Why the Hesitancy in Recommending Combination T3/T4 Therapy?

Kaniksha Desai, MD; Antonio Bianco, MD, PhD


May 25, 2023

Editorial Collaboration

Medscape &

This transcript has been edited for clarity.

Kaniksha Desai, MD: Welcome to the Thyroid Stimulating Podcast, created in partnership with the American Thyroid Association. Our goal is to discuss up-to-date diagnosis and management of a wide array of thyroid diseases.

Today, we'll discuss hypothyroidism and its treatment. Hypothyroidism is a common condition present in almost 5% of the population, so it's likely that most doctors will have treated someone with hypothyroidism.

I have the pleasure of talking with Dr Antonio Bianco about treating hypothyroidism. Dr Bianco is an internationally recognized expert in the field of thyroidology and a past president of the American Thyroid Association. His clinical practice focuses on the treatment of hypothyroidism. He has authored over 240 peer-reviewed journal articles and recently published the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do, which we'll talk about.

Dr Bianco joins us from the University of Chicago, where he's currently a professor of medicine. Thank you so much for joining me today, Dr Bianco. It's a great honor to have you.

Antonio Bianco, MD, PhD: Thank you for having me.

Desai: I wanted to start by asking you about your journey in medicine. What inspired you to become a physician scientist, and how did you enter the field of thyroidology?

Bianco: I wanted to be a scientist since my early childhood. I have an older brother who is a doctor. We used to play scientists at home. I went to medical school because my brother thought I would be a better scientist if I went to medical school as opposed to having a PhD in biology or in a basic science area.

I fell in love with patients and with clinical practice. Early on in medical school, I worked in the Department of Physiology, where my first mentor worked with the thyroid gland. Back in 1978, I had the pleasure of working with Dr Douglas in São Paulo, and we started on the thyroid journey.

Desai: Thank you for sharing that. I also wanted to congratulate you on your recent book, which has received wonderful reviews. I've personally had the opportunity to read it.

In your book, you discuss how hypothyroidism was initially treated with animal extract containing T4 and T3 combination; then the medical community rapidly changed to treating with levothyroxine, which is T4 treatment only. Can you comment on how we got where we are today and how this change has affected patients with hypothyroidism?

Bianco: As you know, since the understanding that hypothyroidism existed as a clinical syndrome, we started giving animal thyroid extract for patients. For the better part of the 20th century, patients were treated with desiccated thyroid extract until around 1970, when people understood the seminal work by Dr Braverman, Dr Ingbar, and Dr Sterling, showing that T4 got converted to T3 inside our bodies.

We didn't know that. The interesting thing is that back in the 1950s, there was an idea that T4 could be converted to T3. However, that idea was abandoned. There was a publication, then the paper was retracted, and it was then rediscovered by Dr Braverman in the 1970s.

People did not like desiccated thyroid extract very much because its potency was inconsistent. Different brands had different potency, and even within the same brand, different batches could have different potency. That is because, in the thyroid, the amount of T4 and T3 fluctuates by season and by the amount of iodine we eat. Understandably, they were taking thyroids from different animals in different places in the country and making thyroid extract of different potency. Doctors didn't like that much, but it was effective, so they had experience using it.

With the discovery in 1970 that T4 was converted to T3, doctors said, "Well, wait a minute, we don't actually have to have to use this desiccated thyroid extract anymore. We'll just give T4, which has a very long half-life and will provide a steady level of T3 in the circulation, and we know exactly how much we're giving because this is synthetic and it's advantageous over that treatment with desiccated thyroid extract." It took about 10 years, and then people completely forgot about the desiccated thyroid extract.

When I was in medical school, I learned about these things. They said, "What, desiccated thyroid extract? What is that?” We couldn't conceive of the idea that someone could treat a patient with hypothyroidism with desiccated thyroid extract. I never learned what desiccated thyroid extract was in medical school or during my clinical training. We were just told to use levothyroxine because it's great. And you know what? It is great. It resolves the problems for most patients with hypothyroidism.

During that time, there was noise brewing in the background. Some patients who were switched from desiccated thyroid extract to levothyroxine said, "Wait a minute, I don't feel that great. I want to go back to my desiccated thyroid extract." Some doctors said, "Fine, just do it." Some doctors said, "No, you have to be on levothyroxine."

