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 medication have quickly grow to be notorious for a large number of widespread unwanted effects, from diarrhea to “Ozempic face,” probably the most outstanding warnings on their official U.S. Meals and Drug Administration (FDA) labels alert customers to a small variety of rarer however extra severe opposed occasions. These extra extreme issues embody gallbladder illness, kidney illness, allergic reactions, pancreatitis, and thyroid most cancers.
All these opposed occasions are thought of uncommon, and consultants doubt that some are legitimately brought on by GLP-1 medication. But it surely’s vital to know the warning indicators and prevalence of those unusual Ozempic unwanted effects.
Gallbladder Ailments
“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. Whenever you eat, the gallbladder releases bile into the gut, which helps you break down fat in your meals.[1]
GLP-1 medication 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 are going to block the discharge of bile.
- Cholecystitis, or irritation of the gallbladder, often outcomes from the formation of gallstones. It causes a wide range of uncomfortable or painful signs, and will be harmful in extreme circumstances.
Cholecystitis is mostly felt in assaults lasting two or three days. Signs embody sharp belly ache, ache close to the shoulder blades, jaundice, darkish urine, clay-colored stool, and gastrointestinal discomfort equivalent 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. Medicine will help break up gallstones, however in some circumstances surgical procedure to take away gallstones is important. In probably the most extreme circumstances, gallbladder removing (cholecystectomy) is an choice.
Happily, these issues are comparatively uncommon. “It is likely to be one in a couple of hundred” sufferers who expertise a gallbladder situation because of GLP-1 drug use, says Dr. Drucker.
And a few of these gallbladder points is probably not brought on by weight reduction medication however by the burden loss itself, which promotes the formation of gallstones.[2] When GLP-1 medication provoke particularly speedy weight reduction, a clinician might advise their sufferers to make use of a drug equivalent to ursodial (Actigall) so as to stop 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 docs about prophylactic remedy.
Acute Kidney Damage
On the FDA label for Ozempic, “acute kidney damage and worsening of continual renal failure” is listed as a possible opposed response.
This can be counterintuitive, because it appears clear that GLP-1 medication have overwhelmingly optimistic results on kidney operate. The most recent knowledge means that, in sufferers with sort 2 diabetes and continual kidney illness, Ozempic slashes the chance of kidney failure, substantial lack of kidney operate, or dying from kidney causes by 24 p.c. It isn’t but solely clear if GLP-1 medication enhance the kidney instantly or if many of the profit is a results of weight reduction.
Nonetheless, hundreds of Individuals 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, equivalent to liraglutide and exenatide, that are often prescribed for sort 2 diabetes quite than weight reduction.[3]
Acute kidney damage, which was referred to as acute renal failure, happens when the kidneys are out of the blue unable to filter and evacuate waste from the blood. The situation can develop rapidly (inside 48 hours) and its signs embody decrease physique swelling, decreased have to urinate, and ache within the again and chest.[4]
When kidney accidents do happen, they’re usually precipitated by dehydrating unwanted effects equivalent to vomiting, which will be most severe when initiating the remedy or stepping up the dosage.[5] Most kidney accidents happen throughout the first two months of beginning a GLP-1 drug, throughout the interval of dose escalation.[3] The usage of diuretics and different medicines that have an effect on fluid and electrolyte stability also can play a task.
“Studies of acute kidney damage are nearly at all times 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 reviews 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 web site are most typical. In massive trials of semaglutide and tirzepatide, between 2 and 4 p.c of customers had delicate to reasonable allergic reactions.[6]
Anaphylaxis, which is far rarer, is a severe and doubtlessly lethal allergic response. This situation often develops in a short time, usually starting with rash, itching, or hives showing throughout the physique. Extra extreme circumstances of anaphylaxis, often known as anaphylactic shock, embody problem respiratory, excessive swelling, dizziness, and a speedy weak pulse. This situation, which may progress to lack of consciousness, organ failure, and dying, requires emergency medical remedy. A examine of practically 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 individuals, antidrug antibodies and allergic reactions could also be provoked by inactive components in a medicine. In these circumstances, a clinician could possibly prescribe a suitable different supply methodology ready by a compounding pharmacy, however customers are suggested to be very cautious when selecting their very own provider.
There isn’t any proof that individuals who have hypersensitivity to GLP-1 medication take pleasure in lesser advantages from the therapies. And however circumstances 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 medical trials, and that anybody experiencing pancreatitis ought to completely discontinue utilizing the remedy.
However the professional consensus is now that semaglutide and different GLP-1 medication don’t enhance the chance of pancreatitis, says Drucker.
Why is the illness listed as a attainable facet impact? About 15 years in the past, trials of sitagliptin, one other GLP-1 drug, discovered {that a} excessive proportion of rats on the remedy developed pancreatitis.[9] “This received lots of people involved and , however we subsequently discovered that many alternative species of rats exhibit terribly excessive charges of spontaneous pancreatitis,” says Drucker. In different phrases, these early rodent circumstances of pancreatitis had been most likely a false alarm.
