Byetta

Byetta is surely the most hyped new diabetes drug to come along in years. Claims for it include massive weight loss without dieting, normalizing blood sugars, and regenerating beta cells.

Needless to say, the truth about it is more complex. Still, if you have type 2 diabetes, it would be worth giving it some attention.

What Byetta Does

Byetta is a substance that mimics a kind of hormone called an "incretin hormone" that no one in the general public ever heard of until Byetta was released. These incretin hormones are found in the gut. One important incretin hormone, GLP-1, stimulates the secretion of insulin when blood sugars rise. Byetta is a molecule that is similar to naturally occurring GLP-1, however, unlike natural GLP-1 it does not break down swiftly, so its effects are longer lasting. The orginal molecule that formed the basis for designing Byetta was found in the spit of Gila Lizards, hence Byetta's nickname of "Lizard Spit."

Byetta is injected and its effects last for about two hours. In the context of treating diabetes, it does two main things. It keeps your stomach valve from opening, producing a feeling of fullness and in some people it stimulates the beta cells in the pancreas to produce more insulin.

Delayed Stomach Emptying

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.

Byetta causes 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.

Byetta's effect on the stomach is probably the major thing it does for many of the people who find it 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, with Byetta 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 Byetta, you need to test for a few hours after you'd usually test, to make sure that when the stomach finally releases the food into your gut you don't see a sudden 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 Response

Another thing that Byetta may do, at least in some people, is stimulate the pancreas to release more insulin in response to food. This, of course, is what the sulfonylurea drugs like Amaryl and Glyburide do, and when they do it, it leads, eventually to poorer control, because there's evidence sulfonylurea drugs burn out the beta cells.

However, the claim is made that Byetta does this in a different manner. Since Dr. Richard K. Bernstein is prescribing Byetta to his patients, and he is on record as one of the earliest experts to warn that sulfonylurea drugs burn out beta cells, it's possible that this is true. But this is far from proven.

What is known is that GLP-1, unlike the sulfonylurea drugs only stimulates the pancreas to secrete insulin after the blood sugar rises after 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 much more dramatic changes, 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%.) That said, I keep running into some of these "anecdotal" successes online, and their enthusiasm is hard to ignore.

What are the Characteristics of These "High Responders"

Quite a few people who report the dramatic response to Byetta were in good control to start with. Unlike the people in the studies cited in the Prescribing Information, they started out with A1cs nearer 6% than 8%. That may be significant.

Several of them also are Jewish. This may also be significant, because we know that there is a defective gene found among people with Type 2 diabetes who are of Ashkenazi Jewish descent, HNF4-a, which has the effect of decreasing the postprandial secretion of insulin. Given the strong response of all the Jewish people I know who are on Byetta, it is possible that the incretin hormone does do something that corrects this genetic defect and allows the insulin to be secreted in response to an incoming load of carbs.

Though I did not have any citations to back up this anecdotal finding, I recently corresponded with a distinguished researcher in the MODY field who explained to me that GLP-l, the hormone Byetta mimics, is like the sulfonylurea drugs in that it is effective in people whose diabetes is caused by a genetic defect in HNF1-a or HNF4-a which affects an earlier stage in the beta cell's production of insulin as long as they still have a decent amount of functioning beta cells. This means that if your diabetes is caused by a defect in one of these genes which causes a secretory defect, rather than insulin resistance at the cellular level in other organs, you may see a dramatic improvement with GLP-1 mimics or drugs like Januvia which increase your body's load of GLP-1.

June 2007 Study Confirms Byetta Works Great for a Few but 70% of those Taking it have 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.

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.

The ADA's 7% A1c target is helpful for people with Type 1 diabetes, but the major study of people with Type 2 diabetes, the UKPDS, found that maintaining a 7% A1c only reduced microvascular complications in Type 2s by 12% far, far less than it did for Type 1s. In short, it's dangerously high for a Type 2.

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 Lilly's own press release claims 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.

