This content material initially appeared on On a regular basis Well being. Republished with permission.
By Ross Wollen
Medically Reviewed by Sean Hashmi, MD courtesy of American School of Way of life Drugs
Though semaglutide (Ozempic, Wegovy) and different GLP-1 medicine have quickly turn out to be notorious for a large number of frequent unintended effects, from diarrhea to “Ozempic face,” probably the most distinguished warnings on their official U.S. Meals and Drug Administration (FDA) labels alert customers to a small variety of rarer however extra severe antagonistic occasions. These extra extreme issues embrace gallbladder illness, kidney illness, allergic reactions, pancreatitis, and thyroid most cancers.
All these antagonistic occasions are thought of uncommon, and consultants doubt that some are legitimately brought on by GLP-1 medicine. But it surely’s necessary to know the warning indicators and prevalence of those unusual Ozempic unintended effects.
Gallbladder Illnesses
“Gallbladder occasions are actual,” says Daniel Drucker, MD, an endocrinologist and a professor of medication on the Lunenfeld-Tanenbaum Analysis Institute in Toronto.
The gallbladder is a sac that shops bile, a digestive fluid produced by the liver. Once you eat, the gallbladder releases bile into the gut, which helps you break down fat in your meals.[1]
GLP-1 medicine are particularly related to two associated gallbladder situations, cholelithiasis and cholecystitis:
- Cholelithiasis is the formation of gallstones. Whereas some gallstones will sit harmlessly contained in the gallbladder, for a minority of sufferers they’ll block the discharge of bile.
- Cholecystitis, or irritation of the gallbladder, normally outcomes from the formation of gallstones. It causes quite a lot of uncomfortable or painful signs, and will be harmful in extreme instances.
Cholecystitis is usually felt in assaults lasting two or three days. Signs embrace sharp belly ache, ache close to the shoulder blades, jaundice, darkish urine, clay-colored stool, and gastrointestinal discomfort corresponding to nausea, bloating, and vomiting. These signs could also be worse after fatty meals, which require the discharge of extra bile.
A clinician can verify the presence of gallstones with an imaging check. Treatment may also help break up gallstones, however in some instances surgical procedure to take away gallstones is important. In probably the most extreme instances, gallbladder elimination (cholecystectomy) is an possibility.
Thankfully, these issues are comparatively uncommon. “It could be one in just a few hundred” sufferers who expertise a gallbladder situation resulting from GLP-1 drug use, says Dr. Drucker.
And a few of these gallbladder points will not be brought on by weight reduction medicine however by the burden loss itself, which promotes the formation of gallstones.[2] When GLP-1 medicine provoke particularly speedy weight reduction, a clinician might advise their sufferers to make use of a drug corresponding to ursodial (Actigall) with a view to forestall the formation of gallstones. Drucker additionally says that individuals who have a historical past of gallbladder points earlier than initiating a GLP-1 drug ought to converse to their medical doctors about prophylactic therapy.
Acute Kidney Damage
On the FDA label for Ozempic, “acute kidney damage and worsening of power renal failure” is listed as a possible antagonistic response.
This can be counterintuitive, because it appears clear that GLP-1 medicine have overwhelmingly optimistic results on kidney perform. The most recent knowledge means that, in sufferers with kind 2 diabetes and power kidney illness, Ozempic slashes the chance of kidney failure, substantial lack of kidney perform, or loss of life from kidney causes by 24 p.c. It isn’t but completely clear if GLP-1 medicine enhance the kidney instantly or if many of the profit is a results of weight reduction.
Nonetheless, hundreds of People have been recognized with acute kidney damage that was suspected to have been brought on by a GLP-1 drug. About 45 p.c required hospitalization, and 4 p.c have died. Many of those reactions, nevertheless, occurred with older medicines, corresponding to liraglutide and exenatide, that are normally prescribed for kind 2 diabetes somewhat than weight reduction.[3]
Acute kidney damage, which was once known as acute renal failure, happens when the kidneys are all of the sudden unable to filter and evacuate waste from the blood. The situation can develop rapidly (inside 48 hours) and its signs embrace decrease physique swelling, diminished must urinate, and ache within the again and chest.[4]
When kidney accidents do happen, they’re typically precipitated by dehydrating unintended effects corresponding to vomiting, which will be most severe when initiating the treatment or stepping up the dosage.[5] Most kidney accidents happen throughout the first two months of beginning a GLP-1 drug, in the course of the interval of dose escalation.[3] Using diuretics and different medicines that have an effect on fluid and electrolyte stability may also play a task.
“Studies of acute kidney damage are virtually all the time related to not consuming and consuming,” says Drucker. “Please name [your clinician] in the event you’re not consuming or consuming for twenty-four to 36 hours.”
