For all the buzz surrounding Ozempic and similar GLP-1 drugs for weight loss, there are also plenty of concerns about potential serious or long-term side effects.
Among the scariest of these fears is that GLP-1 drugs may cause certain types of thyroid cancer. The risk is relevant enough that the Food and Drug Administration has long required GLP-1 drugs to carry warnings advising people with a higher risk, such as those with a family history of certain cancers, to avoid using them.
The first GLP-1 medication (for type 2 diabetes) hit the market 20 years ago, however. Since their arrival, scientists have conducted numerous studies examining whether these drugs really do trigger thyroid cancer— including a study published last January in JAMA Otolaryngology–Head & Neck Surgery.
Overall, this research, like many but not all studies, found no significant increased risk in thyroid cancer associated with GLP-1 use (compared to other diabetes medications). Beyond the main results, the findings might also provide an important clue as to why some studies have found such a link.
Gizmodo spoke to study author Rozalina McCoy, an endocrinologist at the University of Maryland, about the origins of the potential link between GLP-1s and thyroid cancer. She discussed her team’s findings and the trade-offs involved in starting any new drug, no matter how miraculous it might sound. The following conversation has been lightly edited for clarity and grammar.
Gizmodo: Why have doctors and agencies like the FDA been worried about this possible risk of thyroid cancer from using GLP-1s?
Rozalina McCoy: So as these drugs were being developed, they were also being tested. This testing is done in animal models, typically rodents. In those early preclinical studies, which were done before these drugs were ever used in humans, there was concern about what’s called C cell tumors, which are very specific and rare types of thyroid cancer, being found in rats. And because this was observed in rats, when the very first GLP-1 medications were approved, they came with a FDA warning that these medications should not be used in individuals who either have a personal or family history of these sort of tumors, such as medullary thyroid cancer.
Ever since then, there was concern about whether this actually happens in people. So over the two decades that this drug class has been around, scientists have been looking to understand: is this something that impacts people? And the challenge is that in clinical trials, the randomized controlled trials that study these medications, they typically enroll up to several thousand patients. And perhaps because this specific type of thyroid cancer is so exceptionally rare, this risk hasn’t been seen in trials.
So the questions are always: Well, is that because the trials involve very low risk patients? Because again, since there’s this black box warning, trials could never involve patients who knowingly are at risk, so maybe they’re selecting for low risk people. Or are we not seeing cancers because the trials are generally short? Most of the clinical trials only last up to a few years, because they are so expensive to conduct. So are we not following patients long enough? Or is there really no risk at all?
So research using real world data really seeks to complement the clinical trial data in order to detect rare events. What if we just look at what happens now that we have millions of people who are taking these medications—can we see this signal?
Gizmodo: How does your research differ from past attempts to look for this signal?
McCoy: We’re building on this really strong body of evidence that has looked at this before. But those studies had some limitations that we really sought to address, and there were some specific things we wanted to do differently.
For one, we use only the largest data set possible to do this. So we have insurance information for people with private insurance, for people with Medicare Advantage insurance, which is now about half of people with Medicare, and for people with traditional Medicare. So we have people across the country with different types of insurance, different exposures, different health systems. We were able to include nearly 400,000 patients overall, and about 41,000 patients who were treated with GLP-1s, so a very large patient population using all the different kinds of GLP-1 medications.
The second is that we looked at the rates of thyroid cancer being diagnosed from day one of starting treatment and onward, and specifically focusing on year one, then year two, and then beyond. When we looked at the prior literature, many of the differences in study results—some studies finding a difference and others not finding a difference in cancer risk—seemed to come from the fact that some studies do what we did, that they looked since the start of treatment and onward. But other studies didn’t really look at the first six months or a year, and it was these studies that tend to find no increase in risk, whereas studies that looked at the entire time span, they did tend to find an increase. So there was this question of: What’s happening here?
Gizmodo: Just to clarify, one reason why this timing is important is because it’s unlikely that a GLP-1 related cancer would emerge within just six months to a year of someone taking these drugs, is that right?
McCoy: Exactly, because thyroid cancer typically takes a long time to develop. Now there are, of course, aggressive cancers that do develop quickly. However, those aggressive cancers would be expected to harm patients and cause people to go to the hospital, to need treatment, or to even die. And we know that’s not happening because we have a lot of literature showing that GLP-1s tend to decrease the risk of death.