Does Byetta Restore Beta Cell Function?

This is a huge question, and the companies that make this stuff are making this claim in the media 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 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 to me that Byetta does not regenerate beta cells significantly 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 slightly again. The plateau reached is usually still at a level where the patients have diabetic blood sugars.

The Downside of Byetta

There are several major problems with Byetta. Some are well known, and the most troubling one is not.

Byetta Makes People Very Nauseated

About 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 People

If you scan through the many months worth of data at the Byetta blogs at http://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. What seems strange to me is how many people keep taking the drug long after it seems it isn't having a positive effect on them.

Byetta Can Provoke Antibodies

A serious problem with Byetta may be that, like any injected protein, it provokes 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.

One other concern with Byetta is that people who have been taking it for a while, with success, find that their blood sugars go right back up when they stop taking it, even if it is just for a few days, which casts some doubt on the claim that Byetta is regenerating beta cells.

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.

Will You Have Two Heads in Ten Years?

That takes us to the final issue with Byetta. It is just plain too new for anyone to know what the long-term effect will be of taking it. There is no long term data about its effects on the body, because it has only been very recently invented.

We've learned over time that when you boost hormones, over time you often end up with unexpected, disastrous side effects, because there are receptors for that hormone places other than the organ you are targeting. Estrogens cause cancers, testosterone harms the heart.

With Byetta we are manipulating a brand new set of hormones whose activity throughout the body is not well understood. What the impact will be over a decade or more of boosting this hormone remains to be seen. And it will be seen, alas, in the bodies of the enthusiastic guinea pigs who are taking it now. Many thousands of them.

FDA Warns of a Very Serious Side Effect: Pancreatitis

On Oct 16, 2007, the FDA posted a warning about Byetta, saying that they had received 30 post-marketing reports of acute pancreatitis (a severe inflammation of the pancreas which can be fatal) some of which went on to kidney failure. The FDA said doctors and patients need to be alert to the signs and symptoms of acute pancreatitis, which include persistent, severe abdominal pain that can radiate to the back and may be accompanied by nausea and vomiting. The incidence of this side effect appeared to rise after patients moved from the 5 mc to 10 mc dose.

FDA Safety Alert

If you believe you may be developing pancreatitis

A Sane Strategy

Clearly, there has to be a cost-benefit analysis here. There 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.

Only if you can't get your blood sugar into the safe zone after lowering your carb intake, using metformin, and after adopting a carefully designed insulin regimen, does it make sense to gamble with a new drug.

It's also worth remembering that some newer oral drugs that also impact the incretin hormones will be coming to market within the next year or two. As they are not injected, it is much less likely that they will provoke an antibody effect.

Lose Weight Without Dieting?What Else Will You Lose?

Your heart? Your lungs? That's what's happened with previously touted and effective diet drugs, so it's a bit disturbing that the main reason patients are jumping on the Byetta bandwagon is because it is being promoted to family doctors as a "lose weight without dieting" drug.

Byetta was approved for use in people with Type 2 diabetes who could not get control using the proven diabetes drugs.

Unfortunately, if you scan the Byetta blog it is clear that doctors who have been influenced by drug company salespeople and their hype are prescribing Byetta to newly diagnosed diabetics who have not yet even tried modifying their diet, to say nothing of other drugs.

They are also prescribing it, off label, as a weight loss aid to people who do not have diabetes at all--all before we know what the long term effect of this drug may be.

Yes, it's hard to resist the temptation to take a drug that promises so much, but given the endless list of drugs that the FDA has approved and then removed from the market, and the fact that the body you are walking around in is the only one you get, take a deep breath, consider your options, and use the proven strategies for weight loss before you go overboard on this one.

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 Gliburide, it is not likely that you will get better blood sugar control with Byetta. You may be too insulin resistant for the amount of insulin secreted to make a difference, or your beta cells may be dead and no longer capable of secreting at all. In that case, you will need 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.