GLP-1 Agonists: Ozempic, Wegovy, Victoza, Bydureon, Saxenda, Trulicity, Tanzeum, Byetta, and Rybelsus
TL:DR The GLP-1 drugs cause significant weight loss and improved blood sugar in 30% of those who take them over the short term, but that effect wears off. Research including a decade of reports to the FDA make it clear they also raise the risk of Thyroid Cancer, Pancreatitis and Pancreatic Cancer. The drug companies have convinced doctors to ignore this risk using poor quality, short term studies to support their arguments. These cancers may not show up for a decade or more.
The GLP-1 agonist drugs are all members of the incretin drug family. These drugs are injected drugs, except for the latest entry, Rybelsus, which is a pill form of semaglutide, yet another GLP-1 drug, which is thee same drug found in injected Ozempic and Wegovy. These drugs are all artificially made hormones that are very similar to a naturally occurring gut hormone, GLP-1.
However, natural GLP-1 breaks down very quickly. Changes in the molecular structures of these drugs makes them resistant to breakdown so their effects are longer lasting. There are significant differences in how long these drugs stay active. Byetta (exenatide) is injected several times a day, Victoza (liraglutide) and Adlixin, marketed outside the U.S. as Lyxumia, (lixisenatide) once a day. Saxenda is the same drug as Victoza, but it has been approved for people without diabetes who need to achieve weight loss. Bydureon is a long lasting version of exenatide. It, Trulicity, (dulaglutide) and Tanzeum (albiglutide) are injected once and last a full week. A pill version of semaglutide, Rybelsus, was approved by the FDA in September of 2019.
Ozempic and Wegovy are versions of Semaglutide that have a higher dosage than what is prescribed for blood sugar control. They were approved for people who are clinically obese (BMI greater than 30). But they have been in the news in early 2023 because influencers active on social media are taking these drugs to achieve quick weight loss, causing many of their followers to demand prescriptions. Data discussed later in this article suggests that if taken over several years the effect of some GLP-1 drugs on hunger and stomach emptying and blood sugar declines.
Anecdotal evidence about the GLP-1 drugs prescribed for weight loss suggests that any weight lost comes back when the drugs are stopped. There is also some question as to whether they are leading to the loss of muscle rather than body fat.
There are also important differences in how effective these drugs are at lowering blood sugar and how likely they are to cause severe side effects, most notably thyroid cancer. However it is very possible that all drugs of this class cause abnormal cell growth in the pancreas over time, which you can read about further on in this article.
What These Drugs Do
GLP-1, the hormone whose function these drugs simulate is secreted by cells in the gut when people eat. GLP-1's functions include stimulating the secretion of insulin when blood sugars rise and controlling the valves that cause the stomach to empty food into the small intestine. GLP-1 passes into the brain, too, where it has effects on eating behavior and other metabolic functions that are not well understood.
The original molecule that formed the basis for designing Byetta, the first of these drugs to hit the market, was found in the spit of Gila Lizards, hence Byetta's nickname of "Lizard Spit."
The delayed stomach emptying may be what causes the nausea these drugs can cause. It is also the reason you should NOT take these drugs if you have developed gastroparesis from long-term exposure to high blood sugars.
The Fatal Flaw with These Drugs: They May Cause Abnormal Cell Growth and Precancerous Tumors in the Pancreas
All these drugs come with a black box warning that they have been found to cause thyroid cancer in animals and that it is not known if they will do this in people. Doctors appear to believe it is safe to ignore this and prescribe these drugs widely. But there is an even bigger problem with these drugs which was brought to the attention of specialists in 2010 after the first drug this class was released.
The drug companies have been very vocal in publicizing the small, questionable studies that supposedly laid this concern to rest, but anyone who has read the actual studies involved knows that the concerns still remain.
The Important Studies that Flagged Pancreatic Cancer Risk
There is quite a bit of evidence stemming from unrelated research in animals, humans, and large populations that suggests that people who take these drugs experience abnormal cell growth in their pancreases. (The pancreas is the organ that where the beta cells that make insulin reside).
