Dpp4 inhibitors

Embed Size (px)

DESCRIPTION

DPP4 inhibitors

Text of Dpp4 inhibitors

  • 1. DPP4- inhibitorsAmman-Sheraton Hotel Dr.Ibrahim Tuffaha 16-feb2014

2. Introduction Each of usevery human adultis composed of roughly 100 trillion individual cells. Our health depends on effective communication between those cells. Over time, it has become clear that the systems that coordinate cellular activity are far more complex than we originally believed. 3. One example is the incretin hormones, such as GLP-1. These are rapidly secreted from the gut following food intake. Research continues to shed light on their role in health and disease, causing many physicians to rethink the processes underlying glucose metabolism and type 2 diabetes. 4. Prevalence of Diabetes in United States 25 2023.615 1016.119.31988-941999-20025 0 2008 5. Treatment of diabetes 6. Therapeutic Options for Type 2 DM 20081995 Sulfonylurea INSULIN NPH Regular UltralenteSulfonylurea INSULIN NPH Regular Insulin analogues InhaledMetformin TZDs Alpha glucosidase inhibitors Meglitinides Endocannabinoid receptor Incretin mimetics Amylin analogues DPP IV inhibitors 7. Reduced Incretin Effect in Type 2 Diabetic Patients Control SubjectsIncretin effect40 * * * * * * *2003060 90 120 150 180 TIME (min)INSULIN ( mU/L )INSULIN (mU/L )600Type 2 Diabetic Patients80 Intravenous Glucose Oral Glucose 608040 * *200030*60 90 120 150 180 TIME (min)Nauck M, et al. Diabetologia. 1986;29:46-52. 8. GLP-1 Modes of Action in ManUpon ingestion of foodGLP-1 is secreted from the L-cells in the jejunum and ileum Slows gastric emptying Reduces food intake Suppresses glucagon secretion Stimulates insulin secretion Long term effects demonstrated in animals Increases beta-cell cell mass and maintains beta-cell efficiency Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171 9. GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 releaseT1/2 = 1 to 2 min GLP-1 (7-36) active DPP-4 GLP-1 (9-36) inactive (>80% of pool)Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131 . 10. GLP-1 Functions 11. GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 releaseT1/2 = 1 to 2 min GLP-1 (7-36) active DPP-4 GLP-1 (9-36) inactive (>80% of pool)Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131 . 12. N.B 1-2 minutes only ;80%Glp-1 active ------to GLP-1 inactive This happened by DPP4 TO GET MORE BENEFITS OF INTERNAL GLP-1 we have to : 1)Prolong the half life 2)Decrease the amount of inacttivity 13. THIS LEADS US TO INHIBIT THE DPP4 14. DPP4 inhibitors (gliptins) is hypoglycemic class that inhibiting the action of DPP4 (which degrade the action of GLP-1 to convert it to inactive form ) 15. Inhibition of DPP-4 Increases Active GLP-1 Mixed meal Intestinal GLP-1 release GLP-1 (7-36) GLP-1 (7-36) active active DPP-4 DPP-4 inhibitorGLP-1 (9-36) inactiveAdapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. 16. DPP 4 Inhibitors Once daily ingestion Reduce fasting and postprandial glucose,reduce HbA1c Decrease glucagon response to ingested meal Initial studies in combination with metformin 17. DPP4 inhibitors drugs Drugs belonging to this class are : Sitagliptin[5] (FDA approved 2006, marketed by Merck & Co. as Januvia), Vildagliptin[6] (EU approved 2007, marketed in the EU by Novartis as Galvus), Saxagliptin (FDA approved in 2009, marketed as Onglyza), Linagliptin (FDA approved in 2011, marketed as Tradjenta by Eli Lilly Co and Boehringer Ingelheim),[7] Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)[8] Teneligliptin (approved in Japan in 2012[9]) Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company) Gemigliptin (being developed by LG Life Sciences) 18. DPP-4 inhibitors (eg, sitagliptin, saxagliptin, linagliptin) are a class of drugs that prolong the action of incretin hormones. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucosedependent insulinotropic polypeptide (GIP). 19. Comparative Effectiveness of Treatment Options: Intermediate Outcomes Glycemic control (HbA1c) Weight Lipids Low-density lipoprotein (LDL) High-density lipoprotein (HDL) Triglyceride (TG) 20. Summary of DPP-4 Inhibition Increases fasting and postprandial GLP-1 levels Reduces fasting and postprandial glycemia Improves -cell function Increases insulin secretion, reduces proinsulin/insulin ratio Increases beta-cell massInhibits glucagon secretion Reduces hepatic glucose productionIncreases insulin sensitivity Reduces postprandial lipemia No effect on gastric emptying or body weight Reduces HbA1c by ~1% Is safe and tolerable in short term In renal impairment, dose decreased by 50% 21. DPP-4 inhibitors can be used as a monotherapy or in combination with Metformin or a TZD. They are given once daily and are weight neutral. 22. A study shows that added to insulin (with or without Metformin ) decrease FBS by 15 mg/dl And decrease 2h PPBS by 36 mg /dl 23. In nephropathy it is safe to use DPP4 inhibitor as GFR >30 ml /min with halving the dose In ESRD linagliptin and sitagliptin only used 24. The clinical observations that DPP4inhibitors associated with pancreatitis or pancreatic cancer is refused by ADA because no proofs. But they suggesting not to use in patient who has pancreatitis 25. Clinically observed that upper respiratory infection is related to the use of DPP4 inhibitors . On the other hand, a meta-analysis suggested that treatment with DPP-4 inhibitors could reduce the risk of bone fractures.