The Byetta Mystery

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.