Patients complained about impaired cognition as well as difficulty managing body weight. During those five decades, this noise became louder and louder. You can imagine with social media, all these patients got together, got a huge megaphone, and their complaints became louder.

We now have this natural product that has resolved the potency issue because the US Pharmacopeia (USP) has developed a new standardization method for desiccated thyroid extract. The issue is maybe it contains a little bit too much T3, and the patients taking desiccated thyroid extract may complain of palpitation and tachycardia. Right now, the vast majority of patients are treated with thyroxine.

A staggering 1.5 million patients in this country with hypothyroidism are treated with desiccated thyroid extract. In the far third place, we have about 300,000 or 400,000 patients using a synthetic combination of levothyroxine and liothyronine.

Desai: Currently, you would need either a noninferiority or a superiority trial to bring a new medication to the market. Was there any sort of comparison of levothyroxine when it came out?

Bianco: No. The US Food and Drug Administration (FDA) never asked for one because levothyroxine was isolated in 1914 by Dr Kendall before the FDA existed. I think he had a patent and they had a licensing agreement with Squibb Laboratories at that time. Squibb sold levothyroxine to treat patients with hypothyroidism in 1916 or 1917, even before the FDA. When the FDA was created, levothyroxine was grandfathered in.

In the 1950s, a British pharmaceutical company developed the synth patent — the synthetic method to make synthetic thyroxine no longer extracted from pigs. Again, the FDA accepted it because they already had grandfathered in the natural product, the levothyroxine extracted from pigs. The FDA never asked for safety testing or effectiveness of levothyroxine.

Today, the normal thing would be, okay, we have a standard of care, which was desiccated thyroid extract back then. You have a new product. Okay, let's do a randomized clinical trial that's blinded and let's see which one is better, looking at effectiveness and safety. That was never asked.

Desai: Do you think anybody would do that in the future?

Bianco: Yes, they are because of desiccated thyroid extract. This is a very popular product. As I told you, 1.5 million people take it. It's not fully approved by the FDA because it grandfathered in desiccated thyroid extract. They let pharmaceutical companies make it and sell it, but it's not fully approved by the FDA.

Now, the FDA is telling these companies, "Listen, we want to resolve this situation. Either you come as a new product and demonstrate that this is effective and safe, or eventually we will need to not let you sell this anymore." As a result of that FDA request, the companies that make desiccated thyroid extract are running against the clock in these randomized clinical trials to compare with levothyroxine, because levothyroxine is the standard of care and they want to show noninferiority with levothyroxine.

We have already, I believe, one trial was done. The results of a large multicenter were published last year in the journal of the American Thyroid Association. We have another multicenter trial starting now from a different company.

Desai: You briefly mentioned some of the side effects of desiccated thyroid hormone, but why do you think the medical community in general is so hesitant to recommend either combination therapy or desiccated thyroid hormone? What are the main reservations that people or physicians seem to have?

Bianco: There are two main reservations. Number one is the inconsistent potency. I think that's a historical reservation that should not be discussed anymore because it's no longer a problem. The second thing is that T3 peaks. In desiccated thyroid extract, we have 4 molecules of levothyroxine to 1 triiodothyronine. Our thyroid contains a different ratio. It's like 14 to 1.

There's an idea that perhaps the desiccated thyroid extract could give a little bit too much T3. If a patient takes, let's say, 100 mg of desiccated thyroid extract, T3 levels will increase. You can measure it 3 hours later. There will be a T3 peak. The experts think we don't have sufficient data on safety for these peaks of T3. What happens if a patient takes desiccated thyroid extract for life — could these peaks of T3 be a problem with the heart or bone? This is a historical concern again.

Today, we know better. I can tell you that there were 20 randomized clinical trials comparing synthetic combination therapy with levothyroxine, and the effectiveness and safety was identical. There were no more adverse reactions in the combination therapy as opposed to levothyroxine, number one.

Number two, there were two clinical trials using desiccated thyroid extract, and they didn't find more adverse reactions as compared with levothyroxine. Number three, there was a commercially sponsored, multicenter clinical trial with desiccated thyroid extract published at the ATA meeting last year, showing again there were no more adverse reactions with desiccated thyroid extract.