Beginning in 2010 the FDA has been warning that Byetta and Victoza may be associated with pancreatitis, a painful inflammation of the pancreas that can destroy large portions of it and lead to full-fledged Type 1 diabetes. The drug companies behind these drugs used a very questionable study run by a big mail order pharmacy, Medco, to defuse this claim. The study analyzed its patient's medical records appeared to suggest that Byetta was not causing pancreatitis.
Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin: A retrospective observational pharmacy claims analysis. Rajesh Garg et al. Diabetes Care Diabetes Care November 2010 vol. 33 no. 11 2349-2354
However, this was a relatively short study. These drugs had not been in use for the decade or longer it would take for a significant cancer signal to become clear. The commercial organization that conducted this review also profits from selling these very expensive drugs.
The Autopsy Study that Found Very Disturbing Evidence Connecting Incretin Drugs with Abnormal Pancreatic Cell Growth
A more conclusive and damaging study was conducted by highly regarded researchers at UCLA's Medical School. They carefully autopsied the pancreases of people with diabetes who had died of strokes and head injuries. About half of these people had been taking an incretin drug. The term "incretin drug" includes all drugs that manipulate the activity of GLP-1. There are two different families of these drugs, the GLP-1 agonists, which we are discussing here and the DPP-4 inhibitors, the best known of which is Januvia/Janumet. While most of the subjects int he pancreas autopsy study were taking Januvia, one was on Byetta.
The most troubling finding of this study was that all the people with diabetes who had taken these incretin drugs for a year or more had very abnormal things going on in their pancreases at the time they died. The abnormalities included the presence of an unusually high number of both beta cells and alpha cells--more than three times greater than normal--and the fact that these cells were arranged in "eccentric" islets that were growing into the pancreatic ducts in an unusual way.
The people taking these incretin drugs were also found to have tiny glandular tumors scattered throughout their pancreases.
None of the people in this study who had had diabetes but who had not taken incretin drugs displayed any of these abnormalities.
More worryingly, the researchers also pointed out that people on these drugs, despite having more than three times more beta cells than normal people, were still experiencing diabetic blood sugar levels. This suggests very strongly that the newly created beta cells they had grown were not functioning normally.
The researchers added that they had indeed observed that that many of the cells found showed signs they had been secreting both insulin (secreted normally by beta cells) and glucagon (secreted normally by alpha cells) . This kind of secretion pattern is characteristic only of the immature cells found only in fetal tissue. It is never found in the beta cells of normal adult humans.
This study can be found here:
Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with increased Exocrine Pancreas Dysplasia and the potential for Glucagon-producing Neuroendocrine Tumors. Alexandra E Butler et al. Published online before print March 22, 2013, doi: 10.2337/db12-1686. Diabetes March 22, 2013
There May Be No Symptoms Until the Abnormal Cell Growth Is Well Under Way
These abnormalities are very serious. More importantly, they have also been found in animals treated with these drugs. So although this is only one human study, its findings should be taken as confirming that yes, the dangerous changes seen in animals taking these drugs also occur in humans.
The kind of tumors found here are undetectable until they cause pancreatitis or cancer. The researchers point out in their discussion of their findings that when there is any suspicion that a person has one of these benign pancreatic tumors the treatment is immediate surgery. But what they don't mention is that suspicion that such a tumor is present only arises when it is causing clear-cut symptoms.
Chronic pancreatitis itself raises the risk of pancreatic cancer by a factor of 8.
https://pubmed.ncbi.nlm.nih.gov/28762376/
Unfortunately, the first symptom of cancerous tumors in the pancreas is an increase in blood sugar. Since doctors consider rising blood sugars in people with diabetes to be normal, the are unlikely to suspect a pancreatic tumor in a person already diagnosed with diabetes until other, more troubling symptoms emerge--by which time it is usually too late to save the patient's life.
Bottom line: All incretin drugs appear to have the potential of being so dangerous to your long term health.
In addition, people who do not have diabetes who are taking much higher doses of Semaglutide drugs Wegovy and Ozempic are taking a much Greater Risk than they realize.
Because the higher dose weight loss drugs have hit the market far more recently it will take another 10 years for their impact to show up.
