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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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

Diminishedinsulin

Diminishedinsulin

Alpha cellproduces excess glucagon

Beta cellproduces less insulin

Sulfonylurea ; Novonorm

Metformin

glitazonen

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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

Bloodglucose control

GI tract

Glucagon from alpha cells

(GLP-1)Glucose

dependent

Alpha cells

Increased insulin and decreasedglucagon reduce hepatic glucose output

Glucose dependent Insulin

from beta cells(GLP-1 and GIP)

Beta cells

Insulinincreases peripheral glucose uptake

Ingestion of food

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GLP-1 and GIP zijn de twee belangrijkste Incretines

GLP-1Glucagon-like peptide 1

GIPGlucose-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 polypeptideAdapted 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.

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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;26:2929-2940.

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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;26:2929-2940.; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

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Hb

A1

c (

% ±

SE

)

LS mean change from baseline (for both groups): –0.67%

Achieved primary hypothesis of

noninferiority to sulfonylurea

aSpecifically glipizide; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); Per-protocol population; LS = least squares

Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.

52-week Sitagliptin vs Sulfonylureaa Add-on Therapy to Metformin Study

Sitagliptin Once Daily Showed Comparable Glycemic Efficacy to Sulfonylurea When Added to Metformin (52

Weeks)

Weeks

5.8

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

Sulfonylureaa + metformin (n=411)

Sitagliptinb + metformin (n=382)

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-3

-2

-1

0

1

2

3

0 12 24 38 52

Weeks

52-week Sitagliptin vs Sulfonylureaa 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)

Hypoglycemiab

P<0.001

32%

5%

0

10

20

30

40

50

Week 52In

cide

nce

(%)

LS mean change in body weight over timeb

Bod

y w

eigh

t (k

g ±

SE

)

aSpecifically glipizide; bAll-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)

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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;26:2929-2940.; Baggio LL, et al. Diabetes. 2004;53:2492-2500.

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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;117:77-88. 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 – NH2

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 – NH2

Exenatide

GLP-1Human

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-0.5

-1.5

-1

0

-0.9 *

-0.6 *

+0.1

-0.7

-1.4 *

-1.9 *

-2.0

-1.5

-1.0

-0.5

0

Large Phase 3 Clinical Studies: Exenatide bid Reduced HbA1c 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;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;Kendall DM, et al. Diabetes Care. 2005;28:1083-1091

Ch

ang

e in

Hb

A1c

(%)

Ch

ang

e in

Wei

gh

t (k

g)

Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID

Combined Results of 3 Exenatide Phase 3 , Placebo-controlled Studies*

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Lange termijn effecten van Byetta op HbA1c en gewicht

0 10 20 30 40 50 60 70 80 90 1001106.5

7.0

7.5

8.0

8.5

8.3%

-1.1%

0 10 20 30 40 50 60 70 80 90 100110-7

-6

-5

-4

-3

-2

-1

0

1

100 kg

-4.7 kg

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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