RANDOMIZED CONTROLLED TRIAL EVALUATING THE CARDIO-METABOLIC EFFECTS OF LEVOTHYROXINE AND LIOTHYRONINE

[helvella]

An interesting preprint paper re liothyronine.

(Apologies for SHOUTING - using capitals - but I usually try to copy exactly.)

Thyroid. 2023 Sep 19.

doi: 10.1089/thy.2023.0135. Online ahead of print.

PRELIMINARY RESULTS OF A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL EVALUATING THE CARDIO-METABOLIC EFFECTS OF LEVOTHYROXINE AND LIOTHYRONINE COMPARED TO LEVOTHYROXINE WITH PLACEBO IN ATHYREOTIC LOW RISK THYROID CANCER PATIENTS

Bernadette Biondi MD 1 2 , Martina Pucci 3 , Gilda Pontieri 4 , Pietro Formisano 5 , Roberta Esposito 6

PMID: 37725587 DOI: 10.1089/thy.2023.0135

Abstract

Background: Evidence is needed on the risks and benefits of combination therapy with Levothyroxine (LT4) + Liothyronine (LT3) for treatment of hypothyroidism.

Objective and methods: We performed a randomized double-blind placebo-controlled study to assess the effects of LT4 + LT3 therapy vs LT4 + placebo in a homogenous group of athyreotic patients, without cardiovascular risk factors during long-term replacement monotherapy with LT4. The primary objective of the study was to assess the effects of combination LT4 + LT3 therapy on heart rate, cardiac rhythm and sensitive cardiovascular parameters of cardiac morphology and function by means of electrocardiography and Doppler echocardiography. The secondary objective of the study was to evaluate patient compliance, tolerability, and potential adverse events.

Results: Thirty-eight patients with post-surgical hypothyroidism satisfying the inclusion criteria were selected form a group of three hundred patients with low-risk thyroid cancer followed for a routine follow-up; they were randomized to receive LT4 + LT3 or LT4 + placebo. Twenty-four patients were evaluated after one year of treatment. All clinical and laboratory parameters were compared to the results obtained in fifty healthy euthyroid volunteers without comorbidities, matched for gender, age, physical activity and lifestyle. Participants and clinicians remained blinded to the treatment allocation. After one year of combination therapy, a significant improvement in the diastolic function, evidenced by a significant reduction in the E/e' ratio (p =0.046) and its positive trend over time, was observed in the LT4 + LT3 group vs. the LT4 + placebo group. In addition, the univariate analyses showed a significant relationship between F-T3 levels (pg/ml) with Δ of variation of E/e' ratio in LT4 + LT3 group. (Standardized ß coefficient = 0.603 (CI 95%: 0.001 - 1.248), p-value = 0.050) after combination therapy. No adverse events including tachycardia, arrhythmias, atrial fibrillation, or other important events occurred between the first administration and the end of the study.

Conclusion: In this preliminary report, combination treatment with LT4 + LT3 induced favorable changes in cardiovascular parameters of diastolic function without any adverse cardiovascular events.

Trial registration: EUDRACT n: 2017-001261-25

As so often, the rest of the paper is behind an insurmountable paywall:

pubmed.ncbi.nlm.nih.gov/377...

[Hidden]

I fit all the criteria for this study -post surgical hypothyroidism / thyroid cancer. Im not surprised at the outcome.

They should go further and do another study which shows the negative effects of Levothyroxine only on cardio metabolic systems in such subjects

A pity they didn’t have a control group

So it’s all true!! We poor souls can’t cope without T3.

What happens to all these studies? Do they ever inform practice? Or will they continue to waste three years of our lives trying to prove that we’ll die if we have T3 before they scrape us up from the floor and start again?

[helvella in reply to Hidden]

They did have a control group - on LT4 + placebo.

Obviously lots more work to be done. But 'tis a good start. (After 60+ years of not starting this research.)

[Hidden in reply to helvella]

Sorry. Missed the control group. Must read more carefully!

[Mollyfan in reply to Hidden]

They had a T4 plus placebo group which is effectively T4 only. They did less well!

[JGBH]

Thank you for the link… So it looks like it is safe to have a combination Levothyroxine and Liothyronine after all! I wonder if any endocrinologist/cardiologist will now try to refute this….

[helvella in reply to JGBH]

Beyond safe. Positively favourable!!!!!

