The two newest classes of prescription drugs for controlling type 2 diabetes are both hormones that make glucagon-like peptide-1 or GLP-1 work longer for us. But they work quite differently.
One of these new classes of drugs help us control our blood glucose by mimicking how our GLP-1 works, except that it works for hours, not couple of minutes that it normally works in humans. Amylin Pharmaceuticals’ Byetta (exenatide) is the only drug of this type available yet. But the drug companies are racing to develop many more. The closest to approval are a long-acting version of Byetta and Novo Nordisk’s liraglutide.
The other new class of diabetes drug works indirectly by inhibiting an enzyme that reduces the breakdown of GLP-1. This is a dipeptidyl peptidase-4 inhibitor or DPP-4. Merck’s Januvia (sitagliptin) is the first and only drug of this class that we have yet.
In spite of the similarities of these two new classes of drugs, they have major differences. GLP-1 mimetics like Byetta are large molecules like insulin that so far we have to take by injection. We can take DPP-4 inhibitors like Januvia as a pill.
Byetta and forthcoming drugs in its class target GLP-1 specifically and at a higher level than the DPP-4 inhibitors, which is not at all specific for GLP-1. In fact, the DPP-4 inhibitors chop up more than 60 different peptide hormones.
But for most people with diabetes the biggest difference is that drugs like Byetta can help us lose weight. On the other hand, DPP-4 inhibitors are weight neutral. A lot of the excitement about Byetta has to do with weight loss, since 85 percent of people with diabetes are overweight or obese, according to U.S. government statistics.
The key reason why the Food and Drug Administration approved Byetta in April 2005 is because Byetta can reduce our blood glucose levels. In clinical trials of Byetta used together with metformin or a a sulfonylurea the participants were able to reduce their blood glucose levels, as measured by a drop in A1C, by almost one percent in just 30 weeks. This was in a setting where the researchers told clinical trial participants to make no other changes in their life.
But what most separates Byetta from other classes of diabetes drugs are the help it gives us to lose weight. So I asked Dr. John Eng, the endocrinologist who almost 20 years ago discovered what became Byetta, when it was that he first realized that Byetta could lead to weight loss. “I didn’t,” he replied. It was only in its clinical trials that the weight loss became apparent, he told me.
In those clinical trials people lost an average of just 6 pounds after 30 weeks. That fact often surprises people who take Byetta, since they often experience much greater weight loss by listening to the satiety signals that they begin to get.
Until recently blood glucose control and weight loss have been the only benefits of Byetta getting much discussion. But it does still more.
Taking Byetta can reduce our risk of heart attacks and strokes, the most common and deadly complications of diabetes. “Our hearts have GLP-1 receptors,” Dr. Jens Holst, professor at the University of Copenhagen, told me recently. Five studies, including two in humans, support his statement.
Byetta also helps our hearts by reducing high blood pressure and improving cholesterol levels. This was the main conclusion of a presentation at the American Diabetes Association’s scientific sessions this summer in Chicago.
The GLP-1 mimetics like Byetta also cause beta cell mass expansion, Dr. Alain Baron, Amylin’s senior vice president of research, told me. But we don’t know yet if this expansion is because our beta cells don’t die prematurely (apoptosis), whether our beta cells give rise to more beta cells (proliferation), or if non-beta cells somehow get transformed into beta cells (neogenesis).
“We do know that Byetta actually does a full tune-up on the beta cells,” he says.“It tends to have what we call a trophic effect, a persistence of growth, even ‘a rejuvenating effect.’ So it takes an old tired beta cell and makes it start (figuratively) to pump iron.”
If you expose beta cells in a person with type 2 diabetes to Byetta, it restores the immediate function to a great degree. Dr. Baron says he is most reluctant to call this a cure for diabetes, because we don’t know whether our beta cells would later return “to their old sorry state.”
I asked Dr. Baron if he would say that Byetta can temporarily reverse diabetes. “It’s like going from being flabby to exercising and lifting weights and now you are all buffed, and then you stop exercising,” he replied. “Do you stay buffed or you go back to your flabby self? Giving Byetta to beta cells is like putting it through some training. The question is how long lasting does that training persist after you discontinue the drug?”
A study now under way might answer that question, showing whether beta cell rejuvenation persists after people stop using Byetta. We could have those results by the end of the year.
David Mendosa is a freelance journalist and consultant specializing in diabetes and lives in Boulder, Colorado. When he was diagnosed with type 2 diabetes in February 1994, he began to write entirely about that condition. His articles and columns have appeared in many of the major diabetes magazines and websites. His own website, David Mendosa’s Diabetes Directory, established in 1995, was one of the first and is now one of the largest with that focus. Every month he also publishes an online newsletter called “Diabetes Update.” Twice weekly he writes for his blog at http://blogs.healthcentral.com/diabetes/david-mendosa. He is a coauthor of What Makes My Blood Glucose Go Up...And Down? (New York: Marlowe & Co., and second American edition 2006, and other publishers in the U.K., Australia, and Taiwan).
This article originally appeared in the September 2007 issue of Diabetes Wellness News, pages 1 and 8.
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