EFFICACY AND MECHANISM

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 GLP -1 (gut hormone) + GIP = incretin effect =Augmentation of insulin after oral glucose  Type 2 diabetics little incretin effect  Reduced GLP-1 secretion.

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Presentation transcript:

EFFICACY AND MECHANISM DPP-4 INHIBITORS EFFICACY AND MECHANISM OF ACTION

DPP IV ACTION/INHIBITION GIP GLP-1 (biologically [1-42] [7-36 amide] active) DPP IV action/ GIP GLP-1 (biologically [3-42] [9-36 amide] inactive) inhibition 127945-5/04

DHbA1c(%) -0.5 -1.0 EFFECT OF SITAGLIPTIN ON HbA1c: CHANGE FROM BASELINE (HbA1c ~ 8.0%) Diabetes Care 29:2638, 2006; Clin Ther 28:1556, 2006; Diabetolgia 49:2564, 2006 DHbA1c(%) -0.5 -0.60 -0.67 -0.85 -1.0 Drug Naive Metformin Pioglitazone ADDITION OF SITAGLIPTIN TO

Int J Clin Prac 63:1395, 2009; Diab Ob Metab 10:376, 2008 EFFECT OF SAXAGLIPTIN ON HbA1c: CHANGE FROM PLACEBO (BASELINE HbA1c ≈ 8.0%) Int J Clin Prac 63:1395, 2009; Diab Ob Metab 10:376, 2008 Diab Care 32:1649, 2009; JCEM 94:4810, 2009  HbA1c (%) -0.5 -0.63 -0.64 -0.76 -0.83 -1 DRUG NAIVE GLYBURIDE METFORMIN PIO/ROSI ADDITION OF SAXAGLIPTIN TO:

DPP-4 Combo

ADDITION OF LIRAGLUTIDE VERSUS SITAGLIPTIN IN 665 METFORMIN-TREATED T2DM PATIENTS (HbA1c = 8.4%) Pratley RE, Lancet 375:1447-56, 2010 SITA LIRA - 1.2 mg LIRA - 1.8 mg 0.5 0.9% Decrement in HbA1c (%) 1 1.2% 1.5% P<0.0001 1.5 P<0.0001 2

Decreased Incretin Effect Decreased Insulin Secretion OMINOUS OCTET Decreased Incretin Effect Decreased Insulin Secretion Increased Lipolysis Islet–a cell HYPERGLYCEMIA Increased Glucose Reabsorption Neurotransmitter Dysfunction Increased Glucagon Secretion Increased HGP Decreased Glucose Uptake DeFronzo RA, Diabetes 58:773-795, 2009