dpp-4_response_pathway

Research shows us that patients with type 2 diabetes mellitus (T2DM) have an impaired incretin secretion response to glucose. This finding has encouraged the development of a new class of anti-diabetic drugs classified as incretin-based therapy [1]. One such class that has become increasingly available for patient use in the U.S. is Dipeptidyl Peptidase-4 inhibitors or DPP-4 inhibitors.

Beginning in 2006, the FDA approved Januvia (sitagliptin), the first product in this class of DPP-4 inhibitors. In 2007, the FDA approved Janumet, another DPP-4 inhibitor that combines sitagliptin with metformin in one pill. Again, this past January, the FDA announced the approval of three more types of DPP-4 inhibitors, bringing the total now to five DPP-4 inhibitors that have all been approved as anti-hyperglycemic medicines [2].

How Does It Work

Dipeptidyl peptidase-4 (DPP-4), also called gliptin, is an enzyme responsible for degrading the hormone incretin. Incretin is a natural gut-derived peptide that is responsible for releasing insulin after meals. Insulin lowers blood sugar.

When your body produces incretin, an enzyme called dipeptidyl peptidase-4 (DPP-4) removes it from your body. This is a normal, routine process for healthy people without diabetes [3].

Since type 2 diabetics are partially deficient in secreting incretin, DPP-4 inhibitors are helpful medicines because stopping (inhibiting) DPP-4 helps the incretin already present in the body to stay there longer [4]. This triggers insulin to be released, which lowers blood sugar. These anti-diabetic properties are based on the two hormones activated by incretin, hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Both GLP-1 and GIP stimulate insulin secretion after meals, but GLP-1 can further mitigate hyperglycemia through inhibiting glucagon secretion, delaying gastric emptying, and by possible induction of early satiety [5].

incretin_effect

Previous methods tried using incretin directly as a pharmacological agent, but their very short half-life (approximately 2 minutes after intravenous administration) resulted in a reduced effect due to the rapid breakdown by this native protein DPP-4 [6]. Instead, the use of gliptins stimulates insulin secretion while simultaneously blocking the DPP-4 enzyme from interfering in glucose uptake. Due to the distinct mechanism of action, DPP-4 inhibitors can be used as add-on therapy to other classes of drugs for treatment of T2DM. And since DPP-4 inhibitor drugs are taken daily as oral medication, they can be a highly effective and non-invasive way to increase the efficiency of glucose utilization.

Why Are They Used

Around the world, approximately 97% of people who have diabetes have type 2 diabetes mellitus (T2DM) [7]. Among the classic limitations of insulin therapy most patients with T2DM face, hypoglycemia remains a major barrier to glycemic control along with obesity. Oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and exacerbated weight gain. In addition to the expected benefits associated with limiting insulin dose, other specific advantages of DPP-4 inhibiters include improvements in pancreatic B-cell function and gastric emptying [8]. These five gliptin compounds are generally well tolerated and demonstrate various degrees of efficacy in treating type 2 diabetes at doctor recommended doses. This suggests that inhibition of DPP-4 activity represents a desirable therapeutic approach for T2DM, and could justify combing with insulin use [9]. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have already started to emerge.

There are many anti-hyperglycemic drugs available to help patients with T2DM to control their blood sugar levels. Most of these drugs are designed to use the patient's own natural stores of insulin. This new class of incretin-based therapies, however, is as effective as older oral hypoglycemic drugs, particularly metformin. Largely, DPP-4 inhibitors are considered a safe and effective treatment strategy that can adequately reduce the regimen complexity required to control T2DM [10].

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Citations

[1] [2] [9] Dipeptidyl Peptidase-4 (DPP-4) Inhibitors.http://health.utah.gov/medicaid/pharmacy/drugutilization/files/Criteria%20Review%20Documents/DPP-4%20Inhibitors%20February%202013.pdf

[3] Latest DPP-4 Inhibitor, Alogliptin, Reaches US Market. http://www.medscape.com/viewarticle/806461.

[4] [6] Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663457/?tool=pubmed.

[5] Therapeutic Class Overview Dipeptidyl Peptidase-4 (DPP-4) Inhibitors.http://www.medicaid.nv.gov/Downloads/provider/Dipeptidyl%20Peptidase-4%20%28DPP-4%29%20Inhibitors.pdf

[7] Essentials of Anatomy & Physiology. by Rod R. Seeley, Trent D. Stephens, Philip Tate; McGraw-Hill, 6th edition, Mar 2006. Page 623.

[8] [10] Incretin Mimetics and DPP-4 Inhibitors: New Paradigms for the Treatment of Type Diabetes.http://www.jabfm.org/content/19/6/612.full.pdf+html

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