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DPP-4 Inhibition


A means to enhance intact incretins

After release, GLP-1 (7-36) and GIP (1-42) are rapidly metabolized by the enzyme DPP-4, 13,27 which is located in various tissues, on the capillary surfaces, and in soluble form in the circulation. 38

DPP-4 cleaves off the first 2 amino acids from the intact peptides, producing 2 truncated peptides, GLP-1 (9-36) and GIP (3-42), 13,25,39 which are mainly eliminated through the kidneys. 28,40

These truncated peptides do not activate the respective GLP-1 or GIP receptors in the pancreatic alpha and beta cells 40 and do not affect insulin release or glucose control. 38,41

DPP-4 inhibition has been shown to slow the degradation of GLP-1 and GIP to their truncated forms, therefore prolonging the survival of intact GLP-1 and GIP and their effects on glucose regulation. 13,14,15

dpp-4 inhibitor
 


Important Information About JANUMET and JANUVIA
JANUMET is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.

JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

JANUMET / JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

JANUMET / JANUVIA have not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET / JANUVIA.

Before prescribing JANUMET, please read the Prescribing Information, including the Boxed Warning about lactic acidosis. The Medication Guide also is available.
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13.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365372.
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14.
Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87100.
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15.
Pospisilik JA, Stafford SG, Demuth H-U, et al. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes. 2002;51:943950.
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25.
Weber AE. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem. 2004;47:41354141.
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27.
Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:11261131.
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28.
Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654662.
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38.
Vilsboll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609613.
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39.
Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80:952957.
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40.
Roges OA, Baron M, Philis-Tsimikas A. The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management. Expert Opin Investig Drugs. 2005;14:705727.
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41.
Vahl TP, Paty BW, Fuller BD, et al. Effects of GLP-1-(736)NH2, GLP-1-(737), and GLP-1-(936)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab. 2003;88:17721779.
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42.
Elrick H. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;10761082.
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43.
Nauck M, Stockmann F, Ebert R, et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:4652.
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44.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 736: a physiological incretin in man. Lancet. 1987;2:13001304.