By: Lynn F.W. Bilar MD
INCRETIN BASED THERAPY
There is always something new in the management of type 2 diabetes. It is a never ending quest for finding new treatment modalities as we learn more about the disease. The latest is the INCRETIN BASED THERAPY. This write up is not an extensive discussion of the topic, but will just be an overview. There are 2 types of incretin based therapies, the INCRETIN MIMETICS and DPP 1V INHIBITORS.
INCRETINS are peptide hormones secreted from the GIT following ingestion that augment glucose stimulated insulin secretion. Oral glucose provokes 3-4 fold higher insulin response than an equivalent dose given intravenously. This is so because oral glucose causes release of gastrointestinal hormones principally GLP-1 (Glucagon like peptide-1) and Glucose dependent insulinotropic polypeptide (GIP 1) that augment glucose induced insulin release. This “incretin effect” is reduced in patients with type 2 diabetes. GLP 1 secretion (but not GIP 1) is impaired in patients with type 2 diabetes and when GLP 1 is infused in these patients it stimulates insulin secretion and lowers glucose levels. These represent a novel class of therapeutic agents that: targets deficient insulin secretion, reduce post prandial glucose, reduce glucagons levels, preserve/ restore beta cell mass, delays gastric emptying time and promotes satiety.
Native GLP1 and GIP in vivo are short lived (about 2 mins) due to the rapid inactivation of the proteolytic enzyme Dipeptidyl peptidase 1V. DPP 1V is expressed and can be found on the surface of various cell types including lymphocytes and epithelial cells. It is also found on the surface of the capillary endothelial cells in the vasculature of the small intestine, directly adjacent to the sites of GLP-1 and GIP secretion. Thus inhibition of DPP1V activity prevents the rapid breakdown and stabilizes the post prandial levels of bioactive endogenous Incretins thereby prolonging physiologic actions.
EXENATIDE (Exendin-4) marketed as Byetta is a GLP-1 receptor agonist isolated from the saliva of the Gila monster that is more resistant to DPP1V action. It lasts about 10 hour (vs 2 mins with native GLP-1). When given to patients by subcutaneous injection BID, this lowers blood glucose and HBa1c levels and produce weight loss of about 6-10 lbs in most patients. It can be used alone or in combination with sulfonylurea, metformin or insulin. The main side effect is nausea. This will be available in the
Two Oral DPP 1V inhibitors are currently available, Sitagliptin (JANUVIA) which was launched over a month ago and the soon to be out Vidaglipitin (GALVUS). Sitagliptin can be used alone or in combination with Metformin or TZD. It is fairly well tolerated and is weight neutral.
References:
GREENSPAN’S BASIC AND CLINICAL ENDOCRINOLOGY
JCEM VOL 92 NO. 40
