What’s the Best Ratio of Thyroid Medication?

Intro:

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Combination Formula Thyroid Treatment

DrMichaelRuscio:

Hi everyone. Welcome back to another episode of Dr. Ruscio Radio. This is Dr. Ruscio. Today we are going to discuss thyroid hormone medications. Specifically, is there something special about a combination formula of T4 plus T3? If you’re a patient or a clinician you’ve likely heard of Synthroid or Levothyroxin, however, there’s this other theory that you should have a thyroid hormone that also contains T3 and there there are speculative reasons for this. Because the thyroid gland itself releases both T4 andT3. So something like Armour or Nature Throid or WP thyroid, or adding Cytomel in conjunction with your Levothyroxine or Synthroid is purported to be better. So that’s what we’re going to discuss today. The short answer to the question is no. The preponderance of the evidence does not support that T4 plus T3 is better for the majority of patients.

DrMR:

It’s more like 10% or less. To the counter-argument that is sometimes levied against that, which is, well, you need to have a special ratio. When looking even further into this issue, you don’t find that a certain ratio is needed either. So that’s what we’re going to outline today. If you remember back, for those who read the clinician’s newsletter, you may recall that I went through a fairly deep dive analysis on this maybe a year or a year and a half ago, because it’s a fair question. One of the most common philosophies or principles in Functional Medicine is we must have this particular ratio, or we must, more simply, have a combination formula containing both T4 and T3. This is something that I kind of parroted early in my career because it was what everyone else was saying.

DrMR:

As I’m sure at this point in time, you’re becoming familiar with the way I look at these things is now sad but true guilty, proven innocent. Many of these concepts don’t really have a good basis in science. Why that matters is even though on the surface, we are doing these different things in an attempt to help patients. If we’re actually championing a message that’s not based in science, what we often end up doing is making it more difficult for an individual to get well. If the promises this that this special thyroid hormone is going to resolve your symptoms, but that’s actually not substantiated by the scientific evidence, what ends up happening is clinicians keep giving patients this hormone and don’t realize that they’re missing another cause of the problem. Oftentimes, but not always, this may be problems in the GI. Again, why this is so important is if you’re expecting your therapy to be helpful, but adequately performed trials have shown it not to be helpful, but you haven’t looked at those trials, you’re actually giving someone a therapy that is not effective.

DrMR:

Sadly what ends up happening, and we’ve published a number of case studies that have showcased this, is that patients will be given different iterations of medications, different dosages, different ratios, different formulations for months, in some cases over a year and suffer needlessly because of this philosophy that hasn’t been adequately fact-checked. So this takes us back to when I went through the review, again about a year, year and a half ago, in the Future of Functional Medicine Review clinical newsletter, but we have discussed it on the more, you know, broader platform and in the podcast in the past also. So in reply to that episode or that issue of the FFMR, one of our readers in there commented the following.

Does the Ratio Make a Difference?

DrMR:

“You forget that many of the studies showing no benefit from T4 plus T3 therapy use a very low dose of T3, 14 to 1, T4 to T3 ratio. Look at studies with a T4 T3 ratio of around 4 to 1, and you see benefits in every single study. It’s so simple”.

DrMR:

Okay, I’m going to kind of single this person out and I’m not doing this to pick on the person, but I’m doing this because it’s such a shining example of some of the things that we as a field need to remedy and improve. This is a very confident statement. I have found that the Dunning-Kruger effect is true, not only in I guess, political discourse, which is where I think that observation initially stems from, but in scientific and medical. So this is a very confident statement and the Dunning-Kruger effect essentially says that the less someone knows about a field, the more confident they are in conclusions in that field.

DrMR:

This is something I’ve definitely found to be true. It’s one of the things that frustrates me, which is the person who knows just what they’ve been told, and they parrot it with a lot of zeal. Usually, when you speak with someone who is very, very educated on the topic, they kind of hem and haw that you could argue both sides based on the evidence. When you understand all the evidence, it’s very hard to make a strong statement because you understand for any opinion or any position there’s evidence supporting and refuting. In this case, my bias alert is already going off because this is a very strong statement. At the same time, it’s also a fair question.

