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09-Aug-2008-JAN-2007-BE-1263-SS Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan.

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Presentatie over: "09-Aug-2008-JAN-2007-BE-1263-SS Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan."— Transcript van de presentatie:

1 09-Aug-2008-JAN-2007-BE-1263-SS Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; Rhodes CJ Science 2005;307:380–384. The Pathophysiology of Type 2 Diabetes Includes Three Main Defects Hyperglycemia Liver Insulin deficiency Excess glucose output Insulin resistance (decreased glucose uptake) Pancreas Muscle and fat Excess glucagon Islet Diminished insulin Alpha cell produces excess glucagon Beta cell produces less insulin Sulfonylurea ; Novonorm Metformin glitazonen

2 09-Aug-2008-JAN-2007-BE-1263-SS Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483. Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function Active GLP-1 and GIP Release of incretin gut hormones Pancreas Blood glucose control GI tract  Glucagon from alpha cells (GLP-1) Glucose dependent Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output Glucose dependent  Insulin from beta cells (GLP-1 and GIP) Beta cells Insulin increases peripheral glucose uptake Ingestion of food

3 09-Aug-2008-JAN-2007-BE-1263-SS GLP-1 and GIP zijn de twee belangrijkste Incretines GLP-1 Glucagon-like peptide 1 GIP Glucose-dependent insulinotropic polypeptide •Secretie door L-cellen in distale darm (ileum en colon) •Stimuleert glucose-dependente insulinevrijzetting •Secretied door K-cellen in de proximale darm (duodenum) •Stimulateert glucose- dependente insulinevrijzetting •Suppressie van de hepatische glucoseproduktie door inhibitie van de glucagon secretie (effect op adipocyten) •verhoogt beta-cel proliferatie en overleving in diermodellen en geisoleerde humane eilandjes •verhoogt beta-celproliferatie en overleving in eiladjes cellijnen GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122: 531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.

4 09-Aug-2008-JAN-2007-BE-1263-SS Effect van 6 weken behandeling met GLP-1 infuus bij patiënten met type 2 diabetes •Verlaging van nuchtere glycemie met 77 mg/dl en gemiddelde glycemie met 100 mg/dl •Verlaging van HbA1c met 1,3 % •Gewichtsdaling met 2-3 kg •Verbetering van de insulinegevoeligheid met 77 % Snelle inactivatie (enzyme DPP-4), Korte eliminatie : t 1/2 ~1-2 min GLP-1 moet via continu infuus toegediend worden Ongeschikt voor behandeling van een chronische ziekte zoals type 2 diabetes Drucker DJ, et al. Diabetes Care. 2003;26:

5 09-Aug-2008-JAN-2007-BE-1263-SS Strategieën voor Verbetering van het Therapeutisch Potentieel van GLP-1 •Produkten die de werking van GLP-1 nabootsen (incretin mimetics) –DPP-4–resistente GLP-1 derivaten •bv: GLP-1 analogen, albuminegebonden GLP-1 –Nieuwe peptiden met glucoseregulerende werking gelijkaardig aan GLP-1 •Exenatide •Produkten die de activiteit van endogeen GLP-1 verlengen (incretin enhancers) –DPP-4 inhibitors •Bv sitagliptine (Januvia, Merck), vildagliptine (Galvus, Novartis), SYR 322 (Takeda, fase 3 studies) Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

6 09-Aug-2008-JAN-2007-BE-1263-SS HbA 1c (% ± SE) LS mean change from baseline (for both groups): –0.67% Achieved primary hypothesis of noninferiority to sulfonylurea a Specifically glipizide; b Sitagliptin (100 mg/day) with metformin (≥1500 mg/day); Per-protocol population; LS = least squares Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194– week Sitagliptin vs Sulfonylurea a Add-on Therapy to Metformin Study Sitagliptin Once Daily Showed Comparable Glycemic Efficacy to Sulfonylurea When Added to Metformin (52 Weeks) Weeks Sulfonylurea a + metformin (n=411) Sitagliptin b + metformin (n=382)

7 09-Aug-2008-JAN-2007-BE-1263-SS 52-week Sitagliptin vs Sulfonylurea a Add-on Therapy to Metformin Study Sitagliptin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycemia Sulfonylurea + metformin (n=584) Sitagliptin 100 mg/day + metformin (n=588) Hypoglycemia b P< % 5% Week 52 Incidence (%) LS mean change in body weight over time b Body weight (kg ± SE) a Specifically glipizide; b All-patients-as-treated population. LS = least squares; LSM between-group difference at week 52 (95% CI):  in body weight = –2.5 kg [–3.1, –2.0] (P<0.001); LSM change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001) Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205. Sulfonylurea + metformin (n=416) Sitagliptin 100 mg/day + metformin (n=389)

8 09-Aug-2008-JAN-2007-BE-1263-SS Strategieën voor Verbetering van het Therapeutisch Potentieel van GLP-1 •Produkten die de werking van GLP-1 nabootsen (incretin mimetics) –DPP-4–resistente GLP-1 derivaten •bv: GLP-1 analogen, albuminegebonden GLP-1 –Nieuwe peptiden met glucoseregulerende werking gelijkaardig aan GLP-1 •Exenatide •Produkten die de activiteit van endogeen GLP-1 verlengen (incretin enhancers) –DPP-4 inhibitors •Bv sitagliptine (Januvia, Merck), vildagliptine (Galvus, Novartis), SYR 322 (Takeda, fase 3 studies) Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

9 09-Aug-2008-JAN-2007-BE-1263-SS Exenatide (Exendin-4) –Synthetic version of salivary protein found in the Gila monster –Approximately 50% identity with human GLP-1 –Resistant to DPP-4 inactivation Development of Exenatide: An Incretin Mimetic Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117: Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycaemic control of type 2 diabetes, 77-88, 2004, with permission from Elsevier for English use only. Site of DPP-4 Inactivation H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH 2 H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH 2 Exenatide GLP-1 Human

10 09-Aug-2008-JAN-2007-BE-1263-SS * -0.6 * * -1.9 * Large Phase 3 Clinical Studies: Exenatide bid Reduced HbA 1c and Weight Over 30 Weeks ITT 30-week data; N = 1446; Mean (SE); *p<0.005; Weight was a secondary endpoint. Data on file, Amylin Pharmaceuticals, Inc. * DeFronzo RA, et al. Diabetes Care. 2005;28: ; Buse JB, et al. Diabetes Care. 2004;27: ;Kendall DM, et al. Diabetes Care. 2005;28: Change in HbA 1c (%) Change in Weight (kg) Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID Combined Results of 3 Exenatide Phase 3, Placebo-controlled Studies*

11 09-Aug-2008-JAN-2007-BE-1263-SS Lange termijn effecten van Byetta op HbA1c en gewicht % -1.1  %

12 09-Aug-2008-JAN-2007-BE-1263-SS Waar situeren ? •Gliptines in 2de lijn na metformin –Gewicht –Geen risico op hypo’s –Weinig neveneffecten “instapmodel” –Af : HbA1c > 7 % onder metformine –Starten met staal ! •GLP-1 analogen vóór insuline –Gewicht –Minder risico op hypo’s –Cave misselijkheid –Af : HbA1c > 7,5 % onder metformine + sulfonylureum •Drempel vooral financieel en Af


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