Profound Class Effects of Incretin Mimetics: Emerging Therapeutic Benefits of GI Hormone-based Therapies for Type 2 Diabetes

This Pri-Med East symposium was supported by an educational grant from Eli Lilly and Company and Amylin Pharmaceuticals, Inc.
Saturday, October 30, 2004
6:15 am – 8:00 am

Program Faculty:
Sherry A Martin, MD
Frank Svec, MD, PhD

Reviewed by Aric Fader, PhD

Patients with type 2 diabetes have specific characteristics, including familial history and genetic predisposition. The hyperglycemia that occurs among those patients results from metabolic defects in the pancreas, liver, and peripheral tissues such as skeletal muscle and adipose. As it progresses, patients experience increased insulin resistance, failure among β-cells and resulting declines in insulin, and increases in both fasting and post-meal glucose levels. Although plasma insulin declines rapidly among healthy subjects, beginning within an hour of glucose ingestion, it and plasma glucose will stay elevated among type 2 patients for several hours. These facts, as demonstrated in several studies completed within the preceding decade, have resulted in appreciation of the clinical relevance of postprandial glucose (PPG), including the fact that it is the earliest detectable glycemic abnormality, correlates very well with A1C, and is associated with diabetic macrovascular and microvascular complications. In addition, targeting PPG can result in better glycemic control. Since decreases in β-cell function progress over time, and this is not addressed by any conventional therapies, targeting postprandial hyperglycemia in order to improve β-cell function is a goal of treatment in the future.

Metabolism of glucose is complex, and several factors are involved. Levels of glucose depend upon insulin and glucagons, which are the hormones of glucose deposition and glucose liberation, respectively. The insulin deficiency that characterizes type 2 diabetes is accompanied by hypersecretion of glucagon. Incretins, which are peptides derived from gastrointestinal tissue after insulin release, include glucose-dependent glucagon-like peptide (GLP-1) and insulinotropic peptide (GIP). GLP-1 enhances secretion of insulin and decreases secretion of glucagon, gastric emptying, and food intake, making it a logical therapeutic target. Exenatide, which is an incretin-based therapy that acts as a GLP-1 receptor agonist, has been shown to produce significant decreases in A1C and PPG over a period of 28 days. When administered in combination with metformin, exenatide produced decreases in A1C and body weight over a period of 52 weeks. Liraglutide, which is another GLP-1 receptor agonist, has also produced decreases in A1C and body weight, along with an increase in β-cell sensitivity. Another compound labeled LAF237, which is an inhibitor of a protease labeled dipeptidyl peptidase IV (DPP-IV) that is involved in degradation of both GIP and GLP-1, has been shown to decrease A1C and fasting plasma glucose in 12-week studies. The decrease in A1C produced by administration of LAF237 has also been maintained over a period of 52 weeks.