The bottom line is, yes, we can treat someone with levothyroxine with combination therapy, either synthetic or desiccated thyroid extract, and normalize thyroid-stimulating hormone (TSH) without having more adverse reactions.

The problem is many doctors, when they use T3, with synthetic, combination, or desiccated thyroid extract, they give more than actually needed to treat hypothyroidism. They're ignoring — and this is something wrong, I think — the TSH. Using combination therapy in many settings has become synonymous to suppressive therapy. In that case, of course, if you're suppressing your TSH, you're taking T3, you're going to have side effects, you're going to have palpitations. If you're monitoring TSH, the studies have shown that we don't have more adverse reactions.

Desai: Because the education is actually changing our knowledge of T3 and the combination therapy, do you have any advice for fellows or fellow thyroidologists who would want to use this therapy in their practice on how to get started with using combination therapy? Who would be an appropriate candidate to use it for?

Bianco: What I'm going to tell you comes from the European Thyroid Association guidelines from 2012. This has been around for a while and was developed in Europe. I recommend fellows read the 2012 European Thyroid Association guidelines.

The principle that the guidelines are based on is a patient is being treated with levothyroxine and develops residual symptoms, either cognitive or metabolic symptoms, and the patient doesn't feel well and their quality of life is impaired. The first thing you do is determine whether this patient has hypothyroidism. It's common today. The threshold for prescribing levothyroxine is so low. If the patient comes with symptoms and borderline TSH, we are going to put that patient on levothyroxine.

My first reflex reaction is that we need to document that this patient has, at some point, an elevated TSH. If the patient doesn't have a record, I would stop. In my clinic, we stop many patients from taking levothyroxine and wait a few weeks until the TSH goes up. If the TSH doesn't go up, I would just say, "You're in luck. You don't have hypothyroidism, so you don't have to worry about this anymore."

The second thing we have to do is, once we are sure that the patient has hypothyroidism and is still symptomatic, find out whether there are other chronic conditions that could cause the symptoms. The symptoms are very nonspecific. There's nothing pathognomonic about residual symptoms of hypothyroidism. Patients note symptoms, including, "My memory doesn't work, I feel tired all the time, and my skin is dry." These symptoms are everywhere these days.

As it turns out, in my experience, the most confusing factor is menopausal syndrome. The symptoms are very similar. Most patients with hypothyroidism are women. Are we getting close to menopause? Are we dealing with this? Is estrogen replacement therapy an option for this woman? Should we consult a colleague?

In addition, we should consider anemia, iron deficiency, other autoimmune diseases, and diabetes. Because Hashimoto thyroiditis is an autoimmune disease, it's more likely you're going to have a second autoimmune disease complicating the situation. We need to look for other reasons. If we can't find another reason, it's an exclusion situation — you exclude everything that you know.

Use your common sense. You're a doctor. Look at the patient. What are you investigating? If you can't find anything, you say, "Okay, maybe in this patient, then, levothyroxine failed. It resolved the overt hypothyroidism, but we do have some residual symptoms. In that case, we will try combination therapy. It's a trial. It's not for sure it's going to work, but it's the only thing we have today that has been proven to work for many patients."

The experience varies, but maybe 50%-60% of patients respond positively to combination therapy. Which combination therapy? I like synthetic because I want to control the amounts of T4 and T3 I'm giving. I have to tell you that patients love desiccated thyroid extract. I don't have that great of an experience with it. Right now, the guidelines are completely against it. We really need to think on this because the reality is almost 2 million patients are taking it — 1.5 million patients — and we need to understand what this is doing.

If we decide to go to combination therapy, we have to explain to the patient what we're doing. We need to set up expectations. We need to explain that this is a trial and it might or might not work. After we have all the bases covered, we start by doing what? We reduce the amount of levothyroxine we're giving. Many physicians think that combination therapy is just adding the liothyronine to whatever dose of levothyroxine you're taking. That's not right. You have to create room for the introduction of liothyronine.