Gizmodo: So what were the major takeaways?
McCoy: First, we found that when we look at the overall study period, there’s no increase in the risk of cancer, which was great. However, when we look at just the first year, we did see an increase in risk. So that made us look deeper into why that might be happening, what’s driving it?
And we looked at the rates of thyroid ultrasound, which is how you would detect these thyroid cancers. We saw that patients who are started on a GLP-1, they have a much higher rate of getting thyroid ultrasounds than other patients. And this is important because we know that there’s a lot of overdiagnosis of thyroid cancer. We’re detecting these lesions or nodules in the thyroid that when biopsied look like cancer, so we call them cancer. And yet if we would have never detected them and never removed the thyroid, the patients would have most likely been just fine. So these are very low risk, very slow, if not at all, growing cancers.
Going back to our study, I think what we found is that GLP-1 patients are getting more diagnosed with thyroid cancer really very close to the start of treatment because they’re getting more ultrasounds.
Gizmodo: That obviously raises the question of why.
McCoy: I think it’s probably threefold, though our data can’t specifically tell us that.
One thing that could be happening is that patients may feel something in the neck that worries them, like a lump, or maybe they had a recent CT scan. But if you’re worried about there being something in the thyroid, and if you’re taking a GLP-1 that has this black box warning, people might get more anxious and want to check it out, to be much more thorough just because of the prescription.
The second is that some clinicians and patients may be anxious about even starting a GLP-1 if they don’t have definitive proof that there’s nothing wrong with their thyroid. So there may be a little prophylactic ultrasound being done just to be sure, especially if there’s any family history of thyroid problems, which are very common and are usually not related to thyroid cancer.
And the third possible explanation is that when people lose weight while taking a GLP-1, most weight loss happens in the first few months of therapy. So as people become thinner, they may now be able to feel nodules during an exam. And again, coupled with extra vigilance, doctors may then be more likely to biopsy and diagnose a cancer.
The key point in this study is that we’ve shown GLP-1s lead to more diagnoses of thyroid cancer. But they don’t lead to more cases of thyroid cancer because it’s the detection that’s the issue. And we know that people who are taking GLP-1s, that their risk of dying is less than patients who are treated with sulfonylureas and DPP-4s [two other classes of diabetes medication].
Gizmodo: This is obviously not the only study to look at the risks and benefits of this drug class. Overall, where would you say that calculation rests right now? For the people they’re prescribed to, do their benefits outweigh the risks that we know about and that we’re looking for?
McCoy: The way that you phrase the question is exactly how patients should be thinking about it. And this is what I tell my patients every time we come to a point of deciding if they should start a new medication and what should that medication be. Because it’s always a trade-off between what are the benefits to a specific patient and what are the potential risks? And that calculation is unique to every person in their situation, which is why it is so important for patients to talk to their clinicians and understand the balance of benefits and risks specific to them.
So for GLP-1s, we know that there is a lot of benefit in terms of reduced events and deaths for people who have heart disease—their risk of heart attack and stroke is decreased. People who have heart failure, they have fewer heart failure related hospitalizations. People who have chronic kidney disease, the rate of their kidney disease getting worse is slowed, and the rate of developing kidney failure is lower. People who have extra weight and lose that weight—the problems that are associated with weight loss seem to get better. So things like metabolic liver disease, arthritis, sleep apnea, they tend to get better.
So in patients for whom this matters, who may have heart disease, kidney disease, or obesity complications, then the benefits of GLP-1s do outweigh the potential risks, which are typically gastrointestinal side effects. We know that they can cause— though not always—nausea, diarrhea, bloating. In people who lose weight rapidly, there’s an increased risk of gallstones, as there would be with any kind of rapid weight loss. If people lose a lot of weight without exercising, then they lose muscle mass, so they can become more frail.
So the key is: Will you benefit? And will you be harmed? And can your risk be lessened through lifestyle changes, like exercising or eating healthier so that you don’t have as much as nausea, bloating, or diarrhea—maybe by eating smaller meals or less fatty meals or less spicy meals. So there’s always trade-offs. If I have a patient who has really bad GI side effects, then the benefits may not be worth it because they’re so miserable. But if they’re tolerating it, I think they are. It’s really an individual decision for every patient.
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