Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
GLP-1 weight loss drugs; how safe are they? Regulatory authorities have expressed concerns about the potential risk of acute pancreatitis, thyroid cancer, and kidney failure––warnings that are appropriately conveyed in every box of drugs handed to a patient. Here’s the actual package insert for high-dose Ozempic, sold for weight loss as Wegovy. Warnings and precautions include thyroid tumors, acute inflammation of the pancreas, acute gallbladder disease, heightened risk of low blood sugars if you’re on blood sugar-lowering medications, acute kidney Injury, allergic reactions, worsening eye disease for those with type 2 diabetes, an increase in heart rate that should be monitored, and suicidal thoughts and behaviors. And the package insert for the other major GLP-1 weight loss drug, tirzepatide, sold as Zepbound, reads almost word for word the same.
Let’s start with the good news: suicide. The possibility of an adverse psychiatric event on GLP-1 drugs is biologically plausible because GLP-1 receptors are widely expressed in the central nervous system, including our brain. So, what does the science show? This meta-analysis of randomized controlled trials did not highlight any detrimental effect of these drugs on mental health, including suicide. Now, this meta-analysis only covered studies up through the end of 2023, and only clinical trials, and those with mental illnesses are usually excluded from such studies. But there have been newer studies done with subjects out in the real world, and again, no clear increased risk. And this study, on the association of the Ozempic drug semaglutide with risk of suicidal ideation in another cohort, found the drug was associated with a lower risk for incident, and recurrent, suicidal ideation––apparently cutting suicidal thoughts by more than half compared to those on the older, less effective weight-loss drugs. After all, a weight-reducing treatment that limits the burden of obesity could improve mood.
I told you suicide was the good news!
Now, on to cancer. Both Wegovy, high-dose Ozempic, and Zepbound (tirzepatide) carry so-called black box warnings for thyroid cancer risk. Black box warnings are the U.S. Food and Drug Administration’s strictest caution about potentially life-threatening hazards. In rodents, these drugs cause dose-dependent and duration-dependent thyroid tumors, at clinically relevant exposures––meaning the kind of doses prescribed to humans. Now, we don’t know yet whether these drugs cause a thyroid cancer called medullary thyroid carcinoma in humans, which is a cancer of the thyroid C cells. To be on the safe side, the drugs shouldn’t be prescribed for high-risk individuals, like those with a personal or family history of thyroid cancer, but it’s not like the rats had thyroid cancer running in their families.
Doctors should counsel their patients to remain alert for symptoms of thyroid tumors, like a lump or swelling in the neck, trouble swallowing, shortness of breath, or persistent hoarseness. I’d be curious in the comments to see if any viewers who’ve been prescribed these drugs were told any of this by their prescribing physicians.
Can’t we just ultrasound people’s necks to see if they develop thyroid tumors on these drugs? That’s considered to be of uncertain value, since no such studies have been done.
But there have been studies done on GLP-1 drugs, like Ozempic, and the risk of thyroid cancer in people. This was the first major one raising concern, published in 2023. Researchers found increased risk of all thyroid cancers, and specifically medullary thyroid cancer, in people using these drugs––particularly after taking them for a few years. A commentary citing the study asked, “Is it the time to be concerned?” Maybe that one study was just a fluke? No, after putting together all the best studies, a systematic review and meta-analysis of randomized controlled trials found, again, a significant increase in the risk of overall thyroid cancer, about 52 percent greater odds. That sounds bad, until you realize just how rare the cancer is overall.
The incidence of thyroid cancer in this kind of population is 0.285 cases per 1,000 patient years. This means that over a span of 10 years, we’d only expect about three people out of 1,000 to get that cancer. So, even if you bump up that risk by 50 percent, you’re still only talking about four in 1,000 getting it over a decade, compared to three in 1,000 if they hadn’t started taking the drugs. That translates to a five-year “number needed to harm” of 1,349. That means that even if this were truly cause and effect, it would take treating 1,349 people for five years to cause a single additional case of thyroid cancer.
And even if you are the unlucky soul who gets it, it’s pretty mild as cancers go. The five-year relative survival rate, meaning the likelihood you’ll still be alive five years after diagnosis, compared to people without the cancer, is 98.4 percent.
Okay, but what about the risk of pancreatic cancer with the use of these drugs? That has a relative five-year survival rate of only 12.8 percent. You can see the difference between the incidence rates, and the death rates. For thyroid cancer, a bunch of people are diagnosed with it, but very few die from it, whereas for pancreatic cancer, almost everyone who gets it dies from it. So, do these drugs cause pancreatic cancer?
The most common adverse side effects of Ozempic-type weight-loss drugs are gastrointestinal issues, including nausea, vomiting, diarrhea, and constipation, which I talked about in a previous video––as well as excessive lean muscle loss and gallbladder issues, discussed in a subsequent video. But Ozempic may also heighten the risks of pancreatitis, kidney failure, and thyroid cancer. I talked about the thyroid cancer risk in my last video. Many of the kidney issues may stem from dehydration due to excessive vomiting or diarrhea caused by the drugs.
