Comparative Effectiveness of Levothyroxine, Des... - Thyroid UK

Thyroid UK

137,137 members160,818 posts

Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism

helvella profile image
helvellaAdministratorThyroid UK
15 Replies

Another interesting paper (and letters), supporting use of T3 - both synthetic and as desiccated thyroid.

J Clin Endocrinol Metab.2021 Nov; 106(11): e4400–e4413.

Published online 2021 Jun 29. doi: 10.1210/clinem/dgab478

PMCID: PMC8530721

PMID: 34185829

Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism

Mohamed K M Shakir,1,2 Daniel I Brooks,1 Elizabeth A McAninch,3 Tatiana L Fonseca,4 Vinh Q Mai,1,2 Antonio C Bianco,4 and Thanh D Hoang1,2

Author information Article notes Copyright and License information Disclaimer

Associated Data

Data Availability Statement

Go to:

Abstract

Introduction

Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.

Methodology

Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.

Results

Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component).

Conclusions

As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.

Paper freely accessible here:

ncbi.nlm.nih.gov/labs/pmc/a...

The paper then received a letter as response. Unfortunately, I have no access to the letter - if you follow the link, it offers it as a PDF but I am denied access. If anyone does have access, even just to read, please let us know what the letter said.

“Letter to the editor from Steen Joop Bonnema et al: (Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism)”

Steen Joop Bonnema, Kamilla Ryom Riis, Christian Zinck Jensen, Marianne Thvilum, Birte Nygaard

The Journal of Clinical Endocrinology & Metabolism, dgab778, doi.org/10.1210/clinem/dgab778

academic.oup.com/jcem/advan...

That letter then received a response from the authors of the paper! And this response letter is accessible - you can download a PDF.

Unfortunately, that rather leaves us guessing what the first letter said.

Response to Letter to the Editor from Steen Joop Bonnema: (Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism)”

Mohamed K M Shakir, Daniel I Brooks, Elizabeth A McAninch, Tatiana De Lourdes Fonseca, Vinh Q Mai, Antonio C Bianco, Thanh D Hoang

The Journal of Clinical Endocrinology & Metabolism, dgab779, doi.org/10.1210/clinem/dgab779

Dear Editor,

We thank Bonnema et al1 for giving us the opportunity to provide further details on our recent publication2 while addressing their insightful questions.

1. In reference to the consequences of long-term treatment with LT3, we respectfully point out that there is now solid data that LT3 does not increase the frequency of adverse reactions if serum TSH levels are maintained within the normal range. For example, an observational study during 1997-20143 that compared nearly 34,000 patients taking only LT4 with those using LT4+LT3 (n = 327) or LT3 alone (n = 73) during a mean follow-up of 9.3 years (SD 5.6) and a maximum follow-up of 17.3 years. The study did not reveal higher mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures. In addition, an analysis of 20 clinical trials that included almost 1,000 patients observed for up to 1 year indicated that peaks of serum T3 observed after the LT3 tablets only minimally affected serum TSH, heart rate, and blood pressure; the frequency of adverse reactions was similar to patients taking LT44. Bone turnover markers were studied in two trials, and they remained within normal range. This was confirmed in a recent meta-analysis by Millan-Alanis et al5 in which 18 clinical trials comparing LT4 vs LT4+LT3 therapy were evaluated found no differences in adverse events. In fact, we are unaware that combination therapy containing LT3 has ever been associated with increased occurrence of adverse reactions in patients maintaining normal TSH levels.

2. In reference to a potential placebo effect associated with “entering a trial”, we found that 20 patients comprised the subgroup with the worst outcomes while on LT4 therapy and these patients were randomly distributed across the 3 treatment arms. 7 patients received LT4 on Arm-1 and 9 patients received LT4 on Arm-2. Thus, it is unlikely that a placebo effect played a role.

3. Baseline values were considered in the analyses. As stated under methods, differences between treatments were evaluated using mixed effects models. The primary outcome model included a fixed effect for treatment and a random effect of subject. Models were run with and without the inclusion of baseline scores to isolate between treatment differences. In the sub-analysis we also considered the baseline values but were not able to detect differences between baseline and LT4-treated arm.

4. In reference to a subgroup analysis of patients on DTE or LT4+LT3 prior to the trial, we found that there were 8 patients on DTE and 3 patients on LT4/LT3 at baseline. At the end of the study, out of these 11 patients, 6 preferred DTE and 5 preferred LT4/LT3 combination. This suggests that a placebo effect could not explain our findings. An appropriately powered study could address this point further. Of note, a preference for DTE had already been identified in our previous study6. It has been our experience that most patients taking DTE show strong preference for continuing on DTE rather than switching to LT4.

academic.oup.com/jcem/advan...

There was another relevant recent thread:

healthunlocked.com/thyroidu...

And this post about a highly relevant paper from some of the same people nine years ago:

Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study.

healthunlocked.com/thyroidu....