DrMR:

You know, we have the data table of all these studies and we’ve laid them out. We’ve clearly seen that when you take all these studies and you kind of label them as people prefer T4 plus T3, or they don’t, the majority of data show that patients do not prefer T4 plus T3, it’s no more effective. However, maybe I missed this more subtle nuance within the dataset where if we looked at and broke the analysis kind of into a sub-analysis of only the studies with this certain ratio, there will be benefits. So this is a fair question. Now, again, the way it was posed makes me extremely suspicious that this person doesn’t have a high level of familiarity with this issue. But again, it is a fair question. So it’s worth looking into. So to lead with the summary, “there is no evidence from a review of 16 randomized controlled trials, assessing various ratios of T4 to T3 for a clear benefit of a specific ratio of T4 to T3 compared to T4 alone”.

DrMR:

There is some evidence of patients preferring combination therapy, meaning T4 plus T3 over T4 alone, but it is not correlated to any particular ratio. Where to begin here to kind of substantiate that claim. In 2019, a systematic review with meta-analysis was published, entitled “A systematic review and meta-analysis of patient preference for combination thyroid hormone treatment for hypothyroidism”. They looked at 348 hypothyroid individuals. Essentially they conclude there was a signal of patient preference for T4 plus T3 versus T4 alone. To quote “in conclusion, randomized control trials in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination therapy compared to T4 alone”. This is the key right here. “This finding was not distinguishable from chance”, meaning it didn’t appear to be statistically significant. Continuing. Now, “when the researchers investigated the potential mechanisms or reasons for this apparent preference for combination therapy, they found that there was no correlation to a particular ratio”.

DrMR:

Okay. So to quote “in a secondary dose response, meta-regression analysis, a statistically significant association of treatment preference was identified for total daily T3 dose, but not the ratio”. Said simply, it may just have been giving patients more T3 was helpful, but it didn’t correlate with a ratio of T4 to T3. So there’s pretty clear evidence cutting against the reader’s claim. Now, if we go into the meta-analysis and go even deeper, and if you are a reader of the Future of Functional Medicine Review, you’ll see this in the issue that we’ll be publishing for December of 2020, we make a table and we take eight studies. These are the eight quality studies in question. Here’s what you see, and it’s pretty visually compelling if you can look at this table because essentially, here’s the evidence that answers the question.

DrMR:

Let’s take every study and let’s label the study as 1) supports you need a certain ratio, 2) does not support you need a certain ratio, or 3) finds, no difference, no matter what the ratio. Two of the eight studies suggest that a specific ratio is best. One of the eight studies suggests that that particular ratio, that 4 to 1 ratio is actually worse and five of the eight studies suggest that ratio does not matter. Again, two of the eight studies support this reader’s contention, one of the eight studies suggest that it’s actually worse and people have more adverse events, and five of the eight studies suggest the ratio does not matter.

DrMR:

So I return to the initial observation that when someone has a highly confident conclusion, they usually don’t possess all the information. Who knows, maybe there is something that I am still missing. I mean, at this point, I doubt it because we have literally gone through this issue with a fine tooth comb. And now we’ve even gone through a sub-analysis. As the other meta-analyses that have done meta-regressions, meaning a meta-analysis can do a sub-analysis and it is essentially a meta-regression, they’ve concluded the same thing. So if the best scientists who are going through meta-analyses and meta-regressions are finding this, and then just to make sure that we’re not missing something, we put all the data into a table and we label each of the data points as supporting or not supporting and that shows the same thing, then I would be shocked if we’re missing something here.

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It’s Compelling…But is it Valid?