[JGBH in reply to helvella]

Hourra! At long last! You’ve made my day…

[Hidden in reply to helvella]

But only for those who are surgically hypothyroid following cancer.

It’s a start but don’t get too excited yet 😉

[amala57 in reply to Hidden]

What about hypothyroid following RAI or surgery for graves?

[Hidden in reply to amala57]

Can’t say as sadly that doesn’t fit the study criteria.

As far as I’m concerned though, no thyroid is hell - whatever the reason for its removal

[redhead41 in reply to Hidden]

You don't have to have it removed to have no thyroid gland. After 30 years of being under treated, the thyroid gland had completely atrophied so that there was not even a tiny remnant left.

[Hidden in reply to redhead41]

Agree entirely. I’m referring to the narrow terms of reference of this particular study.

[SlowDragon Administrator]

Brilliant research and results though 😀

NIKEGIRL take a look

[Mollyfan]

Has anyone read the full trial? I am wondering how they chose the T4/T3 doses, especially if it was double blind. Was it on TSH? Were the groups comparable? As always we are left wondering!

[SilverAvocado]

The outcome measure they look at in this study makes me curious!

I have dabbled a tiny bit in trying to figure out typical hypothyroid markers in an ECG. In the end it for too confusing and I gave up, but definitely got the compression there is loads of information in an ECG, and of course most of the time they only get an extremely cursory analysis.

I suspect there are many many common medical tests which can give indications of how well our metabolism is working, which could work out as (semi) objective measures of how symptomatic we are with hypothyroid. And indicators in an ECG is a prime example of that.

It would be so great to be knowledgeable enough to use these measures as part of the picture in dose adjustment.

[stiltzski]

This is hood news but more & larger trials are needed & will these results filter down, I wonder?

[Hidden in reply to stiltzski]

I think this study is too small. It’s not likely to be a great influencer

[helvella in reply to Hidden]

Obviously far too small.

But will likely be used to help justify funding a larger T3 study.

From outside, it appears that many endocrinologists are less confident in T4-only, and for everyone, than they used to be. While continuing to practice precisely that.

[Hidden in reply to helvella]

I hope it justifies funding for a larger trial

I think endocrinologists are far more aware of the need for combination T3/T4 dosing in some patients. That said, their practice of monotherapy continues because they are pulled into the politics of funding at so many levels.

[Topsy33 in reply to Hidden]

Yes, possibly but in a small group the results they reported would be less likely so drawing on that, there is a good chance that a larger study replicating the methodology would show a definitive advantage to combination treatment.

[Hidden in reply to Topsy33]

I very much hope so.

What is not understood is that once athyreotic patients have had their bodies crucified by unsuccessful attempts at mono therapy, there is no going back even after T3 in some form has been introduced.

[helvella in reply to Hidden]

This trial appears to be being presented as a breakthrough. A "Wow!" moment.

Provided it isn't destroyed by critics, it could demolish the "No trial has ever ..." statements. Forever.

You actually only need one single valid trial to break through that barrier.

Obviously, the unconvinced will ignore it, and dredge up other statements.

Eratosthenes of Cyrene both demonstrated that the world is round and measured it fairly accurately. But that has not stopped many claiming otherwise in the two millennia and more since.

[Hidden in reply to helvella]

Very true

[Hidden in reply to helvella]

Thank you for confirming that the world is round 😉

I seem to get the feeling that I’m falling off it. 🙈

[TaraJR in reply to Hidden]

Love this!

[waveylines]

Ah ha! Are they daring to say that the combo group fared better than the god of levo only! Oh wow......stunning!!

I really hope this is the start of u turn we have been hoping for and the big bad wolf T3 will eventually be allowed into play..... & who knows the scary NDT monster will no longer be banned from even consideration. 🤣. 😍🥲😍 I pray this is the very beginnings of the reinvention of the greatness and goodness of combination thyroid hormone therapy back into mainstream....allowing for another 20yrs of cogitation!! T3 only may still be a step too far for the slowness of Endocrinology is far far slower than the time it takes to be optimally treated. I'll probably not be around to witness the rebirth! But will celebrate the pin point on the horizon.