You reduce the levothyroxine by a few micrograms, maybe 20 μg. A paper from the European Thyroid Association gives a nice formula to calculate how much you're going to reduce levothyroxine and how much you're going to give of liothyronine. We're talking about 5 μg, we're talking about 7.5 μg twice a day or even once a day. I had patients in my office taking 500 μg of liothyronine. This is nuts. It's not combination therapy by any means. You're introducing a little bit of liothyronine, and you monitor the TSH. The TSH needs to be normal.

I'm going to tell you this is a huge point of contention with the patients. Why? The patients say that TSH is not important. We can suppress the TSH. That's not a big deal. They write on my Facebook, "Dr Bianco doesn't know what he's talking about. TSH doesn't do anything." TSH stimulates the thyroid. We need to explain to the patient why we're keeping the TSH normal.

Of course, we know that there's something called central hypothyroidism secondary. Many patients think they do have secondary or central hypothyroidism and you can't trust TSH. Yes, that's true. Many of them have it, but it's such a small number of the population. We should think about that, but it's not the rule. It's the exception. Create room for liothyronine and monitor TSH. Monitor side effects and check for palpitations. You want to adjust the ratio of T4 and T3 until you have a normal TSH in a patient with less symptoms or with no symptoms, and you're adjusting the dose.

Desai: Thank you. I wanted to summarize that a little bit. One, confirm the patient has hypothyroidism. Two, rule out any other causes, including menopause, especially for women, other autoimmune conditions, anemia, or anything else that might be contributing to the patient's symptoms, because many of these symptoms are nonspecific, such as fatigue, hair loss, and cold intolerance.

Then, assuming those conditions are met, start the patient on a combination therapy, preferably synthetic with T4 (levothyroxine) and T3 (liothyronine). When you start it, manage the patient's expectations with counseling up front. Then reduce the dose of levothyroxine and add the T3 slowly until we get a normal TSH and a patient with much better symptoms.

Bianco: Right. The only thing I would note is that it's not preferably with synthetic. It's my personal preference. However, the fact that we have three times more patients taking natural thyroid extract as opposed to synthetic tells me something we don't understand. Remember that there are copays for levothyroxine and liothyronine; patients have to pay two copays. It's two pills. The other one is one copay, one tablet. There are practical issues.

My bias is I respect what the patient wants. I heard my neighbor is on desiccated thyroid extract. That's fine. I'm not going to say no, no, don't do that, you have to go synthetic. I did this many years of my life. Every patient that came into my office on combination therapy, I said, forget about it. I'm going to put you on levothyroxine. We evolved from there. We need to hear what the patients are telling us. If they feel better on desiccated thyroid extract, it's fine as long as the TSH is normal.

Desai: Thank you. Knowing this information, how do you think the practice of treating hypothyroidism is going to change? Is there anything new in the pipeline to come out for medications? Or changing training with new guidelines from the American Thyroid Association? Where are we headed in the future?

Bianco: The guidelines need to be open-minded and recognize reality and that science has evolved. I think that, for the academic physicians who write the guidelines, where do we need to focus? Number one, there were studies showing that the thyroid system is hardwired to preserve serum T3 levels. What does that mean? It means that if you have iron deficiency, T4 will go down, TSH will go up, but T3 levels are normal.

We created a series of mice that were genetically modified to disrupt the feedback mechanism between the pituitary gland and the thyroid. In multiple mouse models, every time we made one, the TSH and T4 were everywhere, but serum T3 was normal. The directive for the hypothalamus is to keep T3 within the normal range.

I think that's an important piece of information because we know, again, based on old papers and recent papers, when we treat someone with levothyroxine, we always have a relative deficiency of T3. You have a relative excess of T4 at 15% higher, and T3 is 10%-15% lower. The hypothalamus wants to keep T3 normal by all means. When we treat our patients, we don't measure T3 levels.

This is a situation the guidelines need to recognize and say, maybe we're not looking at the right thing. Looking at TSH is good. Looking at T3/T4 is wonderful, but we also need to look at T3. That's the number one story. We need to include that because it's important.

Number two, the guidelines need to acknowledge that there are patients with normal TSH and residual symptoms of hypothyroidism. We were so focused on the fact that there were clinical trials that were inconclusive. The clinical trials are part of the solution. What is the problem? The problem is that we will find patients that have normal TSH and they don't feel well only on levothyroxine.

