This content originally appeared on Everyday Health. Republished with permission.

By Ross Wollen

Medically Reviewed by Sean Hashmi, MD courtesy of American College of Lifestyle Medicine

Although semaglutide (Ozempic, Wegovy) and other GLP-1 drugs have rapidly become infamous for a wide variety of common side effects, from diarrhea to “Ozempic face,” the most prominent warnings on their official U.S. Food and Drug Administration (FDA) labels alert users to a small number of rarer but more serious adverse events. These more severe complications include gallbladder disease, kidney disease, allergic reactions, pancreatitis, and thyroid cancer.

All these adverse events are considered rare, and experts doubt that some are legitimately caused by GLP-1 drugs. But it’s important to know the warning signs and prevalence of these uncommon Ozempic side effects.

Gallbladder Diseases

“Gallbladder events are real,” says Daniel Drucker, MD, an endocrinologist and a professor of medicine at the Lunenfeld-Tanenbaum Research Institute in Toronto.

The gallbladder is a sac that stores bile, a digestive fluid produced by the liver. When you eat, the gallbladder releases bile into the intestine, which helps you break down fats in your food.[1]

GLP-1 drugs are especially associated with two related gallbladder conditions, cholelithiasis and cholecystitis:

Cholelithiasis is the formation of gallstones. While some gallstones will sit harmlessly inside the gallbladder, for a minority of patients they will block the release of bile.
Cholecystitis, or inflammation of the gallbladder, usually results from the formation of gallstones. It causes a variety of uncomfortable or painful symptoms, and can be dangerous in severe cases.

Cholecystitis is generally felt in attacks lasting two or three days. Symptoms include sharp abdominal pain, pain near the shoulder blades, jaundice, dark urine, clay-colored stool, and gastrointestinal discomfort such as nausea, bloating, and vomiting. These symptoms may be worse after fatty meals, which require the release of more bile.

A clinician can confirm the presence of gallstones with an imaging test. Medication can help break up gallstones, but in some cases surgery to remove gallstones is necessary. In the most severe cases, gallbladder removal (cholecystectomy) is an option.

Fortunately, these complications are relatively rare. “It might be one in a few hundred” patients who experience a gallbladder condition due to GLP-1 drug use, says Dr. Drucker.

And some of these gallbladder issues may not be caused by weight loss drugs but by the weight loss itself, which promotes the formation of gallstones.[2] When GLP-1 drugs provoke especially rapid weight loss, a clinician may advise their patients to use a drug such as ursodial (Actigall) in order to prevent the formation of gallstones. Drucker also says that people who have a history of gallbladder issues before initiating a GLP-1 drug should speak to their doctors about prophylactic treatment.

Acute Kidney Injury

On the FDA label for Ozempic, “acute kidney injury and worsening of chronic renal failure” is listed as a potential adverse reaction.

This may be counterintuitive, as it seems clear that GLP-1 drugs have overwhelmingly positive effects on kidney function. The latest data suggests that, in patients with type 2 diabetes and chronic kidney disease, Ozempic slashes the risk of kidney failure, substantial loss of kidney function, or death from kidney causes by 24 percent. It is not yet entirely clear if GLP-1 drugs improve the kidney directly or if most of the benefit is a result of weight loss.

Nevertheless, thousands of Americans have been diagnosed with acute kidney injury that was suspected to have been caused by a GLP-1 drug. About 45 percent required hospitalization, and 4 percent have died. Many of these reactions, however, occurred with older medications, such as liraglutide and exenatide, which are usually prescribed for type 2 diabetes rather than weight loss.[3]

Acute kidney injury, which used to be called acute renal failure, occurs when the kidneys are suddenly unable to filter and evacuate waste from the blood. The condition can develop quickly (within 48 hours) and its symptoms include lower body swelling, reduced need to urinate, and pain in the back and chest.[4]

When kidney injuries do occur, they are often precipitated by dehydrating side effects such as vomiting, which can be most serious when initiating the medication or stepping up the dosage.[5] Most kidney injuries occur within the first two months of starting a GLP-1 drug, during the period of dose escalation.[3] The use of diuretics and other medications that affect fluid and electrolyte balance can also play a role.

“Reports of acute kidney injury are almost always associated with not eating and drinking,” says Drucker. “Please call [your clinician] if you’re not eating or drinking for 24 to 36 hours.”