There’s a second problem: GLP-1 medication can set off the discharge of enzymes which might be related to pancreatic problems.
GLP-1 medication act instantly on the pancreas in a wide range of methods, which helps account for a way efficient they’re in treating sort 2 diabetes. One of many modifications 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 docs that they’ve belly ache (a typical facet impact of GLP-1 medication), 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 medication in people. These trials have evaluated the well being of tens of hundreds of individuals. And the info now reveals that GLP-1 medication like Ozempic nearly definitely don’t trigger the event of pancreatic problems.[11][12]
“Now we now have far 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 Individuals to the hospital yearly.[13] It’s good to be accustomed to pancreatitis signs.
On the official Ozempic label, the FDA reviews that pancreatitis is characterised by “persistent extreme belly ache, typically radiating to the again and which can or is probably not accompanied by vomiting.” Further signs of pancreatitis might embody fever, elevated coronary heart fee, and greasy or yellow stool.
Acute pancreatitis often 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 circumstances it may well result in extreme outcomes, together with dying.
Power pancreatitis, by which the signs don’t enhance, or they hold reoccurring, is often related to alcohol abuse.
Pancreatic Most cancers
There isn’t any proof that Ozempic or different GLP-1 medication enhance the chance of pancreatic most cancers.
Actually, the other could also be true. Actual-world knowledge, protecting the experiences of lots of of hundreds of sufferers, discovered that GLP-1s decreased the prevalence of pancreatic most cancers.[14]
“We’ve began to see this now time and again,” says Drucker. Extra actual world knowledge means that GLP-1 medication, that are reputed to assist 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 embody a black field warning concerning the danger of thyroid C-cell tumors. That is the best and most outstanding safety-related warning that the U.S. authorities provides to drug packaging.
Inside 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 elucidate GLP-1 medication shouldn’t be used “in sufferers with a private or household historical past of medullary thyroid carcinoma or a number of endocrine neoplasia syndrome sort 2 (MEN 2).”
At this time, consultants agree that there isn’t any actual danger of thyroid most cancers related to GLP-1 medication. Elizabeth Pearce, MD, an endocrinologist and thyroid specialist at Boston Medical Heart, says that “Unequivocally, we don’t see the identical results in people as we do in rodents.”
Many research have tried to determine a danger of thyroid most cancers inherent in GLP-1 medication, however none has convincingly proven a hyperlink. A latest 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 fee than within the management group.[15] Whereas another research have apparently discovered an elevated danger of thyroid most cancers, these are often counting circumstances of low-risk papillary thyroid most cancers, a situation that’s overdiagnosed and has no suspected hyperlink to GLP-1 medication, says Pearce. The newest complete analysis of the proof concluded that “there isn’t any conclusive proof of elevated thyroid most cancers danger.”[16]
It’s believable that the info has not but revealed an elevated danger of thyroid most cancers, which may take a very long time to develop. “If it’s actual,” says Pearce, “it’s most likely very very uncommon and really low danger.”
There has by no means been any such official thyroid most cancers warning in Europe. Actually, in 2023, European regulators introduced {that a} security panel discovered no hyperlink between GLP-1 medication and thyroid most cancers.[17]
Nonetheless, Pearce means that American clinicians will seemingly proceed to observe prescribing pointers “for medical-legal causes, if nothing else.” Happily 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 docs 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 remedy simply because the sufferers are on these medicines.”
Tirzepatide and Extreme Facet Results
Many of the knowledge shared above was collected from research of semaglutide and different GLP-1 medication. There’s much less recognized 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 medical and real-world settings.
At this time, tirzepatide carries related or an identical warnings in opposition to extreme unwanted 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, nevertheless it moreover mimics the exercise of a second hormone named GIP. This can be the important thing to its exceptional efficacy. At its highest doses, tirzepatide causes significantly extra weight reduction than the best doses of semaglutide.
GLP-1 unwanted 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 danger of those uncommon extreme unwanted effects. Actually, the other could also be true. “There’s some intriguing knowledge suggesting that GIP, at the least in animals, does mitigate a few of the opposed occasions that may be induced by GLP-1,” says Drucker. Based mostly on what we all know up to now, tirzepatide might be no extra prone to trigger any of the uncommon and extreme unwanted effects mentioned on this article.
The Takeaway
The brand new technology of GLP-1 medication for sort 2 diabetes and weight reduction carry some scary warnings on their official labels. There’s an rising professional consensus that a few of these unwanted effects — notably pancreatitis and thyroid most cancers — aren’t really brought on by Ozempic or different medication within the class. However gallbladder illness, acute kidney damage, and allergic reactions are actual prospects, and a very good reminder to be very cautious with the unwanted effects brought on by these highly effective medicines.
