The Incretins: GLP-1 Agonists and DPP-4 Inhibitors

by John Walsh, P.A, CDE

In 1902, Researchers first hypothesized that the gut might directly signal the pancreas. The term incretin was first used in 1930 to describe the enhanced glucose lowering effect that was seen when a gut extract was fed to dogs. In the 1960s, researchers discovered that almost twice as much insulin was released when they infused glucose directly into the gut rather than into the blood as an IV solution, renewing interest in a search for compounds produced by the gut that could lower blood glucose levels.

The first incretin released by the FDA was Byetta which was approved in May of 2005. It is available by prescription for people with Type 2 diabetes who are not on insulin. Byetta is a GLP-1 agonist or drug that works like GLP-1. It is rather unusual in that it is derived from a compound found in the saliva of the Gila monster, a large lizard native to the southwestern US.

When food is eaten, GLP-1 (glucagon-like peptide 1) is one of several incretin compounds that have biologic activity. Following its release into the blood by the intestine in response to food intake, GLP-1 impacts several organs including the intestines where it slows food absorption. This delay in absorption allows the slow insulin response found in Type 2 diabetes to catch up. Improved insulin production by the pancreas is also seen. Both an increase in beta cell mass and an increase of first phase insulin release toward normal have been seen in Type 2 diabetes who take Byetta.1 Rather than being glucagon-like and raisining glucose levels, GLP-a agonists lessen the excessive release of glucagon seen in Type 2 (and Type 1) diabetes.2 Researchers hoped this might delay progression of Type 2 diabetes and this appears to be the case.

So far, Byetta's impact on lowering glucose levels, blood pressure and minor reductions in weight, plus an increase in a sense of well being have largely been positive. Side effects like nausea that does not go away on minimal doses may require that the medication be stopped or that smaller starting doses be given with a syringe rather than using the standard starting dose of 5 mg that is provided in the Byetta pen. On a more serious side, "rare" case reports of pancreatitis and "very rare" case reports of pancreatitis with complications or fatalities have been reported in Byetta users, and the FDA has requested a stronger label warning regarding this. Manufacturers Amylin and Lilly say the proportion of complicated or fatal cases is "similar" to that observed among the general public with pancreatitis.

In addition to the delay in food absorption, GLP-1 agonist also stimulate insulin production and restore first phase insulin secretion. The overall effect is to decrease the postmeal blood sugars and improve control without the risk of hypoglycemia. Research has shown that people on Byetta eat about 20% less and often lose weight.

Giving natural GLP-1 was found to have little benefit because it is broken down by an enzyme called DPP-4 (dipeptidyl peptidose IV) within about 5 minutes. This lead to a search for modified GLP-1 molecules like Byetta, produced by Amylin and Lilly, that are not broken down as quickly. Other new GLP-1 derivatives are currently in clinical trials. These include liraglutide (FDA Warning) by Novo-Nordisk and DAC:GLP-1 by Conju Chem.

Related to the GLP-1 agonists is a second new class of diabetes medications called DPP-4 Inhibitors which work by delaying the breakdown of GLP-1, as well as other incretins. Because DPP-4 is involved in the break down of several peptides in the body, it will take time to be sure there are no unwanted long-term side effects.

  1. Fehse, F., Trautmann, M., Holst, J.J., et al. (2005) Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab, 90, 5991-5997
  2. Kolterman, O.G., Kim, D.D., Shen, L., et al. (2005) Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Sys Pharmacy, 62, 173-181.
  3. Klonoff, D.C., Buse, J.B., Nielsen, L.L., et al. (2008) Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin, 24, 275-286.

Great Books on Medications

Until There Is A Cure Medical Management of Type 1 Diabetes Medical Management of Type 2 Diabetes

Until There Is A Cure

For more easy-to-understand information on diabetes medications to use with or without insulin, see this clear, up-to-date book written for the person with diabetes. Written by Gary Scheiner, MS, CDE.

Medical Management of
Type 1 Diabetes

Published by the American Diabetes Association in 2012, this highly detailed professional book edited by Francine R. Kaufman, MD provides the most current information about all aspects of Type 1 diabetes. Discover the full picture on how to use medications and insulin for people with Type 1.

Medical Management of
Type 2 Diabetes

Published by the American Diabetes Association in 2012, this professional companion to the Type 1 book is a comprehensive presentation of many of the ways insulin and medications can be used alone and together.