GLP-1 Hypersensitivity and Allergies

There have been reports of patients who are hypersensitive or allergic to GLP-1 medications. The reactions have included the following symptoms:

Urticaria (hives)
Eczema
Rash
Angioedema (swelling beneath the skin)
Anaphylaxis

Skin reactions at the injection site are most common. In large trials of semaglutide and tirzepatide, between 2 and 4 percent of users had mild to moderate allergic reactions.[6]

Anaphylaxis, which is much rarer, is a serious and potentially deadly allergic reaction. This condition usually develops very quickly, often beginning with rash, itching, or hives appearing across the body. More severe cases of anaphylaxis, known as anaphylactic shock, include difficulty breathing, extreme swelling, dizziness, and a rapid weak pulse. This condition, which can progress to loss of consciousness, organ failure, and death, requires emergency medical treatment. A study of nearly 700,000 GLP-1 users found that there were 4.2 anaphylaxis episodes for every 10,000 person-years of exposure.[7]

For some people, antidrug antibodies and allergic reactions may be provoked by inactive ingredients in a medication. In these cases, a clinician may be able to prescribe an acceptable alternative delivery method prepared by a compounding pharmacy, but users are advised to be very careful when choosing their own supplier.

There is no evidence that people who have hypersensitivity to GLP-1 drugs enjoy lesser benefits from the therapies. And notwithstanding cases of allergic reactions, this drug family generally has an anti-inflammatory effect.[8]

Pancreatitis

Ozempic’s FDA label warns that pancreatitis has been reported in clinical trials, and that anyone experiencing pancreatitis should permanently discontinue using the medication.

But the expert consensus is now that semaglutide and other GLP-1 drugs do not increase the risk of pancreatitis, says Drucker.

Why is the disease listed as a possible side effect? About 15 years ago, trials of sitagliptin, another GLP-1 drug, found that a high percentage of rats on the medication developed pancreatitis.[9] “This got a lot of people concerned and interested, but we subsequently learned that many different species of rats exhibit extraordinarily high rates of spontaneous pancreatitis,” says Drucker. In other words, those early rodent cases of pancreatitis were probably a false alarm.

There’s a second issue: GLP-1 drugs can trigger the release of enzymes that are associated with pancreatic disorders.

GLP-1 drugs act directly on the pancreas in a variety of ways, which helps account for how effective they are in treating type 2 diabetes. One of the changes they provoke is extra production of the digestive enzymes amylase and lipase. These are both healthy substances that break down food into energy, but too much of either is considered a sign of pancreatic disorder.[10] When patients tell their doctors that they have abdominal pain (a common side effect of GLP-1 drugs), and a blood or urine test shows elevated amylase or lipase levels, “that’s two out of three criteria for pancreatitis,” says Drucker. When a GLP-1 is the apparent cause, however, an imaging scan of the pancreas rarely shows abnormalities.

Decades after those early studies in rodents, we now have excellent data on the long-term effects of semaglutide and other GLP-1 drugs in humans. These trials have evaluated the health of tens of thousands of people. And the data now shows that GLP-1 drugs like Ozempic almost certainly do not cause the development of pancreatic disorders.[11][12]

“Now we have much more data and we really don’t see an increase in pancreatitis standing out with the GLP-1 medicines,” says Drucker.

Pancreatitis Symptoms

While it is unlikely that Ozempic, or other GLP-1 receptor agonists, are causing pancreatitis, the condition remains a very real disorder that sends about 50,000 Americans to the hospital every year.[13] It’s good to be familiar with pancreatitis symptoms.

On the official Ozempic label, the FDA reports that pancreatitis is characterized by “persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting.” Additional symptoms of pancreatitis may include fever, elevated heart rate, and greasy or yellow stool.

Acute pancreatitis usually comes on quickly, and typically lasts only a handful of days. The disease may require an extended stay in the hospital. In a minority of cases it can lead to severe outcomes, including death.

Chronic pancreatitis, in which the symptoms do not improve, or they keep reoccurring, is usually associated with alcohol abuse.

Pancreatic Cancer

There is no evidence that Ozempic or other GLP-1 drugs increase the risk of pancreatic cancer.

In fact, the opposite may be true. Real-world data, covering the experiences of hundreds of thousands of patients, found that GLP-1s reduced the prevalence of pancreatic cancer.[14]

“We’ve started to see this now over and over again,” says Drucker. More real world data suggests that GLP-1 drugs, which are reputed to aid the body’s cancer killing cells, may reduce the risk of colorectal, prostate, and liver cancer, too, says Drucker.

