Incretinas e inhibidores de la DPP-4...Reciprocal Response of Insulin and Glucagon in Postprandial...
Transcript of Incretinas e inhibidores de la DPP-4...Reciprocal Response of Insulin and Glucagon in Postprandial...
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Incretinas e inhibidores de la DPP-4
Dr. Ramon GomisHospital Clínic
Barcelona
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El páncreas normal y el islote de Langerhans
Islote de LangerhansIslote de Langerhans
conducto intralobulillar conducto intralobulillar lóbuloslóbulos
isloteislote vasovaso
Adaptado de y disponible en: http://pathologyoutlines.com/pancreas.html. Acceso el 28 de febrero de 2006.
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El islote de Langerhans
~ 3000 células75 % células beta25 % células no beta
200 µm
Micrografía: Lelio Orci, Ginebra
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Las células beta y alfa en el páncreasde las personas sanas
Células beta Células alfa• Constituyen alrededor
del 50 % de la masa endocrina del páncreas1
• Constituyen alrededordel 35 % de la masaendocrina del páncreas1
• Producen insulina y amilina2
• Producen glucagón2
• La insulina se secreta en respuesta a unaglucemia alta2
• El glucagón se secretaen respuesta a unaglucemia baja2
1. Cabrera O et al. PNAS. 2006;103:2334–2339.2. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.
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La insulina y el glucagón regulan la homeostasis normal de la glucosa
Glucosa en sangre
Producción de glucosa
Absorción de glucosa
Glucagón(célula alfa)
Insulina(célula beta)
Páncreas
Hígado
(+)
(–) (+)
(+)
(–)(–)
Músculo y tejido adiposo
Porte D Jr et al. Clin Invest Med. 1995;18:247–254.Adaptado de Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
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Physiologic Explanation of the Incretin Response
With oral glucose load
With IV glucose load
Plas
ma
insu
lin
Incretins• GLP-1 • GIP• ? Other incretins
Time
IV=intravenousAdapted from Vilsbøll T, Holst JJ Diabetologia 2004;47:357–366; Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659.
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GLP-1
• “Incretin” hormone secreted by jejunal and ileal L cells in response to a meal
• Stimulates insulin secretion• Decreases glucagon secretion• Slows gastric emptying• Reduces fuel intake (increases satiety)• Improves insulin sensitivity• Increases β-cell mass and improves β-cell function
(animal studies)
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GLP-1 release following meal:comparison of control, T2DM & IGT
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Type 2Diabetes Pathophysiology
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Type 2 Diabetes is a Multi-Hormonal Disease
• Pancreatic hormones– Insulin (β-cell)– Glucagon (α-cell)– Amylin (β-cell)
• Intestinal Hormones (Incretins) – GLP-1 (L-cells)– GIP (K-cells)
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Reduced Incretin Effect in Type 2 Diabetic patients
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Abnormal Beta-Cell Function in Type 2 Diabetes
• A range of functional abnormalities is present
• Abnormal oscillatory insulin release
• Increased proinsulin levels • Loss of 1st-phase insulin release• Abnormal 2nd-phase
insulin release• Progressive loss of
beta-cell functional mass
Insu
lin (p
mol
/L)
0 60 120 180
500
400
300
200
100
0
Mixed mealNormal subjectsType 2 diabetics
Time (minutes)
*
* *
*p<0.05 between groups
Adapted from Vilsbøll T et al Diabetes 2001;50:609–613.
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Reciprocal Response of Insulin and Glucagon in Postprandial Period in Persons Without Diabetes
Pancreatic isletCHO meal
Glucose120
mg/
dL α-Cells β-Cells100
30 MM
Islet boundary
80
Insulin120
µU/m
L 80
40
0
–60 0 60 120 180 240Time (min)
90
Glucagon120
pg/m
L
110100
Photomicrograph courtesy of Michael Sarras, PhD, Rosalind Franklin University of Medicine and Science. CHO = carbohydrate
Unger RH. N Engl J Med. 1971;285:443-449.
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Inappropriate Insulin and Glucagon Responses to Glucose in Individuals With IGT
Insulin GlucagonNGTIGT
NGTIGT
20
25
30
35
40
45
–60 0 60 120 180 240 300Time (min)
Glu
cago
n(p
mol
/L)
0
100
200
300
400
500
–60 0 60 120 180 240 300
Insu
lin (p
mol
/L)
Mitrakou A, et al. N Engl J Med. 1992;326:22-29.
