The GLP-1 agonist drugs are all members of the incretin drug family. They are all artificially created molecules that behave in a way that is similar to a human gut hormone called GLP-1 which stimulates insulin secretion and affects appetite. However GLP-1 is quickly destroyed in the body, so these molecules have been modified so that they last longer. 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.
What These Drugs Do These drugs are all substances that mimic GLP-1, a hormone 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.
These drugs are made up of molecules that are similar to naturally occurring GLP-1, however, changes in its molecular structure make them not break down as swiftly as naturally produced GLP-1, so their effects are longer lasting.
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."
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. Nevertheless, doctors are prescribing these drugs widely, and many appear unaware of this cancerous potential
The Fatal Flaw with These Drugs: They Cause Abnormal Cell Growth and Precancerous Tumors in the PancreasThere is an even bigger problem with these drugs that the drug companies have swept under the rug. For several years 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 for at least a year. While most were on 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 findings when their pancreases were examined. The abnormalities included the presence of an abnormally 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 proliferating 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 who had had diabetes but who had not taken these drugs displayed any of these abnormalities.
The proliferative changes observed were of the type 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 explain in their study 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 illuminates the mechanism involved. This means any incretin drug, be it a GLP-1 mimic or a DPP-4 inhibitor will cause these dangerous changes.
They also point out that people on these drugs despite having more than three times more beta cells than normal people were still diabetic, suggesting that the newly created cells were not functioning normally. In fact, they 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 immature cells found only in fetal tissue. It is never found in normal adult humans.
These abnormalities are very serious. More importantly, they have also been found in animals treated with these drugs, so though 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 tumor until other, more troubling symptoms emerge at which time it may be too late to save the patient's life.
Bottom line: All incretin drugs are hazardous to your long term health no matter what their short term benefits.
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 to take any drug in this family.
More of these drugs will be getting released in the next year. You can recognize them because their generic name always ends in "glutide."
The 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. 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 Content Describing These Drugs
In the context of treating diabetes, 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.
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 many of the 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, and if overeating is contributing to 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, people may also see wonderful numbers when they test after a high carb meal without realizing that the food has not yet been digested. 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 report that they see 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 stimulates 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 report dramatic changes in their metabolisms, even complete normalization of their blood sugar by Byetta, which allows 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. But when the question is asked, is this happening in people, the only "data" cited to support the claim that Byetta is regenerating beta cells is data showing Byetta improving people's A1c, which doesn't mean that beta cells are regenerating, only that blood sugar control is improving, which you can also achieve by cutting back on carbs or reducing insulin resistance, without having any effect on the pancreas. Since people on Byetta 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 suggests that Byetta does not regenerate beta cells in humans is that in the people who have been taking Byetta the longest, the blood sugar, after improving, reaches a plateau and then starts to deteriorate again. The plateau reached is usually still at a level where the patients have diabetic blood sugars.
If beta cells were regenerating, control should improve as the drug is taken and remain improved when it is stopped, rather than deteriorate. Anecdotally, users report that stopping Byetta usually results in blood sugars returning to their pre-drug state.
The Downside of ByettaThere are several problems with Byetta. Some are well known, and the most troubling one is not.
Byetta Makes People Very NauseatedAbout half the people taking Byetta get very nauseated. This is related to its effect on stomach emptying. Some people say this effect can be countered by wearing "Sea bands" which are an acupressure seasickness aid. The other half of people taking it do not have this problem.
Byetta Does Not Work for Many PeopleIf you scan through the many months worth of data at the Byetta blogs at Diabetes.Blog.com you'll see that there are quite a few people who do not get dramatic results from Byetta and even a subset of people whose blood sugars worsen dramatically after they start it. What is strange is how many people keep taking the drug long after they have seen that it does not have any measurable positive effect.
Byetta Can Provoke AntibodiesA serious problem with Byetta may be 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, 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 Byetta, 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. 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 post on the Byetta blog that their blood sugar gets far worse after they start Byetta.br>
You can learn more about the side effects experienced by many people who have taken Byetta at the Diabetes Monitor Byetta Page at:
Diabetes Monitor Byetta FAQ
This information is based on the thousands of posts on the Byetta blog sponsored by this web site.
Does Byetta Cause Pancreatitis?
Because Januvia appears to be a far more dangerous drug for reasons discussed HERE Byetta is probably the safest of the incretin drugs, and probably safe to take at the lower dose, especially if you discuss the symptoms of pancreatitis with your doctor before starting it.
