Glucagon-like peptide-1 (GLP-1) and gastric inhibitor peptide (GIP) are naturally occurring hormones (incretins) that are released from cells in the gut in response to food. They bind to receptors on pancreatic beta cells stimulating the release of the hormone insulin, responsible for the regulation of blood sugar levels. GLP-1 also reduces the secretion of glugacon, a hormone produced by the pancreas that stimulates the liver to convert glycogen to glucose thus increasing blood sugar levels. Naturally produced GLP-1 has a very short half-life of less than 2 minutes.
Patients with type 2 diabetes have impaired incretin function and are thus unable to properly regulate their blood sugar levels, which can lead to adverse clinical sequelae. Novartis' Vildagliptin and BMS’s Saxagliptin works by inhibiting DPP-IV, an enzyme that breaks down GLP-1. By delaying the degradation of GLP-1, vildagliptin and Saxagliptin extends the action of insulin while also suppressing the release of glucagon. This leads to a reduction in elevated blood glucose levels (hyperglycaemia) that is a characteristic feature of type 2 diabetes.
Patients with type 2 diabetes experience the progressive loss of pancreatic beta cell function and a concomitant loss of insulin secretion and glycaemic control. In preclinical studies, vildagliptin was found to have a beneficial effect on insulin secretion by increasing beta cell production and inhibiting programmed cell death (apoptosis).
Subsequent clinical studies, in which vildagliptin was administered to patients with type 2 diabetes not previously treated with oral antidiabetic medications, showed that it increased the active forms of GLP-1 and GIP when compared with placebo. This translated into improved beta cell function as measured by enhanced insulin secretion on glucose challenge. The drug's ability to improve the functioning of insulin-producing cells in the pancreas, albeit in studies with small numbers of patients, suggests it may have disease-modifying potential in the treatment of type 2 diabetes.
To summarize the effects of GLP-1 on beta cells, the best documented direct effects in humans are to enhance glucose-dependent insulin secretion. Subacute effects have been demonstrated in incubated human islet cells demonstrating that GLP-1 has major effects on glucose metabolism in beta cells and also increases the synthesis of insulin. Longer-term chronic effects have been observed in animal studies. These include increased proliferation and neogenesis of beta cells, decreased beta-cell apoptosis, and increased expression of important glucose-sensing factors such as Glut-2 glucose transporters and glucokinase.
DPP-IV inhibitors are one of several new classes of antidiabetic medications in development for type 2 diabetes; others include GLP-1 agonists and dual PPAR agonists. The ability to achieve sustainable reductions in HbA1c, the primary measure of blood glucose control, with an orally administered, well tolerated agent is seen as one of the most important advantages of DPP-IV inhibitors. GLP-1 agonists have to be administered by injection and safety issues have dogged many dual PPAR agonists in development for type 2 diabetes. The DPP-IV inhibitors do not have the same magnitude of weight loss associated with them as Byetta, however.
There are currently 3 strategies to enhance incretin action in patients with type 2 diabetes:
1) Create GLP-1 analogues resistant to degradation by DPP-IV, with resultant prolonged pharmacokinetics;
2) Administer exenatide, a synthetic formulation of Exendin 4, a natural component of salivary secretion from the Gila monster lizard, which is resistant to DPP-IV degradation and is a potent GLP-1 agonist developed by Amylin Pharmaceuticals; and
3) Administer inhibitors of DPP-IV with the goal of inhibiting breakdown of endogenous GLP-1 secretion like Saxagliptin (BMS-477118).