Revving the Engine in Type 2 Diabetes: Emerging Therapeutic Benefits of Incretin Mimetics

Supported by an educational grant from Eli Lilly and Co. and Amylin Pharmaceuticals, Inc.

Wed August 11, 2004
12:30 – 2:30 PM

Program Faculty:
Debbie Hinnen, ARNP, BC-ADM, CDE, FAAN
Scott V Joy, MD, CDE
Frank Svec, MD, PhD

Reviewed by Aric Fader, PhD

In 2003, 18.2 million American had type 2 diabetes, an estimated 1.3 million new cases are diagnosed each year, and between 90% and 95% of all patients have type 2 diabetes. One factors that contributes to the increasing prevalence of type 2 diabetes is body mass index (BMI), and among the adult population in United States, 66% are overweight (BMI ≥25), and nearly 1/3 are obese (BMI ≥30). The pathology of type 2 diabetes includes insulin resistance, relative insulin deficiency, and excessive hepatic glucose output, and complications that these patients can suffer include diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and diabetic macrovascular disease.

Once foods that contain carbohydrates are consumed, digestion results in production of glucose. Elevated glucose leads to secretion of insulin, which in turn causes the glucose to enter peripheral tissues. Insulin is the hormone involved in glucose deposition, and glucagon is the hormone that provides glucose liberation. Glucagon acts within the liver to increase the production of glucose, and insulin then reduces the amount of serum glucose by transporting it into cells. Patients with type 2 diabetes suffer from insulin deficiency and hypersecretion of glucagon, as well as hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are two incretin hormones that are under investigation. Although GIP deteriorates too quickly to have potential clinical benefits, GLP-1 has been shown to enhance insulin secretion and decrease glucagon secretion. Incretins can also delay gastric emptying, resulting in slower increases in blood glucose, and may decrease intake of food, thereby reducing obesity. Recent studies have revealed that GLP-1 may play an important role in the development of the pancreas as well as the neogenesis of βcells within the pancreas that produce insulin, thereby benefiting patients that are suffering from diabetes. 

Dr. Joy compared incretin-based therapy to the current pharamocotherapies that are available for management of patients with type 2 diabetes, and noted that currently there are therapies available to reverse the decline in β-cell function that characterizes the disease. Several classes of drugs enable the increase of calcium and cAMP that result in secretion of insulin, such as metformin that decreases the incidence of diabetic macrovascular and microvascular complications, and thiazolidinedione (TZD) that activates PPARγ receptors in fat cells. Oral antidiabetic agent (OAD) monotherapy has been shown to produce decreases in hemoglobin A1C by 0.7-2.0%, which is the greatest efficacy produced by treatments that are currently available. The optimal goals for therapies that are currently under investigation would be to improve glycemic control, reduce the macrovascular and microvascular complications of diabetes, and have minimal risk of adverse events. The several GLP-1 agonists and dipeptidyl peptidase IV (DPP-IV) inhibitors that are currently under investigation may meet those goals by increasing both mass and function of β-cells, and such results have been obtained in long-term animal studies. Some 6-week data obtained from human subjects have shown decreases in body weight and cessation of appetites. Exenatide (AC2993), which is a synthetic exendin-4, was shown to be rapidly absorbed after subcutaneous injections, and when delivered in conjunction with metformin, caused a lowering of fructosamine, postprandial glucose, and A1C along with improvements in β-cell function. Other data have revealed that incretin mimetics can reduce glucose excursions and A1C, improve insulin secretion, and promote weight loss, and data for combination therapies will be available in the near future.