GLP-1 Hypersensitivity and Allergic reactions
There have been experiences of sufferers who’re hypersensitive or allergic to GLP-1 medicines. The reactions have included the next signs:
- Urticaria (hives)
- Eczema
- Rash
- Angioedema (swelling beneath the pores and skin)
- Anaphylaxis
Pores and skin reactions on the injection website are most typical. In massive trials of semaglutide and tirzepatide, between 2 and 4 p.c of customers had delicate to average allergic reactions.[6]
Anaphylaxis, which is far rarer, is a severe and doubtlessly lethal allergic response. This situation normally develops in a short time, typically starting with rash, itching, or hives showing throughout the physique. Extra extreme instances of anaphylaxis, referred to as anaphylactic shock, embrace problem respiratory, excessive swelling, dizziness, and a speedy weak pulse. This situation, which might progress to lack of consciousness, organ failure, and loss of life, requires emergency medical therapy. A examine of almost 700,000 GLP-1 customers discovered that there have been 4.2 anaphylaxis episodes for each 10,000 person-years of publicity.[7]
For some folks, antidrug antibodies and allergic reactions could also be provoked by inactive components in a drugs. In these instances, a clinician might be able to prescribe a suitable different supply technique ready by a compounding pharmacy, however customers are suggested to be very cautious when selecting their very own provider.
There isn’t a proof that individuals who have hypersensitivity to GLP-1 medicine get pleasure from lesser advantages from the therapies. And however instances of allergic reactions, this drug household usually has an anti-inflammatory impact.[8]
Pancreatitis
Ozempic’s FDA label warns that pancreatitis has been reported in scientific trials, and that anybody experiencing pancreatitis ought to completely discontinue utilizing the treatment.
However the knowledgeable consensus is now that semaglutide and different GLP-1 medicine don’t improve the chance of pancreatitis, says Drucker.
Why is the illness listed as a attainable aspect impact? About 15 years in the past, trials of sitagliptin, one other GLP-1 drug, discovered {that a} excessive share of rats on the treatment developed pancreatitis.[9] “This acquired lots of people involved and , however we subsequently realized that many various species of rats exhibit terribly excessive charges of spontaneous pancreatitis,” says Drucker. In different phrases, these early rodent instances of pancreatitis had been most likely a false alarm.
There’s a second challenge: GLP-1 medicine can set off the discharge of enzymes which can be related to pancreatic issues.
GLP-1 medicine act instantly on the pancreas in quite a lot of methods, which helps account for a way efficient they’re in treating kind 2 diabetes. One of many adjustments they provoke is additional manufacturing of the digestive enzymes amylase and lipase. These are each wholesome substances that break down meals into power, however an excessive amount of of both is taken into account an indication of pancreatic dysfunction.[10] When sufferers inform their medical doctors that they’ve belly ache (a typical aspect impact of GLP-1 medicine), and a blood or urine check reveals elevated amylase or lipase ranges, “that’s two out of three standards for pancreatitis,” says Drucker. When a GLP-1 is the obvious trigger, nevertheless, an imaging scan of the pancreas not often reveals abnormalities.
A long time after these early research in rodents, we now have glorious knowledge on the long-term results of semaglutide and different GLP-1 medicine in people. These trials have evaluated the well being of tens of hundreds of individuals. And the info now reveals that GLP-1 medicine like Ozempic virtually definitely don’t trigger the event of pancreatic issues.[11][12]
“Now we’ve got way more knowledge and we actually don’t see a rise in pancreatitis standing out with the GLP-1 medicines,” says Drucker.
Pancreatitis Signs
Whereas it’s unlikely that Ozempic, or different GLP-1 receptor agonists, are inflicting pancreatitis, the situation stays a really actual dysfunction that sends about 50,000 People to the hospital yearly.[13] It’s good to be aware of pancreatitis signs.
On the official Ozempic label, the FDA experiences that pancreatitis is characterised by “persistent extreme belly ache, generally radiating to the again and which can or will not be accompanied by vomiting.” Further signs of pancreatitis might embrace fever, elevated coronary heart price, and greasy or yellow stool.
Acute pancreatitis normally comes on rapidly, and usually lasts solely a handful of days. The illness might require an prolonged keep within the hospital. In a minority of instances it might result in extreme outcomes, together with loss of life.
Power pancreatitis, wherein the signs don’t enhance, or they preserve reoccurring, is normally related to alcohol abuse.
Pancreatic Most cancers
There isn’t a proof that Ozempic or different GLP-1 medicine improve the chance of pancreatic most cancers.
In truth, the other could also be true. Actual-world knowledge, overlaying the experiences of tons of of hundreds of sufferers, discovered that GLP-1s diminished the prevalence of pancreatic most cancers.[14]
“We’ve began to see this now over and over,” says Drucker. Extra actual world knowledge means that GLP-1 medicine, that are reputed to help the physique’s most cancers killing cells, might scale back the chance of colorectal, prostate, and liver most cancers, too, says Drucker.