[Delilahmy]

Is there a study that includes T1 and calcitonin - the other components

there is a thyroid hormone called T1 (thyronine). However, T1 is not as well-studied or well-understood as T4 and T3. It is a metabolite of T4 and is produced in small amounts in the body. The exact role and significance of T1 in thyroid function and health are still being researched. Currently, T1 is not routinely measured or used in clinical practice for diagnosing or treating thyroid disorders. The focus is primarily on T4, T3, and reverse T3. It's important to consult with a healthcare professional for a comprehensive evaluation and interpretation of your thyroid hormone levels.

What are the total chemical components of hormones produced from the thyroid gland?

The thyroid gland produces several hormones, including:

1. Thyroxine (T4): This is the main hormone produced by the thyroid gland. It contains four iodine atoms and is relatively inactive. T4 is converted into the more active T3 hormone in various tissues throughout the body.

2. Triiodothyronine (T3): T3 is the active form of thyroid hormone. It contains three iodine atoms and is responsible for regulating metabolism, growth, and development in the body.

3. Calcitonin: Calcitonin is a hormone involved in regulating calcium levels in the body. It helps to decrease blood calcium levels by inhibiting the release of calcium from bones and promoting its excretion by the kidneys.

These are the primary hormones produced by the thyroid gland. However, it's important to note that the thyroid gland also produces small amounts of other thyroid hormones, such as reverse T3 (rT3) and T1 (thyronine), although their roles and significance are not as well understood.

Just feel a bit like this rabbit hole keeps getting bigger - there seems to be lots of aspects that are not regarded and measured.

No wonder we mostly feel under medicated and ill

Hugs to all

[Rileyfloof in reply to Delilahmy]

I had to laugh when I read rT3 role and significance is not as well understood. Not by mainstream docs, for sure. But good integrative or functional medicine doctors understand it, and those of us who can't convert T4 to T3 properly intimately and severely know its importance!

There's also a T2 thyroid hormone. I took it as a compounded medication for a little while until it became unavailable. Now you can only buy it in supplement form. It allowed me to take a lower dose of T3 without feeling negative affects.

[Delilahmy in reply to Rileyfloof]

This is what I have found on t2

Hello! I'm an AI language model, and I'd be happy to provide you with some facts about the thyroid hormone T2.

1. Triiodothyronine (T3) and thyroxine (T4) are the primary thyroid hormones, but there is also a lesser-known hormone called T2, or diiodothyronine.

2. T2 is derived from the conversion of T3 in peripheral tissues, such as the liver and kidneys.

3. T2 is considered an active thyroid hormone, although its effects are not as well understood as T3 and T4.

4. T2 has been found to have metabolic effects, including increasing energy expenditure and promoting fat breakdown.

5. Some studies suggest that T2 may have a role in regulating body weight and metabolism, potentially offering therapeutic benefits for obesity and metabolic disorders.

6. T2 has been shown to influence mitochondrial function, which plays a crucial role in cellular energy production.

7. Research on T2 is still ongoing, and its exact mechanisms of action and clinical applications are not yet fully understood.

8. T2 levels are typically lower than T3 and T4 in the body, and its measurement is not commonly included in routine thyroid function tests.

9. T2 is being investigated as a potential treatment for certain conditions, such as obesity, insulin resistance, and fatty liver disease, but more research is needed to determine its safety and efficacy.

It's important to note that while T2 shows promise in certain areas of research, it is not currently widely used in clinical practice.

My question is why aren’t all the compounds given even if separately.

Whatever the thyroid excretes we surely should be considering replacing all that we don’t /can’t produce in our own thyroid

As I said it’s rabbit hole / minefield

Thanks for your reply

[helvella in reply to Delilahmy]

Point 1 - There are many more metabolites. My vade mecum has a section on a large number of other thyroid hormones and metabolites under "Thyroid Hormones".

Point 2 - T2 is likely created inside every cell that takes in T3. The "such as the liver and kidneys" phrase does the same disservice as pretty much the same claim with respect to converting T4 to T3. It focuses on one location and ignores a far bigger, more complex and massively more nuanced picture in the real body. That focus misses the extremely important conversion of T4 to T3 within the brain.

Point 8 - it would be very surprising if there weren't less T2 than T4 (and likely less than T3 as well). Unless T2 just sat there and accumulated, the amount present would obviously not be more than the amount of T4 available to convert to T2 (in two steps). And "less" in this sort of situation could be based on molar quantities or mass. T2 is much lighter molecule than T4. And no, T2 is NEVER measured in a routine thyroid function tests. There is no satisfactory T2 test so there is no possibility of it being routine - any testing is a research procedure.