2018 UPDATE: Pancreatitis After Taking These Drugs Is More Likely to Occur in Cystic Fibrosis and Hemochromatosis Gene Carriers
Research published in 2018 suggests that people who are carriers or the genes for Cystic Fibrosis or Hemochromatosis may be at more risk for the pancreatitis caused by this family of drugs. Since these people are carriers, they are not diagnosed with these conditions, but if they have children with others who also carry these genes their children have a significant risk of inheriting these conditions.
Lest you think this applies to only a small group of people, when I indulged in some Ancestry genetic testing I discovered I am a cystic fibrosis carrier, though no one in my extended family has ever had the disease. A second, different test confirmed this finding.
It turns out that these genes, in carriers, may have subtle effects on the pancreas, which may explain why drugs that further irritate the pancreas may cause painful and possibly dangerous inflammation of the organ.
https://diabetes.diabetesjournals.org/content/67/Supplement_1/2296-PUB
2023 UPDATE: Fourteen Years Later the Link Between GLP-1 Drugs and Thyroid and Pancreatic Cancers Shows Up in Statistical Studies.
Mainstream medicine has been convinced by the drug companies whose profits depend on these blockbuster drugs that the cancer link can be disregarded. However, there is still quite a lot of data that suggests this is not true.
A 2022 study that analyzed reports from the FDA Adverse Event Reporting System (FAERS) database found the following disturbing information.
"Significant signals were detected between GLP-1RA [the GLP-1 drugs discussed here] and certain tumors, including thyroid cancers [medullary thyroid cancer (PRR 27.43) and papillary thyroid cancer (PRR 8.68)], pancreatic neoplasms malignant (PRR 9.86), and islet cell neoplasms."
In addition it found that " The combination of GLP-1RA with dipeptidyl-peptidase IV inhibitors (DPP4i) [Januvia, Janumet] perhaps caused the increased reporting rate in some tumors."
It concluded that "Given the wide use of GLP-1RA, clinicians should be well informed about important potential adverse events. Our pharmacovigilance analysis also prompted clinicians to raise concerns about potential tumor-related adverse effects when combining GLP-1RA with DPP4i."
More GLP-1 Agonist Drugs Are on the Way
You can recognize them because their generic name always ends in "glutide." Most troubling are the drugs that combine a GLP-1 agonist with basal insulin. iGlarLixi is one such drug. Previously named LixiLan, it combines Lantus with Lyxumia. Xultophy is another injected drug that combines a basal insulin with a GLP-1 agonist. It combines Tresiba with Victoza. Novo Nordisk, the maker of Victoza is also developing a GLP-1 agonist in pill form. This would be a big selling point since all the current drugs in this family must be injected however it is extremely difficult to introduce hormones into the gut via pills so it may be a while until this drug hits the market.
Early Studies Showing the Unimpressive Long-Term Real World Efficacy These Drugs
The rest of this page gives more information about some of the earlier GLP-1 agonists and what people taking them reported about their experience. I include them for historical purposes, but urge you not to experiment with these drugs now that we know what they do to the pancreas. Almost all the studies cited involve Byetta, which was the first GLP-1 agonist approved for widespread use. Byetta appears to have been the most effective of these drugs. However, it was supplanted by Victoza which required fewer daily injections though it was shown to be less effective in lowering blood sugar.
There are far fewer studies of Victoza and those that exist were conducted by the drug's manufacturer with the goal of expanding its use to new indications, like obesity. That kind of study is not to be trusted as the drug companies have a long history of suppressing any data that emerges in their research doesn't promote the sales of their products. They also design their studies in highly deceptive ways that take advantage of the public (and many doctors') inability to understand statistics.
As you will see reading the information below, these drugs do lower blood sugar and cause weight loss in about one third of those who take them. But whatever their benefits, it seems foolish to take any drug that could cause abnormal cell growth in your pancreas and stimulate the growth of undetectable tumors that could over time turn cancerous or cause pancreatitis requiring surgery that could damage your pancreas and take away what limited function it still has.
Historical Information about GLP-1 Agonists
The discussion below describes the research on Byetta (exenatide), which was the first drug in this class to hit the market. It is rarely prescribed today.
How GLP-1 Drugs Work
These drugs do three main things. They keep your stomach valve from opening, which produces a feeling of fullness, and, in some people, they stimulate the beta cells in the pancreas to produce insulin as blood sugars rise after eating.