Thyroid Most cancers
The FDA labels for Ozempic, Wegovy, Mounjaro, and Zepbound all embrace a black field warning concerning the threat of thyroid C-cell tumors. That is the very best and most distinguished safety-related warning that the U.S. authorities provides to drug packaging.
Throughout the black field, the FDA explains that the medicines trigger rodents to develop thyroid C-cell tumors, however that it’s “unknown” whether or not the identical happens in people. The FDA continues to clarify GLP-1 medicine shouldn’t be used “in sufferers with a private or household historical past of medullary thyroid carcinoma or a number of endocrine neoplasia syndrome kind 2 (MEN 2).”
At the moment, consultants agree that there is no such thing as a actual threat of thyroid most cancers related to GLP-1 medicine. Elizabeth Pearce, MD, an endocrinologist and thyroid specialist at Boston Medical Middle, says that “Unequivocally, we don’t see the identical results in people as we do in rodents.”
Many research have tried to determine a threat of thyroid most cancers inherent in GLP-1 medicine, however none has convincingly proven a hyperlink. A current long-term examine of 145,410 Scandinavian sufferers utilizing GLP-1s, for instance, discovered that over 3.9 years of follow-up solely 76 developed thyroid most cancers, a decrease incidence price than within the management group.[15] Whereas another research have apparently discovered an elevated threat of thyroid most cancers, these are normally counting instances of low-risk papillary thyroid most cancers, a situation that’s overdiagnosed and has no suspected hyperlink to GLP-1 medicine, says Pearce. The latest complete analysis of the proof concluded that “there is no such thing as a conclusive proof of elevated thyroid most cancers threat.”[16]
It’s believable that the info has not but revealed an elevated threat of thyroid most cancers, which might take a very long time to develop. “If it’s actual,” says Pearce, “it’s most likely very very uncommon and really low threat.”
There has by no means been any such official thyroid most cancers warning in Europe. In truth, in 2023, European regulators introduced {that a} security panel discovered no hyperlink between GLP-1 medicine and thyroid most cancers.[17]
Nonetheless, Pearce means that American clinicians will possible proceed to observe prescribing pointers “for medical-legal causes, if nothing else.” Thankfully solely a tiny minority of persons are affected by this warning. “It doesn’t exclude a complete lot of sufferers, remembering that the prevalence of medullary thyroid most cancers and MEN 2 within the common grownup inhabitants is someplace between 1 in 30,000 and 1 in 40,000.”
Pearce provides that sufferers and medical doctors alike shouldn’t be unduly involved by any attainable results on the thyroid. “We shouldn’t be screening for thyroid nodules earlier than or throughout GLP-1 receptor agonist therapy simply because the sufferers are on these medicines.”
Tirzepatide and Extreme Aspect Results
Many of the knowledge shared above was collected from research of semaglutide and different GLP-1 medicine. There may be much less identified about tirzepatide (Mounjaro, Zepbound) as a result of it’s the latest member of this drug household. There merely has been much less long-term examine of tirzepatide, each in scientific and real-world settings.
At the moment, tirzepatide carries related or equivalent warnings towards extreme unintended effects on its FDA labels. Customers are warned about thyroid most cancers, pancreatitis, kidney issues, gallbladder illness, and allergic reactions.
Uniquely on this drug class, tirzepatide is a twin agonist. Like semaglutide, it mimics the exercise of the hormone GLP-1, but it surely moreover mimics the exercise of a second hormone named GIP. This can be the important thing to its outstanding efficacy. At its highest doses, tirzepatide causes significantly extra weight reduction than the very best doses of semaglutide.
GLP-1 unintended effects are usually dose-dependent: reactions are extra frequent and extra extreme at greater doses. However tirzepatide, regardless of its energy, doesn’t essentially entail a better threat of those uncommon extreme unintended effects. In truth, the other could also be true. “There may be some intriguing knowledge suggesting that GIP, at the least in animals, does mitigate a few of the antagonistic occasions that may be induced by GLP-1,” says Drucker. Primarily based on what we all know to date, tirzepatide might be no extra more likely to trigger any of the uncommon and extreme unintended effects mentioned on this article.
The Takeaway
The brand new era of GLP-1 medicine for kind 2 diabetes and weight reduction carry some horrifying warnings on their official labels. There’s an rising knowledgeable consensus that a few of these unintended effects — notably pancreatitis and thyroid most cancers — aren’t really brought on by Ozempic or different medicine within the class. However gallbladder illness, acute kidney damage, and allergic reactions are actual potentialities, and an excellent reminder to be very cautious with the unintended effects brought on by these highly effective medicines.