We do not give all the compounds individually for several reasons. Cost. Claimed belief that every other form is converted from T4 - albeit in several steps. Thus if there is sufficient T4 there will inherently be sufficient of all the rest. Lack of available options. Would side step the controls the body has on the other hormones. Difficulty delivering to the required locations without excess ending up elsewhere. Difficulty in determining doses.

helvella's Vade Mecum document is available here:

helvella - Vade Mecum for Thyroid

The term vade mecum means:

1. A referential book such as a handbook or manual.

2. A useful object, constantly carried on one’s person.

helvella.blogspot.com/p/hel...

[Hidden in reply to helvella]

I believe that calcitonin contributes to maintenance/adjustment of calcium levels but it only has a minor role.

Parathyroid hormones are the main workhorse in this.

Unless you have severe osteoporosis or hyerparathyroidism I don’t think you need to worry about it.

pubmed.ncbi.nlm.nih.gov/145...

[Delilahmy in reply to helvella]

Thankyou Helvella ….

[Delilahmy]

Hi Helvella I wonder why the test numbers are so small - albeit a the test is favourable for t3 (great news) considering the number of us with hypothyroid problems must run into the millions … it would be great to have bigger studies … but great article.

[helvella in reply to Delilahmy]

It is very common for a small trial to be run which firstly helps firm up understanding. Secondly, experiences of the first trial are used adjust trial design for another trial. Third, helps justify the running of a larger and inherently more costly trial with larger numbers.

In this specific case, it might help to inform other cardiac medics. (Though we have sometimes seen them more aware of T3 than some endocrinologists.)

[bikebabe]

Oh that's so interesting Helvella. Thank you for posting.

[waveylines]

Fascinating Helvella. Thank you! Who would've thought that T2 would be looked at!! It was dismissed as a pointless by product a few years back.... There are so many mechanisms that can go wrong in the production/ processing of thyroid hormones maybe as research progresses they will discover that the process of conversion to T2, can fail or be reduced just as it can occur with T4 to T3.I expect the current focus is probably based on the specialism of that research group and the funding source. It's a start though..... 🤞🤞

[helvella in reply to waveylines]

I have no problem in considering T2.

But am still unpersuaded that a few molecules in a desiccated thyroid product is significant. (Though I could be wrong!)

If most T2 is produced within cells from T3 and rT3, then measuring it directly will be very difficult.

[waveylines in reply to helvella]

Very good points Helvella. I know youre not against T2 products. 😊 I was wondering how they test for T2 at cellular level too..... Lol.

[helvella in reply to waveylines]

I have several times suggested that there might be numerous things we can measure which identify issues. For example, slowed reflexes in hypothyroidism. No chemistry required! And SpO2 devices for oxygen saturation in general medicine. No chemistry required!

I don't think I am at all unusual in looking back to Star Trek and the "Tricorder" medical measuring device. And wondering how far we can get in that direction - using non-invasive techniques from which we can infer how our bodies are working.

[Annib1 in reply to helvella]

The Global Healthy Living Foundation and Arthritis Power recently conducted a study (The Wear Study) on progression of rheumatoid arthritis in patients by comparing what patients reported, what their doctors reported and what their smart watches reported. Apparently there was remarkable agreement. I suppose the huge difference with thyroid disease is that doctors are not in agreement with patients or with other doctors as to which symptoms presented by patients can be attributed to thyroid disease.

[waveylines]

I remember that device. I used to think.... Wow.... how amazing.I agree..... They do need to widen assessment beyong blood tests. It's lazy doctoring in my book.... Lol.

[Hashiboy]

Ooh thanks for that helvella always good to have data for anytime I am seen by a professional who thinks those of us on T3 are on a fast track to Afib.

[helvella in reply to Hashiboy]

I do not take any T3 - and have continuous afib!

[thyr01d]

Thanks Helvella very much for this post, it's great news, and 'bah humbug' to those who are being negative!!! It's a move in the right direction.

[jimh111]

Interesting, when it appears in print form it may have free access. I don't understand the details but it seems to show a small benefit for combination therapy. More importantly studies tend to show cardiac risks increase with fT4.

[TaraJR in reply to jimh111]

Have you gained free access to the print version ? If so, how did you manage it?

[jimh111 in reply to TaraJR]

When it appears in print it may have free access!