I think that's the acknowledgment patients are waiting for. I am waiting to hear from the American Thyroid Association to recognize that the effectiveness of levothyroxine is not 100%. Guess what? There were no clinical trials to say that it was. We took it for granted. We took so much for granted in this area. We need to correct that.

Now, there is a concern with combination therapy, which is that the T3 peaks, even if you're talking about 5 μg. It's a valid concern. I don't think we should ignore that, even though today there are large studies. In the United Kingdom, there was a study that followed 400 patients taking combination therapy for 17 years. They looked at cardiovascular events and mortality and found no difference between them and patients taking levothyroxine. In Sweden, 11,000 patients were followed who were taking T3, and again, mortality was not affected.

A study in Korea looked at 1500 patients taking combination therapy, and there they found increased occurrence of heart failure and stroke. They didn't tell us how much they were giving or what the TSH, T3, or T4 levels were. For all we know, those patients could be thyrotoxic. I don't know.

I think that we need to stop the fear without evidence. There's no evidence that combination therapy does anything bad when TSH is normal. To prove it does something bad, we need to have a real trial showing these are the data, this is the excess of T3. The TSH is doing this or whatever. We need to put the fear in the right place.

Now, because of that, the pharmaceutical industry jumped in and there are at least three different independent efforts to produce slow-release T3 formulations, which makes sense. If the T3 peaks are a problem and we are concerned about that, create a slow-release T3. There are two efforts in Europe and one in the US. I suspect that within a few years, we're going to have that in the market.

Desai: It's really exciting that that's coming soon. Hopefully, it'll be affordable for our patients as well.

Bianco: I think so, yes.

Desai: You mentioned that our previous guidelines said many clinical trials comparing combination therapy vs standalone levothyroxine were inconclusive. Why do you think it was that we didn't show a significant benefit, especially for that population that it really seems to help?

Bianco: Great question. There were about 20 randomized clinical trials that compared levothyroxine with synthetic combination therapy. At the end of the trials, when they looked at depression, cognition, and different parameters, there was no superiority. Combination therapy was not better than levothyroxine; levothyroxine was not better than combination therapy. I think that puts to rest the idea of combination therapy for a long time. Those were well-done trials; I don't think we can criticize them.

There was one interesting thing: They concluded that patients preferred combination therapy. Two meta-analyses published recently said the preference was combination therapy. Some colleagues say, I don't think preference is important. I think we need real measurements like a questionnaire or something validated. My point of view is, preference is not important? You can ask someone, what do you prefer? I have these two treatments that are basically the same; if you prefer one, why am I going to force you to take the one you don't prefer? Let's respect the patients, because if there's isn't a reason to prescribe combination therapy and the patient prefers combination therapy, let's do the right thing. That's common sense.

I think that's an important summary of these trials. There were no side effects or negative things associated with combination therapy. They were just the same, and preference was with combination therapy. The voice of the patients and the data are overwhelming. Wait a minute, there's got to be something wrong with those trials because how come in my office, I see these patients that love combination therapy and how come that's not reflected in the trials?

A few years ago, here in Chicago, there was a joint meeting of the American, European, and British Thyroid Associations. Experts from the three societies got together and concluded that maybe what's wrong with those trials is they didn't focus on symptomatic patients. They focused on all patients. When they recruited patients, they recruited patients with hypothyroidism. It didn't have to be patients with residual symptoms.

If I tell you that 15% of the patients have residual symptoms and I start a trial and I recruit 100 patients, but only 15 patients are going to have residual symptoms, and then I'm going to randomize them into two groups, it's going to be completely diluted. I will never see the results in that subgroup because it's not powered to do that. The recommendation was to focus on patients with symptoms. Future trials should recruit preferably or a substantial number of patients that are symptomatic, even though their TSH is normal.

I was fortunate to be a part of a trial that was published a couple of years ago. The trial was from Dr Shakir and collaborators at Walter Reed Army Medical Center in Bethesda, in which they enrolled 85 patients. There was a crossover, three arms. When you analyze the data comparing levothyroxine, desiccated thyroid extract, and synthetic combination, when you look at all patients, it was exactly the same as in trials from the past. There were no differences.