DrMR:

In trying to tie this back to what is happening within the field of Functional Medicine to lead an individual to having such a confident conclusion. My thinking is that there are educators who are probably pointing to the two of the eight studies that found the favorable benefit. Those are probably interspersed into a narrative that goes into copious detail about mechanism and about how animals and humans, Thyroid glands secrete a certain ratio. That ratio was closer to four to one. And what you end up having is exactly the embodiment of what I always criticize in the podcast, which is a very compelling story that is constructed with poor quality evidence. This is one of the biggest problems in the field is when someone, an educator, a guru, a speaker at a weekend seminar, a speaker for a lab company, a speaker for a supplement company, a speaker for an educational body in Functional Medicine speaks eloquently and tells a seemingly compelling story, but it’s built upon low quality evidence. This is like building a mansion out of straw. It’s it’s not going to stand up to scrutiny. You’re much better having a smaller house, so to speak, built upon steel. That’s really what the higher quality data is. It’s a steel man rather than a straw man.

DrMR:

So those are a few of the more salient points from this. Again, I think there is a small kernel of truth to this argument that some patients do prefer, and do better on, T4 plus T3 therapy. It’s not to say that this is something that we should throw out completely. This is the conclusion that I came to and we came to in the review from a year, year and a half ago, which was that there is evidence supporting that people will do better on T4 plus T3. This happens to overlap with the same distribution of people in the population that have a genetic inability or sluggishness of converting T4 to T3, which is about 10%.

The Exception, Not the Rule

DrMR:

Again, the challenge is, is, is that when we use the exception to argue the rule and what ends up happening is the majority of patients in Functional Medicine offices are being given combination therapy. When that’s actually something that’s going to help them minority of patients. Sadly, what we see in the clinic is these patients are being done a huge disservice because that is being done at the exclusion of other things that should be more effectively executed, like improving one’s gut health. So, the grain of truth can sometimes be inflated and this can really lead clinicians and patients astray. Combination therapy is something that you consider, and this is something we have in our thyroid algorithm, after you’ve gone through basic dose titration with T4, and you’ve undergone the dietary lifestyle and digestive health fundamentals. If someone is still not responding, then T4 plus T3 makes sense, but no, a special ratio of T4 to T3 doesn’t seem to matter.

DrMR:

This sequencing is vitally important. In my opinion, one of the reasons why people have vastly different experiences with Functional Medicine is because there’s not uniformity in the sequence or in the prioritization of therapeutics. Unfortunately, it seems that the new and novel is what’s often pursued at the expense of these things that are more foundational. This is why we still see patients who come in, who haven’t even used probiotics the right way. Going even more basic and more fundamental, people who are not even on the right diet. They may be someone who just by making a few dietary tweaks can feel quite a bit better, or someone who has a clear sleep issue and that hasn’t been addressed yet. So these fundamentals, I think sometimes people equate fundamental with simple or not that helpful. They are very helpful. Unfortunately it seems that the correct execution of the fundamentals is not that common. People go to MTHFR and adrenal fatigue and organic acids and if you’re doing that, but you haven’t adequately resolved someone’s digestive issues, perhaps because you don’t understand the proper way to apply the therapies in that toolkit, then it’s going to be near impossible to get the results that one’s looking to get.

How Others See This Issue

DrMR:

A few other things here that I think are interesting. Regarding what other large bodies are recommending regarding ratios and usage, because I have yet to discuss let’s say the European Thyroid Association’s paper “ETA guidelines: The use of T4 plus T3 in the treatment of hypothyroidism”. They recommend exercising caution when prescribing T4 plus T3. They’re not against it, but they are kind of like I am, cautious or leaving it till after other options have been exhausted. They encourage utilizing a ratio of T4 to T3 from 13:1 to 20:1. They also encourage dosing T3 twice per day, since T3 is somewhat fast acting. That’s something important to factor into the analysis. I know that sometimes, especially in the integrative and alternative camps, we like to discount what conventional medicine has to say, but there is actually a fairly large body of research within the conventional medical paradigm that we should borrow from. It shouldn’t limit us.