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Inappropriate Insulin and Glucagon Responses to Glucose in Patients With T2DM
Insulin Glucagon
80
100
120
140
160
–60 0 60 120 180 240Time (min)
Glu
cago
n(p
g/m
L)
0
50
100
150
–60 0 60 120 180 240
Insu
lin (µ
U/m
L)
NGTT2DM
NGTT2DM
Muller WA, et al. N Engl J Med. 1970;283:109-115.
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Incretin Axis: Potential Therapeutic Intervention
GLP-1 or GLP-1 analog
Inactive GLP-1Inactive GIP
Meal
Incretin factors• GLP-1• GIP • ? Other incretins
Inhibition of DPP-IV:MK-431 DPP-IVX
Active GLP-1
15
10
5
0
Meal
DPP-IV inhibitor
Placebo
Time
GLP
-1 a
ctiv
ity
Adapted from Weber A J Med Chem 2004;47:4135–4141; Ahrén B Curr Diabetes Rep 2003;3:365–372; Drucker DJ Diabetes Care 2003;26:2929–2940; Holz GG, Chepurny OG Curr Med Chem 2003;10:2471–2483; Deacon CF et al J Clin Endocrinol Metab 1995;80:952–957; Drucker DJ Curr Pharm Des 2001;7:1399–1412.
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GLP-1 Action Is Preserved in Type 2 Diabetes
NGT (n=9) Type 2 diabetes (n=9)
7.4
51.4
7.5
38.2
GLP-1 infusion (low rate)*GLP-1 infusion (high rate)**
p=0.085 vs NGT
p=0.145 vs NGT
60
Insu
lin (n
mol
lite
r–1
min
)
50
40
30
20
10
0
*Low rate=0.4 pmol kg–1 min–1.**High rate=1.2 pmol kg–1 min–1.NGT=normal glucose tolerance.Nauck MA et al. J Clin Invest. 1993;91:301–307.
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GIP Action Decreases in Type 2 Diabetes But Is Not Absent
GIP infusion (low rate)*GIP infusion (high rate)**
20 18
Insu
lin (n
mol
lite
r–1
min
)
15
p=0.047 vs NGT10
7.7
p=0.14 vs NGT45 3
0NGT (n=9) Type 2 diabetes (n=9)
*Low rate=0.8 pmol kg–1 min–1.**High rate=2.4 pmol kg–1 min–1.Nauck MA et al. J Clin Invest. 1993;91:301–307.
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GLP-1 Improves Multiple Aspects of Beta-Cell Function and Turnover
Functional improvements in beta cell• Stimulates glucose-dependent insulin release*• Enhances insulin biosynthesis and stimulates
insulin gene transcription**• Improves beta-cell responsiveness to glucose**
– By increasing expression of mRNA for glucose transporter-2 and glucokinase
GLP-1
Pancreatic beta cells
Effects on beta-cell turnover• Promotes beta-cell proliferation***• Decreases beta-cell apoptosis**,***
*Studies in patients with type 2 diabetes.**In vitro studies.
***In vitro and ex vivo studies in rodent models.Quddusi S et al. Diabetes Care. 2003;26:791–798; Drucker DJ. Mol Endocrinol. 2003;17:161–171; Holz GG, Chepurny OG. Curr Med Chem. 2003;10:2471–2483; Zhou J et al. Diabetes. 1999;48:2358–2366; Farilla L et al. Endocrinology. 2002;143:4397–4408; Tourrel C et al. Diabetes. 2001;50:1562–1570.
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0
5
10
15
20
25 Plasma glucose (8-h profiles)
Saline
GLP-1
NS
mm
ol/L
Hours
p<0.0001
∆ values: p<0.0001
0
5
10
15
20
25
0 1 2 3 4 5 6 7 8
WEEK 0WEEK 1WEEK 6
Six Weeks of Native GLP-1 Infusion in HumanSubjects With Type 2 Diabetes
NS=not significant.Reprinted from Zander M et al. Lancet. 2002;359:824–830.
mm
ol/L
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Effect of 6-Week Continuous GLP-1 Infusion on Beta-Cell FunctionC-peptide Concentration
During 30 mmol/L Hyperglycemic Clamp7000
Mea
n (S
E)C
-pep
tide
conc
entr
atio
n(p
mol
/L)
Week 0Week 1Week 6
6000
5000
4000
3000
2000
1000
0
0 10 20 30 40 50 60 70 80 90
Continuous Glucose Infusion (variable rate)
Time (min)
5 g L-Arginine intravenous stimulation.Only data of patients treated with GLP-1 shown.n=10.Adapted from Zander M et al. Lancet. 2002;359:824–830.