When you ask yourself, wait a minute, let's focus on the patients that didn't do well on levothyroxine, those are the patients that respond positively to combination therapy. They responded similarly. With synthetic T4 and T3 or desiccated thyroid extract, there was no difference, but they responded well. The idea from this trial was that if you're good on levothyroxine, you're probably not going to be better on combination therapy. Now, if you don't do well with levothyroxine, there's a good chance you're going to respond positively to combination therapy.

I think that trial did well. It's a randomized, double-blinded, crossover trial, and we need more of these trials, but each trial costs millions of dollars. We need funding for these trials. It's not trivial to set up a trial that is powered and there are a few hundred patients to test these things. It costs a large amount of money.

Desai: Designing trials is important, but you also mentioned that the patients prefer one treatment over another. We have many metrics and we're measuring many subjective things, but are we measuring the correct subjective things? Obviously, they \have a preference, but why is it that they have a preference? We're not just catching why they're preferring [a certain type of therapy]; we're assuming that we think that these are the reasons that they might choose it.

Bianco: You're absolutely right. We are asking the wrong questions. Maybe I'm exaggerating, but there's a disconnect between our set of clinical outcomes and the patient's set of clinical outcomes. The patient wants something that they prefer, that they like, and that they feel better on. Why? They don't care. Do you think they care if it's X, Y, or Z?

Desai: They don't have to face the problem.

Bianco: We're not going to harm our patients, right? We want to make sure we're doing something that, in the long run, is not harming anyone. Guess what? There are many data supporting that we're not harming anyone, and there's not a single piece of evidence that we are.

When I started, I was afraid of prescribing liothyronine because I was told, oh my goodness, we can't do that because we're going to have atrial fibrillation, osteoporosis, and all these things. Where are the data to support that? We just don't have any. The data don't exist. I think that's important. I think the guidelines need to recognize that.

Desai: Many of those topics you mentioned desiccated thyroid hormone and then combination T4 and T3, are used in both patients who have a partially working thyroid and those who’ve had their thyroid removed, do you think one group benefits more from these kind of treatments vs another or are they equal?

Bianco: When you do have some residual thyroid activity, studies have shown that T3 levels aren't that low. The relative deficiency of T3 isn't that low, and patients feel better. That is phenomenal because that has helped change practice.

I remember a time when a patient had a thyroid nodule. What are we going to do? Total thyroidectomy or a partial thyroidectomy? That was not part of the equation. Today, the equation is, I want to hold onto as much thyroid as I can because I know it's going to be important for my clinical outcome and my quality of life later. Having residual functional thyroid tissue is really important. There are papers showing that's the case.

Desai: Thank you. Is there anything else you'd like to share with us today?

Bianco: No, I'm just grateful for the opportunity. I think this is a fascinating area that I knew almost nothing about. I was focused on understanding all the details and the molecular mechanisms of these fascinating enzymes, the deiodinases. Little did I know that they are so important in the treatment of hypothyroidism. We were, in a way, taking for granted that these enzymes that I love, dear to my heart, could do such a phenomenal job that they could produce normal amounts of T3 if we just gave levothyroxine. That's not true. They don't.

It's extremely difficult to normalize TSH and T3 levels in the same patient without having a huge excess of T4. It does make sense if the deiodinases by themselves could produce normal T3 levels, why does the thyroid produce T3 and where would the thyroid that comes from the T3 go? If the deiodinases just produce 100% of the T3, the thyroidal T3 now is an excess. Where would that go?

The deiodinases cannot compensate for that. I think the understanding of these enzymes, at least for me, allowed me to see what was wrong with what we were doing. I want to be respectful because I think that, for a number of years, I did not think that was a big problem. I think that not understanding that deiodinases well led us to the situation we are in today. It's critically important to realize there's a T3 deficiency in these patients.

Desai: Thank you for joining me today, and for sharing your thoughts on this important topic. So many people today have hypothyroidism, and it's important we treat everyone and not just a certain population. We really do need to update our practice and how we treat patients. Thank you again for sharing your thoughts.

Bianco: Thank you for having me. It's been a pleasure.

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