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Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5

Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5. Incretins. 1 Drucker DJ. Diabetes Educator . 2006;32(Suppl 2):65S - 71S. 2 Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366. Nutrient stimulated gut hormones Favorable effects on glucose metabolism

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Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 3 of 5

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  1. Pathophysiology in the Treatment of Type 2 DiabetesNewer AgentsPart 3 of 5

  2. Incretins 1Drucker DJ. Diabetes Educator. 2006;32(Suppl 2):65S-71S. 2Vilsbøll T, Holst JJ. Diabetologia. 2004;47:357-366. • Nutrient stimulated gut hormones • Favorable effects on glucose metabolism • Major humans incretins1,2 • Glucagon-like peptide-1 (GLP-1) • Glucose-dependent insulinotropic polypeptide (GIP) • “Incretin effect”

  3. Glucagon-like Peptide-1 (GLP-1) Most well-characterized incretin Secreted from L cells of the intestines Very short half-life Possibly deficient and GLP-1 resistance in type 2 diabetes Adapted from Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190.

  4. Neuroprotection Appetite Brain Stomach Heart Gastric emptying Cardioprotection Cardiac output GLP-1 Insulin biosynthesis b cell proliferation b cell apoptosis Liver GI tract Insulin secretion- overcomes decreased insulin secretion of steroids and tacrolimus Glucagon secretion Insulin sensitivity Muscle Glucose production Summary of Incretin Actions on Different Target Tissues Flint A, et al. J Clin Invest.1998;101:515-520. Larsson H, et al. Acta Physiol Scand.1997;160:413-422. Nauck MA, et al. Diabetologia.1996;1546-1553. Drucker DJ. Diabetes.1998;47:159-169. Schwartz, Kohl, "Type 2 Diabetes Mellitus and the Cardiometabolic Syndrome: Impact of Incretin-based Therapies","Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy". 7/10 Drucker D. J. Cell Metabolism 2006

  5. Hyperglycemia in Type 2 Diabetes Results from Abnormal Meal-Related Insulin and Glucagon Dynamics Normal (n=11) T2DM (n=12) 120 Meal 90 Insulin (µU/mL) 60 30 0 140 130 120 Glucagon (pg/mL) 110 100 90 360 330 300 Glucose (mg %) 270 240 110 80 -60 0 60 120 180 240 Time (min) Müller WA, et al. N Engl J Med. 1970;283:109-115.

  6. Glucose-dependent Effects of GLP-1 Placebo Type 2 Diabetes (n = 10) GLP-1 Glucagon (pmol/L) Glucose (mg/dL) Insulin (pmol/L) 270 300 20 180 200 * * 10 * * 90 100 * * * * * * * * * * * * * * 0 0 0 * -30 0 60 120 180 240 -30 0 60 120 180 240 -30 0 60 120 180 240 Time (min) Time (min) Time (min) Mean (SE); *P < 0.05 GLP-1 = glucagon-like peptide-1 Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

  7. CV effects of GLP-1, GLP-1 RA, DPP-4 Inh.

  8. Added by Dr S Glp1 in major Surgery in DM- Benefit in Stress/ Steroid DM

  9. Strategies for Enhancing GLP-1 Action • GLP-1 receptor agonists (resistant to DPP-4) • Exenatide • Liraglutide • DPP-4 inhibitors • Inhibit actions of DPP-4 • Sitagliptin, saxagliptin

  10. Pharmacologically achieving GLP-1 effects GLP-1 like effect GLP agonists 7-10 x DPP4-I 2-3 x Glucose dependent Glucose uptake by peripheral tissue GLP-1 receptor agonists Resists degradation by DPP-4 Ingestion of food Insulin Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states Sitagliptin Saxagliptin (DPP-4 inhibitors) X DPP-4 enzyme Glucose- dependent Glucagon Hepatic glucose production GLP-1 Receptor Agonists= parenteral, weight loss, nausea risk DPP-4 Inhibitor = oral , weight neutral, no nausea Inactive GLP-1 Inactive GIP GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

  11. DPP-4 Inhibitors Sitagliptin, Saxagliptin • Mechanism: Glucose-dependent  insulin secretion and glucagon secretion Lowers PPG more than FPG •Efficacy: modest (  HbA1c 0.6-0.8%) •Advantages: weight neutral, no hypoglycemia, may use in patients with any degree renal dysfunction (dose appropriately), infrequent dosing •Disadvantages: hypersensitivity reactions, ?pancreatitis (sitagliptin); interaction with CYP3A 4/5 strong inhibitors (saxagliptin); cost

  12. HgA1c Drop with DPP-4 Inhibitors

  13. Weight Changes With Sitagliptin:Mono and Combination Therapy  Weight (kg) * * *P<0.001 vs comparator. 1. Aschner P, et al. Diabetes Care. 2006;29:2632-2637. 2. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205.3. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 4. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 5. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 6. Derosa G, et al. Metab Clin Exp. 2010;59:887-895.

  14. Weight Changes With Saxagliptin:Mono and Combination Therapy * Weight (kg) *P=0.01 vs glyburide uptitration. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622.3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549.5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

  15. DPP-4 Inhibitors: Summary Oral once-daily agents with glucose-lowering potential Can be used as monotherapy and as part of combination therapy strategies (sitagliptin approved for combination with Insulin) A1C reduction Well tolerated Weight neutral

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