These drugs may cause the valve that opens the stomach so food can pass on into the intestines to shut down, sometimes for hours. This makes it physically impossible to overeat. It also leads to painful constipation.
Over time, however, studies of Byetta showed that this effect appears to wear off as does its effect on weight loss. This is clear from the studies cited in the prescribing information.
Because of the delayed stomach emptying these drugs cause, people who take them may see wonderful numbers when they test after a high carb meal without realizing that the food has not yet been digested, so those carbs will only be released into the blood much later.
If you take one of these drugs, you need to test your blood sugar a few hours after you'd usually test it, to make sure that when the stomach finally releases the food into your gut you don't see a sudden blood sugar spike.
People posting about their experiences with Byetta on alt.support.diabetes reported that they saw the peaks they used to see at 1 and 2 hours at 3 and 4 hours. If those 3 and 4 hour peaks are over your target safe blood sugar, any improvements you are seeing at 1 and 2 hours may be illusory.
Improved Glucose Response
However, in some people, Byetta also appeared to stimulate the pancreas to release insulin in a natural manner when food is eaten. The sulfonylurea drugs like Amaryl and Glyburide stimulate insulin release too, but they stimulate constantly. Byetta, unlike the sulfonylurea drugs, only stimulates the pancreas to secrete insulin when the blood sugar starts to rise after a person has eaten a meal containing carbohydrates. This means that it isn't likely to cause hypos the way that the sulfonylurea drugs do.
A subset of people taking Byetta also reported dramatic changes in their metabolisms, even complete normalization of their blood sugar by Byetta, which allowed them to drop their other medications.
These reports are anecdotal. The studies reported in the Byetta Prescribing Information showed Byetta achieving only about a .5% decrease in A1c (i.e. from 7.5% to 7%.) on average.
A June 2007 Study Confirms Byetta Works Great for a Few But 70% of Those Taking It Experience Damagingly High Blood Sugars and Little Weight Loss
A manufacturer-supported study presented at the June 2007 ADA Scientific Session has been touted as if it proved that Byetta is great for people with Type 2 diabetes--and that's how the press is playing it.
But read further and you'll see how sad the results of this study really were.
Byetta Produced Dangerous Blood Sugar Levels in 70% of those taking it.
The press release brags:
After three years of BYETTA treatment, 46 percent of study participants achieved the American Diabetes Association's recommended target A1C of 7 percent and 30 percent of participants achieved an A1C of 6.5 percent. [emphasis mine]
This means that fully 7 out of 10 of those taking Byetta had blood sugars high enough to damage their organs for the full 3 years of the study. Note that Victoza initially lowers blood sugar less than Byetta!
The American Association of Clinical Endocrinologists' (AACE) target of 6.5% which these people did NOT attain is the minimal level at which people with Type 2 diabetes are less likely to develop retinopathy, kidney failure and nerve death leading to amputation. And the 6.5% A1c isn't ideal, as it still represents a higher risk for heart disease than a 5% A1c would be.
So what this study really says is that seven out of ten people taking Byetta in this study, for three whole years, maintained blood sugars high enough to damage all their organs.
Three Year Study Finds Byetta Causes Trivial Weight Loss in Most People
When patients report that Byetta isn't helping their blood sugars, they are told to keep taking it because it causes weight loss. But here's what a press release put out by Byetta's maker, Lilly, reports that their own study found about Byetta's weight loss:
Weight loss from baseline was progressive, with participants losing on average 11.68 +/- 0.88 lbs at three years. In addition, one in four patients lost an average of 28.66 lbs.
What this means is that three out of four people taking this expensive drug that did NOT control their blood sugar lost an average of 11.68 pounds over three years, or not quite four pounds a year. In a group of people who weighed well over 200 lbs each, this is not exactly miracle weight loss.
Did Byetta Restore Beta Cell Function?
This is a huge question, and the drug companies that make this stuff are making this claim based on some very sketchy data.
One finding that suggested that Byetta did not regenerate beta cells in humans is that in the people who had been taking Byetta the longest, the blood sugar, after improving, reached a plateau and then started to deteriorate again. The plateau reached was usually still at a level where the patients had diabetic blood sugars. If beta cells were regenerating, control should have improved when the drug was taken and remain improved when it was stopped, rather than deteriorating. Anecdotally, users reported that stopping Byetta usually resulted in blood sugars returning to their pre-drug state.