Thyroid Cancer

The FDA labels for Ozempic, Wegovy, Mounjaro, and Zepbound all include a black box warning about the risk of thyroid C-cell tumors. This is the highest and most prominent safety-related warning that the U.S. government adds to drug packaging.

Within the black box, the FDA explains that the medications cause rodents to develop thyroid C-cell tumors, but that it is “unknown” whether the same occurs in humans. The FDA continues to explain GLP-1 drugs should not be used “in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2).”

Today, experts agree that there is no real risk of thyroid cancer associated with GLP-1 drugs. Elizabeth Pearce, MD, an endocrinologist and thyroid specialist at Boston Medical Center, says that “Unequivocally, we do not see the same effects in humans as we do in rodents.”

Many studies have attempted to identify a risk of thyroid cancer inherent in GLP-1 drugs, but none has convincingly shown a link. A recent long-term study of 145,410 Scandinavian patients using GLP-1s, for example, found that over 3.9 years of follow-up only 76 developed thyroid cancer, a lower incidence rate than in the control group.[15] While some other studies have apparently found an increased risk of thyroid cancer, these are usually counting cases of low-risk papillary thyroid cancer, a condition that is overdiagnosed and has no suspected link to GLP-1 drugs, says Pearce. The most recent comprehensive evaluation of the evidence concluded that “there is no conclusive evidence of elevated thyroid cancer risk.”[16]

It is plausible that the data has not yet revealed an increased risk of thyroid cancer, which can take a long time to develop. “If it’s real,” says Pearce, “it’s probably very very rare and very low risk.”

There has never been any such official thyroid cancer warning in Europe. In fact, in 2023, European regulators announced that a safety panel found no link between GLP-1 drugs and thyroid cancer.[17]

Nevertheless, Pearce suggests that American clinicians will likely continue to follow prescribing guidelines “for medical-legal reasons, if nothing else.” Fortunately only a tiny minority of people are affected by this warning. “It doesn’t exclude a whole lot of patients, remembering that the prevalence of medullary thyroid cancer and MEN 2 in the general adult population is somewhere between 1 in 30,000 and 1 in 40,000.”

Pearce adds that patients and doctors alike should not be unduly concerned by any possible effects on the thyroid. “We should not be screening for thyroid nodules before or during GLP-1 receptor agonist treatment just because the patients are on these medications.”

Tirzepatide and Severe Side Effects

Most of the data shared above was collected from studies of semaglutide and other GLP-1 drugs. There is less known about tirzepatide (Mounjaro, Zepbound) because it is the newest member of this drug family. There simply has been less long-term study of tirzepatide, both in clinical and real-world settings.

Today, tirzepatide carries similar or identical warnings against severe side effects on its FDA labels. Users are warned about thyroid cancer, pancreatitis, kidney problems, gallbladder disease, and allergic reactions.

Uniquely in this drug class, tirzepatide is a dual agonist. Like semaglutide, it mimics the activity of the hormone GLP-1, but it additionally mimics the activity of a second hormone named GIP. This may be the key to its remarkable efficacy. At its highest doses, tirzepatide causes considerably more weight loss than the highest doses of semaglutide.

GLP-1 side effects are generally dose-dependent: reactions are more frequent and more severe at higher doses. But tirzepatide, despite its strength, doesn’t necessarily entail a higher risk of these rare severe side effects. In fact, the opposite may be true. “There is some intriguing data suggesting that GIP, at least in animals, does mitigate some of the adverse events that can be induced by GLP-1,” says Drucker. Based on what we know so far, tirzepatide is probably no more likely to cause any of the rare and severe side effects discussed in this article.

The Takeaway

The new generation of GLP-1 drugs for type 2 diabetes and weight loss carry some frightening warnings on their official labels. There’s an emerging expert consensus that some of these side effects — particularly pancreatitis and thyroid cancer — aren’t actually caused by Ozempic or other drugs in the class. But gallbladder disease, acute kidney injury, and allergic reactions are real possibilities, and a good reminder to be very cautious with the side effects caused by these powerful medications.

Resources We Trust

Mayo Clinic: Considering GLP-1 Medications? What They Are and Why Lifestyle Change Is Key to Sustained Weight Loss
National Institute of Diabetes and Digestive and Kidney Diseases: Symptoms and Causes of Pancreatitis
U.S. Food and Drug Administration: Finding and Learning About Side Effects (Adverse Reactions)
Johns Hopkins Medicine: Allergies and the Immune System
Stanford University: Why Animal Research?

Editorial Sources and Fact-Checking