The Clinical Impact of Incretin-based Therapies on Type 2 Diabetes Management: One Year Later

A CME symposium supported by an unrestricted educational grant from Novartis

James R Gavin III, MD, PhD
Daniel J Drucker, MD
Steve E Kahn, MB ChB

Reported by Joelle Escoffery, PhD

Incretin hormones are secreted in response to nutrient ingestion and promote glucose-dependent insulin secretion. They were discovered following the observation that orally-administered glucose produces a larger insulin response than insulin administered intraveneously. There are 2 primary incretin hormones: glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Both GLP-1 and GIP are rapidly degraded by the protease dipeptidyl peptidase IV (DPP-IV). In patients with type 2 diabetes, GIP levels are normal or slightly elevated, but their effect on insulin secretion is diminished. Conversely, GLP-1 retains its sensitivity in patients with type 2 diabetes, although GLP-1 production is decreased. GLP-1 has a number of additional effects not shared by GIP, including the ability to delay gastric emptying, suppress glucagon secretion, and promote weight loss. GLP-1 also promotes islet cell proliferation in vitro and islet cell proliferation and neogenesis in vivo. It has also been shown to have beneficial effect on cardiac function in experimental models of cardiac injury.

Two strategies to prolong the action of GLP-1 have been explored: the use of DPP-IV-resistant agents that mimic the actions of GLP-1 and agents that inactivation the degrading enzyme DPP-IV. The use of the incretin mimetic exenatide has been shown to be associated with durable decreases in both A1C and weight. The incretin mimetic liraglutide has also been shown to improve A1C. However, incretin mimetic therapy may cause nausea and other GI effects in some patients. The second strategy, inhibition of the degrading enzyme DPP-IV, increases GLP-1 levels. In clinical research the DPP-IV inhibitor vildagliptin increases intact GLP-1 levels, improves glucose tolerance, suppresses glucagon secretion postprandially, and works synergistically with metformin to improve glycemic control.

Approximately 2/3 of patients with type 2 diabetes fail to meet glycemic targets, resulting in a tremendous financial and societal burden. There are numerous reasons why patients are not meeting glycemic targets, including late diagnosis and therapy initiation, clinical inertia, difficulty of promoting lifestyle changed, secondary failre of existing therapies due to the progressive nature of type 2 diabetes, adverse events, treatment complexity, and the difficulty of targeting postprandial glucose levels. Given these numerous challenges, priorities in diabetes care should include prevention, earlier detection and identification of the disease, preservation of islet cell function, earlier use of combination therapy, and achievement and maintenance of treatment goals.