But what about the pancreas inflammation? Analyzing the prescription records of 16 million Americans, compared to taking an older class of weight loss drugs, the use of GLP-1 drugs like Ozempic was associated with nine times more pancreatitis, as well as four times higher risk of bowel obstruction. Remember, GLP-1 slows down your digestive tract. That’s part of the reason people get nauseous and barfy, but that’s also part of why you feel fuller for longer, and lose weight. But sometimes it can make your gut so sluggish it stops working, and you get a blockage that could become a surgical emergency. It’s super rare, though. The number needed to harm after one year of use is 1,223, meaning more than 1,000 people would have to take the drug for a year to cause a single extra case of bowel obstruction. So, even after 10 years of treatment, your cumulative risk would be less than one percent.
But what about this 800 percent increased risk of pancreatitis? Digestive hormones like GLP-1 act on multiple targets within the body, with multiple effects, perhaps more “magic shotgun” than “magic bullet,” but maybe not so magical for the pancreas. GLP-1 receptors are expressed abundantly throughout the pancreas, and in response to GLP-1 therapy, the cells of the pancreas proliferate, swelling the organ, and potentially squeezing off ducts, causing inflammation, at least in rats. But that led to human studies like this, suggesting that GLP-1 drugs may increase the odds of pancreatitis as much as six-fold. This led some investigators to conclude that the balance of evidence suggests an association between the use of GLP-1–based therapies and acute pancreatitis.
The major concern is not pancreatitis, though. Acute pancreatitis is unpleasant enough, but the major concern is subclinical—asymptomatic—inflammation of the pancreas, because inflammation of the pancreas is well known to predispose to pancreatic cancer, which is one of the deadliest forms of cancer. And some of the rats did show potentially premalignant changes in their pancreases on these drugs. The concern is that the pro-proliferative actions of GLP-1 could take premalignant lesions and accelerate their progression towards cancer.
Remember how these drugs were modeled off a compound found in Gila monster saliva? Few have paused to wonder why they would produce it. The answer is that the Gila monster is a desert lizard that goes for weeks or even months between meals, and conserves energy during those intervals by shrinking its digestive tract, including its pancreas. So, when it finally does eat, it needs a way to rapidly proliferate its tissues.
After reviewing thousands of pages of documents obtained through Freedom of Information requests, a British Medical Journal investigation unearthed unpublished data from animal and human studies that point to pathological changes in the pancreas, including attempts by drug companies to suppress scientific debate by withholding important safety data from the public.
Why have the companies been so slow to respond to this threat? Because of the “three monkey paradigm,” which operates as follows. Companies are legally responsible for monitoring the safety of their own products, but obviously cannot be held responsible for tackling a safety concern that does not exist. A concern that can be plausibly doubted or denied carries no legal liability, whereas one that gives rise to serious consideration leaves the door wide open to lawsuits. Thus, inviting companies to monitor the safety of their own products provides them with the strongest possible incentive for failing to do so––an instance of the law of unintended consequences. The three monkeys, who neither hear nor see nor speak, have been allowed to flourish at the heart of our system for protecting the public.
“After careful reflection,” wrote a professor of medicine at the Mayo Clinic, “most patients and clinicians may opt to avoid GLP-1 based drugs or at least avoid using them for a prolonged period of time.” And this was all before this pivotal study came out, where researchers obtained transplant-quality pancreases from like accident victims who had been taking GLP-1 drugs for at least a year before they died, and every single pancreas showed abnormalities, marked enlargement, dysplasia, and even a few little tumors.
This was all discovered more than a decade ago, though. Where are we now? It remains unclear whether the use of GLP-1 drugs is linked to an increased risk of pancreatic cancer. But trials would have to be enormous to exclude an increased risk, and unless the rules change radically by the time they are to be reported, most of the data will remain hidden from independent scrutiny. And, as one Johns Hopkins drug safety researcher asked, “The fundamental question is who bears the burden of the passage of time while these debates are settled?”
Thousands of pancreatic cancer cases have been reportedly tied to GLP-1 drugs, like Ozempic, based on the U.S. Food and Drug Administration’s Adverse Events Reporting System. But adverse event databases that rely on voluntary reporting are limited by the potential for reporting bias.
That’s like the Centers for Disease Control’s VAERS database—the Vaccine Adverse Events Reporting System. During COVID, the more states were inclined to vote Republican, the more likely their vaccine recipients or clinicians were to report COVID vaccine side effects. So, maybe there was some kind of similar reporting bias among those who submit their pancreatic cancer to the FDA? Either way, if there is even a remote chance that certain drugs can have an impact on cancer development and progression, then such risks should not be taken lightly.
But if you really don’t want to get cancer, then you really don’t want to be overweight. Based on a study following millions of people, the longer you’re overweight or obese, the higher your apparent risk of 18 different types of cancer. So, even if you cared only about cancer, might these drugs actually lower your overall cancer risk if they caused enough weight loss? A meta-analysis of bariatric surgery studies found that those going under the knife tend to lose so much weight that they have a significantly lower risk of getting cancer, and appear to cut their risk of dying from cancer nearly in half. This modeling study suggests that widespread usage of these new generation weight loss drugs like Ozempic could prevent more than like one out of 100 cancers over the next 25 years. And that’s just cancer. Wouldn’t just the cardiovascular benefits of losing a lot of weight alone outweigh any potential risks? That’s the subject of my next video: do the benefits outweigh the risks?
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