XO (6)	2005	27	71/10 (7:1)	No significant differences for fatigue, symptoms of depression, or working memory. FT4 decreased on the combination, FT3 was unchanged.
47	DB, XO (12)	2004	23	123/6.5 (19:1)	No benefit for mood and cognition scores, and little change in thyroid function indices (TSH increased) on the combination.
48	DB, XO (5)	2002	13	65/10 (7:1)	Trend to improved thyroid symptoms and mood on the combination, but no effect on cognition.

Abbreviations. Study designs (all were randomised): DB, double-blind; PG, parallel-group; SB, single-blind; XO, crossover. Other abbreviations, (F)T3, (free) triiodothyronine; (F)T4, (free) thyroxine; HR, heart rate; LT4, levothyroxine; QoL, quality of life; TSH, thyrotropin (thyroid stimulating hormone). ^aDuration of randomized treatment; ^byear of publication; ^cnumber randomized. LT4, T3 ratios are rounded to whole numbers; ^drelates to combination LT4 + T3 therapy; ^ebased on average LT4 dosage of 104 µg at baseline (12.5 µg of T3 was substituted for 50 µg of the pre-existing LT4 dose).

Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.

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