Transcript Document 7493458

The Pathophysiology of Type 2 Diabetes
Includes Three Main Defects
Pancreas
Excess
glucagon
Alpha cell
produces
excess
glucagon
Beta cell
produces
less insulin
Diminished
insulin
Diminished
insulin
Hyperglycemia
Muscle and fat
Liver
Excess glucose output
Metformin
glitazonen
Insulin resistance
(decreased glucose uptake)
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.
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Sulfonylurea ; Novonorm
Islet
Insulin deficiency
Incretins Regulate Glucose Homeostasis
Through Effects on Islet Cell Function
Ingestion
of food
Glucose dependent
 Insulin
from beta cells
(GLP-1 and GIP)
GI tract
Release of
incretin gut
hormones
Pancreas
Beta cells
Alpha cells
Insulin
increases
peripheral
glucose
uptake
Blood
glucose control
 Glucagon
from alpha cells
(GLP-1)
Glucose dependent
Increased insulin
and decreased
glucagon
reduce
hepatic
glucose output
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.
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Active
GLP-1 and GIP
GLP-1 and GIP zijn
de twee belangrijkste Incretines
• Secretie door L-cellen in distale
darm (ileum en colon)
• Stimuleert glucose-dependente
insulinevrijzetting
GIP
Glucose-dependent insulinotropic
polypeptide
• Secretied door K-cellen in de
proximale darm (duodenum)
• Stimulateert glucosedependente 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.
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GLP-1
Glucagon-like peptide 1
Effect van 6 weken behandeling met
GLP-1 infuus bij patiënten met type
2 diabetes
Snelle inactivatie (enzyme DPP-4),
Korte eliminatie : t 1/2 ~1-2 min
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• 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 %
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.
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
• 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
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)
7.8
7.6
LS mean change from baseline
(for both groups): –0.67%
7.2
7.0
6.8
6.6
Achieved primary
hypothesis of
noninferiority to
sulfonylurea
6.4
6.2
Sulfonylureaa + metformin (n=411)
6.0
Sitagliptinb + metformin (n=382)
5.8
0
6
12
18
24
30
Weeks
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.
38
46
52
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HbA1c (% ± SE)
7.4
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
Hypoglycemia
b
LS mean change in body weight over timeb
3
50
Sulfonylurea + metformin (n=416)
Sitagliptin 100 mg/day + metformin (n=389)
40
Incidence (%)
1
0
32%
30
P<0.001
20
-1
10
-2
-3
5%
0
0
12
24
38
52
Weeks
Week 52
Sulfonylurea + metformin (n=584)
Sitagliptin 100 mg/day + metformin (n=588)
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.
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Body weight (kg ± SE)
2
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
• 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
Development of Exenatide: An
Incretin Mimetic
Exenatide (Exendin-4)
Exenatide 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
GLP-1
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
Human
Site of DPP-4 Inactivation
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.
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– Synthetic version of salivary
protein found in the Gila
monster
– Approximately 50% identity
with human GLP-1
– Resistant to DPP-4 inactivation
Large Phase 3 Clinical Studies:
Exenatide bid Reduced HbA1c and Weight
Over 30 Weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
Combined Results of 3 Exenatide Phase 3 , Placebo-controlled Studies*
-0.5
-0.6
*
-1
-0.9
*
0
-0.5
-1.0
-0.7
-1.5
-1.4
-1.5
-2.0
*
-1.9
*
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
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Change in HbA1c(%)
0
Change in Weight (kg)
+0.1
Lange termijn effecten van Byetta op
HbA1c en gewicht
8.5
8.0
8.3%
7.5
-1.1±
%
1
0
6.5
0 10 20 30 40 50 60 70 80 90 100110 -1
100 kg
-2
-3
-4
-5
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7.0
-4.7±kg
-6
-7
0 10 20 30 40 50 60 70 80 90 100110
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 !
–
–
–
–
Gewicht
Minder risico op hypo’s
Cave misselijkheid
Af : HbA1c > 7,5 % onder metformine + sulfonylureum
• Drempel vooral financieel en Af
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• GLP-1 analogen vóór insuline