Written by
helvella profile image
helvella
Administrator
To view profiles and participate in discussions please or .
Read more about...
15 Replies
BB001 profile image
BB001

Thank you Helvella interesting as always. It's a shame the researchers are fixated on 'maintaining normal TSH levels' instead of focusing on the levels of the actual hormones T3 and t4.

helvella profile image
helvellaAdministratorThyroid UK in reply to BB001

It is, I very much agree.

However, the observation that there is strong preference despite that possibly makes it less easy to dismiss - by those who would otherwise point their fingers at over-medication and suppressed TSH, etc.

Zephyrbear profile image
Zephyrbear in reply to helvella

I’d like to know whether anyone out there taking T3 has a TSH within the “normal” range as mine has been suppressed at 0.01 ever since I was prescribed it over 10 years ago! When are these people going to let go of the TSH obsession? I have never had AF and my DEXA scans consistently come back with no evidence of osteoporosis…

BB001 profile image
BB001 in reply to Zephyrbear

Same here. No afib, no signs of over medication. DEXA scans good despite being dosed on levo so slightly above range for years. I'm now on T3.

BB001 profile image
BB001

It is though heartening that they used tests other than blood tests to measure effectiveness.

tattybogle profile image
tattybogle

here a letter Steen Joop Bonnema wrote to another editor in 2019 :findresearcher.sdu.dk:8443/...

methinks the currently inaccessible letter probably said . " T3 is dangerous , and your results are placebo "

helvella profile image
helvellaAdministratorThyroid UK in reply to tattybogle

Includes this sentence:

The majority of doctors treat hypothyroidism with well-established drugs such as levothyroxine

The well-establishedness (did I really write that?) of levothyroxine is very largely irrelevant. Except inasmuch it makes its use uncontroversial and "safe" for the prescriber. Proven efficacy is more important by far.

The lack of the randomised controlled trials that should have been required when levothyroxine was introduced, but were not done, undermine all claims of a comparative nature. A mantra of "levothyroxine is all you need" is as unscientific and unfounded as any other claim based on what amounts to anecdotal evidence. (With the exceptions of a few more recent papers which have look into the issues.)

Tythrop profile image
Tythrop in reply to helvella

It's always the costs that controll the Establishment.I bet if someone started making good t3 and giving it free to NHS they would change their protocol.

helvella profile image
helvellaAdministratorThyroid UK in reply to Tythrop

I think the negativity about T3 is so embedded, they could offer to pay the NHS to accept T3 and it still wouldn't result in change of protocol for a long time.

Tythrop profile image
Tythrop in reply to helvella

I'm thinking that the last thing the NHS establishment wants is uncontrvertable proof that t3 is the good stuff (as you and others have been saying for years) because that might open the flood gates to malpractice claims . ???

wellness1 profile image
wellness1 in reply to helvella

The lack of the randomised controlled trials that should have been required when levothyroxine was introduced, but were not done

Really?! I certainly don't doubt you, but wonder how I have missed this surprising bit of information. I guess this slipped by whatever regulatory/licensing agencies were in place at the time.

helvella profile image
helvellaAdministratorThyroid UK in reply to wellness1

Partly, it was another era in which RCTs were not required and looked at in the same way as now.

Pre-thalidomide (that was withdrawn across Europe in 1961 - levothyroxine became available in the 1950s), formal trials were not as they later became.

So far as I am aware, there was not one single (published) trial to compare desiccated thyroid and levothyroxine.

Even had there been such trials, the potency of desiccated thyroid was measured on the basis of protein-bound iodine - an unsatisfactory measure.

wellness1 profile image
wellness1 in reply to helvella

That all makes sense and I wouldn't doubt the keeper of the Vade Mecum. It is a bit rich though, the way 'lack of clinical trials' is leveled against other treatment approaches.

helvella profile image
helvellaAdministratorThyroid UK in reply to wellness1

Complete agreement.

I suspect at least thousands of thyroid patients have levelled that criticism at professionals.

helvella profile image
helvellaAdministratorThyroid UK

Unless I have missed it, they appear to have managed to avoid referencing diogenes and his associates.

You may also like...

Desiccated thyroid extract vs Levothyroxine in the treatment of hypothyroidism

American Thyroid Association HYPOTHYROIDISM Desiccated thyroid extract vs Levothyroxine in the...

Desiccated thyroid v Levothyroxine

com/blogs/919261/desiccated-thyroid-extract-compared-with-levothyroxine-in-the-treatment-of-hypothyr

Avoid prescribing desiccated (natural) thyroid extract

assertions. Avoid prescribing desiccated (natural) thyroid extract Published 20...

A couple of new papers of interest

significant preference for any treatment, numerically more patients with Hashimoto’s preferred DTE...

Support The Use of Natural Desiccated Thyroid

Armour Thyroid from Levothyroxine Improved Patient Satisfaction in the Treatment of Hypothyroidism,...