The GLP-1 agonist drugs are all members of the incretin drug family. These drugs are injected drugs. They are artificially made hormones 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, whose generic name is semaglutide, is likely to be approved by the FDA in late 2017. 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 there is a high likelihood that all drugs of this class cause abnormal cell growth in the pancreas over time, which makes it impossible to recommend their use until much more comprehensive studies address the evidence from both animal and human studies that these drugs cause permanent, potentially life-shortening changes to a vital organ.
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 was found in the spit of Gila Lizards, hence Byetta's nickname of "Lizard Spit."
The Fatal Flaw with These Drugs: They Cause Abnormal Cell Growth and Precancerous Tumors in the PancreasAll 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 a few years ago. 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 concern is this: 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. A study run by a big mail order pharmacy, Medco, which 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, and it was run under the auspices of a commercial organization that profits from selling this very expensive drug.
A far 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. 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 nto 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.
The way that the abnormal cells were growing into the pancreatic ducts was the kind of cell changes that are associated with pancreatitis. The tumors found in the person taking Byetta were adenomas--a type of glandular tumor that starts out benign but can over time turn cancerous.
The scientists who conducted this autopsy study explained that it is very likely that exposure to abnormally high levels of GLP-1 or to GLP-1 mimics is what is causing these changes, citing animal research which found the same effect and went into the mechanism involved. If this is in fact true, it means any incretin drug, be it a GLP-1 mimic or a DPP-4 inhibitor may cause these dangerous changes.
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.
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.
Since the kind of tumors found here are undetectable until they cause pancreatitis or cancer, they are very worrisome. 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.
Unfortunately, the first symptom of spreading 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 that it is not worth taking them for their short term benefits. There are other ways of lowering blood sugar that are far safer.
The study is 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
You can read another discussion of what this study found HERE.
These findings are so disturbing and the potential for harm so large, that I can no longer see any reason anyone should risk taking any incretin drug no matter how well they manage the person's blood sugars.
The way that the drug companies have tried to white wash this problem to keep their highly profitable billion dollar-earning drugs selling is discussed in depth HERE
More GLP-1 Agonist Drugs Are on the WayByetta is now available in a once a week form called Bydureon, Several new GLP-1 agonist drugs are scheduled to be released in the coming year. 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. They are already available in Europe. The U.S. FDA has delayed approving these drugs but is likely to allow them onto the market by 2017. 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.
Information about the Actual Efficacy and Side Effects of These DrugsThe rest of this page describes more about these drugs and what people taking them report. 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 AgonistsThese 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.
When your stomach doesn't empty you feel full. When you are full, you don't eat. When you stop eating 100 grams of carbohydrate at each meal, your blood sugar drops. When you stop eating 1500 calories at each meal, your weight drops. Nothing magic here.
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.
This effect on the stomach is probably the major thing these drugs do for the subset of people who find them helpful. That's what my endocrinologist has told me, and that's what many people using it report. It stops people from eating, so if overeating carbs is what is causing their high blood sugars and weight gain, the drug will reduce both. Eating rocks would do the same thing, but not as safely.
Over time, however, studies of Byetta have shown, 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 ResponseHowever, 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 LossA 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.
BYETTA(R) Study Showed Sustained Blood Glucose Control Over Three Years in People with Type 2 Diabetes
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.
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.
4>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.
Does 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.
There is some mouse research data showing that incretin hormones may regenerate beta cells, though as we saw above, close inspection of these cells has revealed that they don't secrete insulin in a normal fashion and they don't grow into normal islets in the pancreas. The main "data" cited to support the claim that Byetta was regenerating beta cells was data showing Byetta improving people's A1c, which didn't prove that beta cells are regenerating, only that blood sugar control was improving. You can drop your A1c much more dramatically by cutting down on your carbohydrate intake or reducing insulin resistance. neither of which has any effect on the insulin-secreting beta cells in your pancreas. Since people on Byetta and other GLP-1 agonists are eating a lot less of everything, including carbs, improved A1cs do not necessarily mean beta cells are growing back.
Unfortunately, there is currently no way to examine the pancreas of a living person without destroying it. Because the FDA allows drug companies to make claims for how their drugs work that are not well supported by peer reviewed data, the drug companies can are allowed to claim that their drugs regenerate the pancreas based only on improved A1cs.
Don't get taken in by this hype until it is much better supported. 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 DrugsThere were several problems reported with these drugs.
They Make People Very NauseatedAbout 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 PeopleA 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 ResponsesA 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.
If this is the case, the person might end up in worse shape than before they started the drug, because they have deactivated hormones that might have been working until they took the drug.
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 VictozaIn 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. It is currently the most prescribed drug of all the GLP-1 agonists.
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 VictozaŽ-treated patients [see Adverse Reactions (6.2)]. Some of these events were reported in patients without known underlying renal disease.