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GLP-1 Agonists: Ozempic, Wegovy, Mounjaro, 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 and Pancreatitis. They may also if taken long term promote cellular changes leading to Pancreatic Cancer.
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. Trulicity, (dulaglutide) and Tanzeum (albiglutide) are injected once and last a full week. Semaglutide is found in Wegovy and Ozempic, which are injected once a week. Semaglutide also comes in pill version, Rybelsus, taken once a day.
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.
You can read a detailed analysis of Novo Nordisk's own research on the effectiveness of Wegovy for weight loss in non-diabetic people who took the drug for 2 full years. Read it HERE. The gist of this study is that only about one third of those who took these drugs for weight loss lost 20% of their starting weight or more. The drug company does not give us any information about the characteristics of those who responded to the drug strongly, or even of their gender at birth. At the opposite pole, almost a quarter of those who took it for two years lost less than 5% of their starting weight.
Novo Nordisk's published long-term study shows that weight loss plateaus after about a year an a half. 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. But in the case of earlier GLP-1 drugs like Byetta we know that only about one third of those who take them see dramatic changes in their blood sugar. This is similar to what we see with the weight loss forms of these drugs. The same plateauing that was reported for the weight loss GLP-1 drug discussed above also appears to happen with blood sugar control, which may start to deteriorate again after a few years on one of these drugs.
It is possible that all drugs of this class cause abnormal cell growth in the pancreas over time, which you can read about in detail 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. The food you eat sits undigested in the stomach for far longer than usual, which stifles hunger. GLP-1 passes into the brain, too, where it has effects on eating behavior and other metabolic functions that are not well understood. It appears to make food look unappealing. When I tried Byetta looking at a plate of food felt just like looking at a plate of rocks, or lumps of gravel.
The delayed stomach emptying that is a major part of how these drugs control hunger may be what causes the nausea these drugs can cause. It is also the reason you should NOT take these drugs if you have signs you may have developed gastroparesis from long-term exposure to high blood sugars. Because these drugs affect the brain they may be problematic for people with a history of depression.
These drugs can also be dangerous if you need anesthesia because they stop the stomach from emptying even after a 12 hour fast. Be sure to tell your surgeon you are taking one well before surgery. You may need a longer fast to be safe.
These Drugs 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 published several studies that suggest that pancreatic cancer is not more frequently found in people taking GLP-1 drugs than the general population. Because cancer can take decades to appear and because there is currently no safe way to study the pancreases of living people it is very hard to know whether these drugs are causing cellular changes that could lead to pancreatic cancer.
A final problem is that pancreatic cancer is more common among people diagnosed with diabetes in general, so doctors do not report cases of pancreatic cancer in people taking GLP-1 drugs to the FDA.
Some people with diabetes have found these drugs very helpful, but I am still cautious about their long-term safety. As I have found with other drugs that harm people with diabetes, you often don't learn the actual facts about a drug's harm until it has gone off patent. The GLP-1 drugs being prescribed now have years to go before they go off patent.
Appendix: The Studies that Raise the Question of Whether GLP-1 Drugs Promote Pancreatic Cancer, Including Recent Findings from 2018-2023
There isevidence stemming from unrelated research in animals, humans, and large populations that suggests that people who take these drugs may be experiencing 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.
An Autopsy Study Found Disturbing Evidence Connecting Incretin Drugs with Abnormal Pancreatic Cell Growth
A study conducted by highly regarded researchers at UCLA's Medical School whocarefully 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 that actually looked at pancreatic tissue, its findings are concerning and make us wonder if 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.
Because the higher dose weight loss drugs that contain these GLP-1 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 from 23andMe 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."
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.