Do Not Take Byetta If Your Kidneys Are ImpairedIn late 2009 the FDA analyzed postmarketing data for Byetta and found 78 cases of kidney failure reported between April 28, 2005 and October 29, 2008, a period in which more than 6.6 million prescriptions for Byetta had been dispensed.
Given the prevalence of kidney failure among people with established diabetes this finding may or may not be related to the drug. The FDA now states that Byetta should not be prescribed to people with "severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease." Caution should be used when prescribing it to people with "moderate renal impairment (creatinine clearance 30 to 50 ml/min)."
Because doctors are ignorant of or ignore FDA drug warnings check your creatinine clearance test results before you start Byetta. If your doctor has not given you this test once a year, find a new doctor. All people with diabetes should have their kidney function tested periodically.
Warning signals of kidney problems are: Increased serum creatinine, Changes in urination (color, frequency, amount), Unexplained swelling in the extremities, Increases in blood pressure, Lethargy, Dull ache in the mid to lower back. NOTE: Changes in appetite and digestion are also listed as symptoms of kidney dysfunction but are also normal responses to Byetta.
FDA Safety Information for Byetta
A Sane StrategyThere are other effective treatments for diabetes and if you can get one of them to work for you, it might be better to wait another couple years to see what more we learn about Byetta's effects on the body.
You are going to have diabetes for a long time, so if you can get good control by lowering your carb intake or using a proven drug like metformin or insulin, there's no hurry. In another couple years we'll know much more about Byetta and if it does prove out then, you'll be able to use it safely.
Is Byetta Worth a Try?Because Byetta does have a transformative effect on some people with diabetes, it may be worth trying if you have not been able to control your diabetes with safer, proven therapies like cutting way back on your carbohydrate intake, exercise, and metformin. The following guidelines should help you use it effectively with the least negative impact on your health.
- If you try Byetta for a month and do not see a sharp improvement in your blood sugar level, or if you see your blood sugar get worse, do not continue taking it, but demand your doctor give you more effective medication. People often take Byetta for many months hoping it will "regenerate" their beta cells when the very high blood sugars they are experiencing are guaranteed to kill any beta cells they may still retain. If you don't believe this, please read up on "glucose toxicity" which describes how high blood sugars kill beta cells.
- If Byetta is having a strong impact on your hunger level and helping you to lose weight, but you are still seeing very high blood sugars, Byetta should be treated as a weight loss aid, but you need to talk to your doctor about what you can do while you lose weight to better control those blood sugar levels.
- If you have not responded to drugs that stimulate insulin secretion like Amaryl or Glyburide, it is less likely that you will get better blood sugar control with Byetta. You may be too insulin resistant for the amount of insulin secreted in response to GLP-1 stimulation to make a difference, or your beta cells may be dead and no longer capable of secreting at all. If that is the case, you might do better with a drug that reduces insulin resistance and insulin supplementation rather than beta cells stimulation.
- If you have not responded very strongly to Byetta, Januvia is not likely to do anything for you but lighten your wallet. Januvia raises naturally occurring GLP-1 rather than providing a supplemental form as Byetta dose, and the natural GLP-1 is much milder in its effect than is Byetta. Because Januvia shuts down an enzyme that plays an important role in the way the immune system fights cancer, it is a very dangerous drug, though doctors have not gotten this message even though it has been discussed in the medical press.
In January of 2010, The FDA finally approved Novo Nordisk's long delayed GLP-1 analog, Liraglutide, which is marketed under the name, "Victoza."
This drug was developed in the same time frame as Byetta and is 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 does and it doesn't look as if Victoza has as good an impact on weight as Byetta does, either.
More importantly, the prescribing information 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.
With less impact than Byetta and more dangerous side effects this is a drug there is no reason for anyone to take.
BydureonByetta is now available in a once a week form called Bydureon, however this drug, which was approved in early 2012 is so new, and its release was so long delayed by the FDA because of potential side effects, that it would be prudent to wait a few years to find out what the real side effects are before taking it.
With any long-acting GLP-1 analog drug the longer duration means that if you get the serious gastrointestinal reaction that GLP-1 analogs can cause, it's going to take a lot longer to wash out of your body. Don't try Bydureon unless you've taken Byetta for long enough to determine that it gives you dramatic improvements in both blood sugar and weight control without severe nausea. 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.