DrMR:

We shouldn’t be only evidence based. We should look at evidence-based, but also not be evidence limited and think through these things as holistically as we can. We certainly don’t want to throw out good evidence when we have it. So those are just a few thoughts on thyroid hormone, the ratios of T4 T3 and the appropriateness of when to consider using a combination formula and whatnot.

DrMR:

I think the deeper and more important point is we all have to be better about how we’re thinking through and discussing these issues. I include patients in this also. Patients and providers. I think we have to be much more cautious with what we think we know. We have to admit that we don’t know everything and be open to the fact that we may not know everything because, consider this, this gentleman here who I’m kind of singling out, but I’m doing it with love, care support, and hopefully to use this as constructively as possible, with that level of confidence in the conclusion, what impetus does he have to go searching for further evidence?

Check Your Level of Confidence

DrMR:

What impetus does he have to say? Hmm, maybe the reason some patients aren’t seeing the results I would like them to be is because there’s something in thyroid here that I’m not fully understanding. With that level of confidence, at least as best I can determine, there’s much less motivation to learn more because you must kind of think you have it all figured out. This has a trickle down and snowball effect. You’re confident in that and now your patient’s confident in that and now patient and provider are kind of shut off from exploring other therapeutics. Also, that level of confidence is likely something that permeates much of the thinking and discussion. Then the dietary recommendations. If you’ve got Hashimoto’s, you must avoid gluten. This kind of discounts the paper by Volta that found only 9% of the over 12,000 patients that were assessed for non-celiac gluten sensitivity had Hashimoto’s.

DrMR:

So there was something, yes, but 9% and telling everyone to avoid gluten is pretty dissonant.

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DrMR:

So these things really start to snowball out of control quite quickly. When, when we have this very confident opinion on the ratio, that’s most likely to also be accompanied by a very confident perspective on diet.

DrMR:

There might also be a really confident perspective on adrenal tests and interpreting them literally. Kind of like the gentleman we described before that had “stage three adrenal fatigue”, even though he had no fatigue and was told he couldn’t have coffee and needed to take handfuls of supplements every day for six months to see no improvement in how he was feeling. So this is why I point to this hubris. I think maybe natural integrative providers need to have a little bit of that high level of confidence, especially early on in the game when there was very little science, but now for the field to evolve in the direction it needs to I think we’ve all got to kind of pullback, be a little bit less confident and be a little more quick to criticize our own ideas. If you do that, the upside is that you’re continually going to be improving your ideas and the accuracy of your ideas and giving patients better advice.

DrMR:

So in this case with T4 and T3, again, the ratios don’t seem to make a big difference. I’m very grateful and appreciative of the question. Again, I don’t mean to single this person out but it provided a chance example of how dangerous some of the confidence that that imbues our field can be. If we can all be a little bit more humble and a little bit more inquisitive, then I think we will do a much better job as clinicians and provide our patients with a much higher level and quality of care. So just a few thoughts there on thyroid. I hope you find this helpful. If you have questions or thoughts or disagreements, I welcome you to leave them here because in trying to keep with my own philosophy, I don’t think I know everything.

Episode Wrap-Up

DrMR:

In this case, I was fairly confident after the hours and hours and hours and hours of me and the research team digging through this a year and a half ago, we had it fairly well mapped out. At the same time, if the Dunning-Kruger is true, the more I know, the less confident I become. So this was a fair question because I hadn’t drilled down and answered this question specifically with a high level of detail. It was worth me investigating. That same thinking applies to other questions that seem that they have merit. In this case, I’m hard pressed to think of any other points of contention, about combination therapy and the T4 T3 ratios, but any fair questions will be given the requisite amount of attention. I hope this helps and provides you some insight into not only the issue of combination therapy, but how we can be a bit more cautious with our claims and our level of confidence in attempts to be better clinicians and provide our patients with a better level of care. Also for patients, be wary of a doctor who seems to not be open-minded because you could be getting the short end of that stick also. All right, folks, hopefully this helps. If you have questions or comments, please leave them in the comment section. Otherwise we will talk to you next time. Bye-bye.

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