The Downside of Byetta and Other GLP-1 Drugs
There were several problems reported with these drugs.
They Make People Very Nauseated
About half the people taking Byetta got very nauseated. This is related to its effect on stomach emptying. Some people said this effect could be countered by wearing "Sea bands" which are an acupressure seasickness aid. The other half of people taking it did not have this problem.
They Don't Work for Many People
A blog about Byetta that was maintained online for many years after its released was filled with reports from people who tried the drug but did not see improvement after taking it. Some even saw their blood sugars worsen dramatically after they started it. What was disturbing was how many people kept taking this expensive drug long after they had seen it was not having any measurable positive effect.
In many cases it was because their doctors, influenced by drug company misrepresentations, assured them that despite a lack of results the drug was growing new beta cells for them which would eventually lower their blood sugar. This long awaited improvement never happened.
These Hormone Mimics Can Provoke Antibody Responses
A serious problem with Byetta and any other injected hormone mimic is that, like any injected protein, it can provoke an antibody response which in some cases can be very strong.
When an antibody is produced it latches onto the molecule that provoked it and keeps it from doing its job. If the molecule is the injected Byetta or Victoza molecule, that is one thing, but it is also possible that the antibodies Byetta produces may latch onto a person's own home-made incretin hormones and keep them from working, too.
The information in the Byetta Prescribing Information mentions that antibodies are produced, and that in a small group of people a LOT of antibodies are produced, but there is no further discussion on this, or any further research about it. Bydureon is a longer-acting form of Byetta, approved in 2012. Studies conducted before Bydureon was released revealed that it provoked the formation of more antibodies to exenatide (the synthetic form of GLP-1 found in both drugs) than did Byetta.
FDA: Center For Drug Evaluation And Research Application Number: 022200Orig1s000.
I have asked several knowledgeable endocrinologists about this problem but they say they only know what I know from reading the prescribing information.
It is possible that production of these antibodies is the explanation for why some people posted on the Byetta blog that their blood sugar got far worse after they started Byetta.
Additional Concerns about Victoza
In January of 2010, The FDA finally approved Novo Nordisk's long delayed GLP-1 analog, Liraglutide, which is marketed under the name, "Victoza" when prescribed for blood sugar problems and "Saxenda" when prescribed as a weight loss aid.
Victoza was developed in the same time frame as Byetta and is very similar in concept. But its side effect profile was more troubling, hence the delay. It was released with a warning that it might produce thyroid cancers, though its maker tried to suggest this was only a problem in rodents. In fact, its European prescribing information revealed this data from human trials :
The overall rates of thyroid adverse events in all intermediate and long-term trials are 33.5 [Victoza], 30.0 [Placebo] and 21.7 events per 1000 subject years of exposure for total liraglutide, placebo and total comparators; 5.4 [Victoza], 2.1 [Placebo] and 0.8 events, respectively concern serious thyroid adverse events. In liraglutide-treated patients, thyroid neoplasms [i.e. cancers], increased blood calcitonin and goiters are the most frequently thyroid adverse events and were reported in 0.5%, 1% and 0.8% of patients respectively.
You can read the full FDA-approved prescribing information for Victoza here:
Victoza Prescribing Information.
Based on what is reported there, in return for a more disturbing side effect profile, Victoza appears to produce less blood sugar control than Byetta did and it doesn't look as if Victoza has as good an impact on weight as Byetta does, either. This hasn't stopped the drug's maker from getting the FDA to approve the release of the drug under a different name to be prescribed to people with normal blood sugar for weight loss.That alone makes you wonder how much effect Victoza has on blood sugar since the dose for weight loss, given to people with normal blood sugar is twice that given to people with diabetes for blood sugar control.
Very Troubling Side Effects with Victoza/Saxenda
The prescribing information for this drug now includes a new paragraph reporting that
There have been postmarketing reports of acute renal[kidney] failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza®-treated patients [see Adverse Reactions (6.2)]. Some of these events were reported in patients without known underlying renal disease.