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Thyroid Cancer: A Black-Box Warning on Anti-obesity Medications!?

Thyroid Cancer: A Black-Box Warning on Anti-obesity Medications!?

The Uncommon Side Effects

Ok, we are back and again discussing the downsides of some of these anti-obesity medications. We have reviewed the common side effects, but what about the not-so-common side effects? What about the black-box warning regarding a risk of thyroid cancer that the FDA has placed on the class of medications called GLP-1 Receptor Agonists such as Ozempic, Saxenda, Wegovy, etc.?!

When we throw around words such as ‘black box’ and ‘cancer,’ our ears tend to perk up and we start paying closer attention, which is excellent! By no means are these things we should take lightly. These checks and balances are in place to ultimately protect people! However, as with anything, we need to look at the picture in its entirety to understand what the evidence says exactly and whether it applies to your given situation or not!

First Things First, What Is A Black Box Warning? 

A Black Box warning is the most stringent warning for drugs and medical devices on the market that the FDA and other health agencies can put in place. Its purpose is to alert patients and healthcare providers about the potential for serious side effects, injuries, or death! A pretty big deal, right?! It reminds me of the ‘look’ my mother gave my brother or me in public when we were being little shit disturbers. We knew if we didn’t smarten up, there would be side effects, injuries, or even death! Clearly, I made the smart choice most of the time as I am still here to write this blog. 

Ok, so what does the Black Box Warning: Risk of Thyroid C-Cell Tumors on GLP-1 RAs mean? 

This warning is in place for a very specific type of thyroid cancer called Medullary Thyroid Carcinoma (MTC), which originates from the ‘C-Cells’ in our thyroid. This is a very rare type of thyroid cancer, only accounting for ~3% of all thyroid cancer cases. Another condition we are concerned about is called Multiple Endocrine Neoplasia Type 2 (MEN2), which has been associated with MTC. If you are sitting there, like I was, wondering if you have or have had either of these conditions, I can assure you that you would probably know as a specialist has likely told you so. But, again, they are quite rare and specific. The black box warning is in place for people who either have a family or personal history of the above conditions. In their case, the GLP-1 RAs would be contraindicated or (in English) would be medications they could not take as the potential risk of MTC is too high!

What about everyone else?! 

The interesting thing about the risk of MTC and black box warnings on these medications is that there are a couple of unknowns. You see, this black box warning was ultimately put in place based on animal studies, and what researchers found is that when rodents were exposed to GLP-1 RAs such as Ozmepic, the rodents developed MTC. Now interestingly, these results have not been replicated in humans. There were reports of MTC in the landmark trials with GLP-1 RAs such as Victoza. However, the number of cases was very minimal, and cases occurred equally in both the GLP-1 RA and placebo groups. Further analyses that combined the data from multiple studies found a similar result. 

I know. Providing you with groundbreaking information – rodents and humans are a little different? Stay with me here! 

You see, the issue is we do not entirely understand the mechanism by which GLP-1 RAs cause MTC in rodents. For example, we know that rodent thyroid cells have GLP-1 receptors; therefore, GLP-1 RAs could bind to those receptors and lead to the proliferation of MTC. But, on the flip side, human thyroid cells may also have GLP-1 receptors! So does that mean GLP-1 RAs could lead to the proliferation of MTC in humans as well? Maybe, possibly, we actually have no idea. The reason being is that human thyroid cells seem to have a lot fewer GLP-1 receptors and when GLP-1 RAs bind to human GLP-1 receptors, we don’t see the same reaction that takes place when GLP-1 RAs bind to rodent GLP-1 receptors. What a confusing cluster f*ck, right?! 

Thankfully, I have a nice little picture below that will hopefully explain this in a lot better detail. Figure A is what happens in rodent cells, and Figure B is in human cells. 

So do we take said drug or not?

For now, we should continue to follow the Black Box Warning: those individuals with a family or personal history of MTC or MEN2 should avoid GLP-1 RAs until we have a greater understanding of what is happening in the human thyroid c-cells. Black box warnings do get revised or removed as more evidence is presented! So stay tuned! 

For everyone else, GLP-1 RAs are likely safe, and the risk of MTC is near nil. As for other types of thyroid cancers, tumours, etc., there should also be no issue based on the literature. Cause I know it will come up: if you have a history of hypothyroidism or Hashimoto’s, you can also use these medications! However, as with everything, please follow up with your personal care team to ensure these medications are safe and appropriate for you and your specific circumstances! 

Until next time my friends, always remember small tweaks lead to massive peaks.

Dr. Dan

 

 

References:

  1. Nauck, M. A. & Friedrich, N. Do GLP-1-based therapies increase cancer risk? Diabetes Care 36, S245–S252 (2013).
  2. Bethel, M. A. et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 6, 105–113 (2018).
  3. Pfeffer, M. A. et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).
  4. Holman, R. R. et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).
  5. Marso, S. P. et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).
  6. Nordisk, N., Bagsvaerd, D.-M. & Hospi, S. J. Liraglutide and cardiovascular outcomes in type 2 diabetes. Drug and Therapeutics Bulletin vol. 54 101 (2016).

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