The Byetta Mystery

The biggest mystery about Byetta is why some people are so successful at losing a lot of weight on it and others are not. I know people who have lost more than 60 pounds in less than a year on Byetta. Yet I hear of others who have lost very little weight, if any.

The answer may be in our genes.

Even though I knew about Byetta long before it became available, I didn’t start on it myself until February 6th. (I wrote about my initial results here ). Full disclosure: I own stock in Amylin, which developed and sells Byetta.

One reason why I didn’t start on Byetta earlier was that the official “Prescribing Information” documented an average weight loss of just about six pounds in 30-week clinical trials. The first doctor whom I tried to get a prescription from was not impressed and refused to prescribe it for me.

It wasn’t until I read and reviewed a new book by a great endocrinologist, Dr. Joe Prendergast, that I was inspired to take Byetta myself. The tipping point for me was when he told me that the average weight loss of some 200 patients he has had on Byetta since the first of them started in May 2005 is 35 pounds.

So I asked him if he has noticed differences between his patients on Byetta who lose weight and those who don’t. Do all of those who lose weight go on a low-carb or low-GI diet? Do they have more nausea, so they eat less to avoid it? Do they eat right after a shot, or do they wait almost an hour?

“None of those things seem to matter,” Dr. Joe replied. “I keep trying to have a good solid explanation – plausible – but enough data is not available. The whole thing may take twenty years to unwind.”

Another of my favorite endocrinologists, Dr. William C. (Reddy) Biggs, is as puzzled by this difference. Calling Byetta by its technical name, exenatide, he told me, “I haven’t found a good indicator that will predict a good response to exenatide.”

But he goes on to says that when he starts people on Byetta, he stresses the importance of diet in order to maximize the benefits of the medicine. “My impression of those who fail to lose weight is that they are not experiencing the bloating and fullness when overeating, and find that they are able to eat as much as they want.”

That is likely to be a big piece of the puzzle. The question remains, why are some people able to keep overeating on Byetta?

The answer to this question may well be genetic. Some preliminary scientific research indicates that some of us may have a polymorphism or mutation in the receptor for GLP-1, which is the site of action for Byetta. People often use the terms “polymorphism” and “mutation” interchangeably. But technically a mutation is a rare change in a DNA sequence, while a polymorphism is a common variation.

Dr. Biggs, an endocrinologist practicing in Amarillo, Texas, led me to this recent research, as he has to so much else. For example, it was Dr. Biggs who first told me about what became Byetta in June 2001, when it was still called AC2993 (synthetic exendin-4).

I rarely write about diabetes medications before they become available. My April 2002 column for the American Diabetes Association on Byetta and subsequent articles on what became Lantus and Levemir are, I think, the only exceptions. In fact, these turned out to be the most important new drugs for those of us with diabetes since metformin came on the market in 1995.

Dr. Biggs is always well-informed and generous with sharing his professional knowledge. He has written more than 800 messages on the misc.health.diabetes newsgroups since June 1995. It’s one of the main reasons why I read that group.

The report that Dr. Biggs told me about appeared in the August 2005 issue a highly technical journal called Regulatory Peptides. These are peptides that regulate physiological processes, including GLP-1. The journal has nothing to do with governmental regulation as I thought at first.

This study reported that, “Glucagon-like peptide-1 (GLP-1) and its cognate receptor play an important physiological role in maintaining blood glucose homeostasis. A GLP-1 receptor (GLP-1R) polymorphism…has been recently identified in a patient with type 2 diabetes but was not found in non-diabetic control subjects….Sequence variability of the GLP-1R within the human population can result in substantial loss-of-function.”

Dr. Biggs told me that no one knows if this is a common mutation. “However, it could explain why some patients respond to Byetta and others don’t. If this mutation turned out to be very frequent, you could almost envision developing a test for it that would allow predicting which patients would respond to Byetta. We might be able to develop an alternative strategy for those with mutant GLP-1 receptors that would address the loss of GLP-1 function.”

To follow-up it was obvious to me that I needed to contact the lead author of the study. He is Martin Beinborn, M.D., a pharmacologist and assistant professor at Tufts-New England Medical Center in Boston.

When I called Dr. Beinborn he answered right away. He was most helpful in explaining this highly technical science to me.

Dr. Beinborn started by saying that I need to be cautious not to over interpret what they discovered, since they found it in just one person who has diabetes. He went on to say, “It sounds somewhat plausible to speculate that the polymorphism, which was a loss of function, so that endogenous GLP-1 acts less efficiently in this person. And probably if he were treated with [exogenous] GLP or exendin, he would probably react less than a normal person.”

We don’t even know how frequent this polymorphism is in the general population, he tells me. It is a possibility that it might be the answer to the Byetta mystery, but it hasn’t been proven yet.

Dr. Beinborn tells me that other scientists are now planning to study a large number of people to see if they carry this polymorphism. He says that he brought the study to Amylin’s attention.

A test for the polymorphism would be technically feasible, “just a simple sequencing thing,” he says. But consent of the people who are tested would be required.

“It is still a big question what makes a difference,” he says in conclusion. “And polymorphisms like the one we described may be part of the answer. It is probably not as simple as to say that it is in a single receptor; it is in a full spectrum of different receptors that make people more or less susceptible.”

My guess is that I don’t have this polymorphism, because Byetta is working so well for me. I hope that you don’t have it either.

This article is based on an earlier version of my article published by HealthCentral.