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Six Weeks of GLP-1 Infusion Lowers Body Weight in Type 2 Diabetes
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
GLP-1 (n=10)Placebo (n=10)
Cha
nges
in w
eigh
t (kg
)
*
**
*p=0.02 GLP-1 group.**p=0.4 saline group.Difference between groups at Week 6 not significant (p=0.13).Adapted from Zander M et al. Lancet. 2002;359:824–830.
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Six Weeks of Native GLP-1 Infusion inSubjects With Type 2 Diabetes
• Reduces fasting and mean plasma glucose by 4.3 and 5.5 mmol/L, respectively
• Reduces HbA1c by 1.3% and normalizes fructosamine
• Results in a weight loss of 1.9 kg presumably because of significantly reduced appetite (range - 4.2 to +1.2)
• Improves insulin sensitivity and enhances beta-cell secretion
• Had no significant side effects
Zander M et al. Lancet. 2002;359:824–830.
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GLP-1 Preserved Morphology of Human Islet Cells In Vitro
GLP-1–treated cellsControl
Day 1
Islets treated with GLP-1 in culture were able to maintain their integrity for a longer period of time.
Day 3
Day 5
Adapted from Farilla L et al. Endocrinology. 2003;144:5149–5158.
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Insulin secretionGlucagon secretion
Gastric emptying
Appetite
CardioprotectionCardiac output
Insulin biosynthesisBeta–cell proliferationBeta–cell apoptosis
Neuroprotection
Glucose production
Insulin sensitivity
Brain
Heart
GI tractLiver
Muscle
Stomach
GLP-1
Summary of Incretin Actions on Different Target Tissues
Adapted from Drucker DJ. Cell Metab. 2006;3:153–165.
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Overview of Incretin-Based Therapies
• Incretin mimetics– Compounds that mimic the effect of the endogenous
incretin GLP-1Examples– GLP-1R agonists
» (ie, Byetta® [exenatide], liraglutide)– Subcutaneous injection
• GIP analogs• Incretin enhancers
– Compounds that prevent the breakdown of the endogenous incretins GLP-1 and GIP
Examples– DPP-4 inhibitors (ie, sitagliptin, vildagliptin)
– Given orally
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Cha
nge
in H
bA1c
from
bas
elin
e (%
)
Time (weeks)0 10 20 30 40 50 60 70 80
-1.5
-1.0
-0.5
0.0
0.5
PlaceboN=128
5 µg BIDN=128
10 µg BIDN=137
Blinded Open-label
Exenatide10 µgBID
Exenatide5 µgBID
Exenatide Showed Durable Effect on HbA1c
Combined baseline HbA1c=8.3%; Completer population (n=393) at 82 weeks.Blonde L et al. Poster presented at the 65th Scientific Session of the American Diabetes Association; June 10–14, San Diego, Calif. Abstract 477-P.
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Liraglutide Reduces Body Weight and HbA1c in Type 2 Diabetes
Glimepiride 1–4 mg open labelLiraglutide 0.75 mg QD
∆W
eigh
t (kg
) (vs
plac
ebo)
p=0.0096-2
-1
0
1
2
-1.0
-0.5
0.0
∆H
bA1c
(%) (
vspl
aceb
o)
p=0.9605
QD=once daily.Data from Matthews D et al. Diabetes. 2002;51(suppl 2):A84.
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Long-Acting GLP-1R Agonists
• Exenatide LAR– Once-weekly injection– 15-week Phase 2 study– 2% reduction in HbA1c– 50 mg reduction in FPG– 9 lbs weight loss– 20% nausea rate– 12/14 subjects HbA1c <7% after 15 weeks
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Dipeptidyl Peptidase 4 (DPP-4)
Active siteAlpha/beta-hydrolase
domain
Beta-propeller
domain
• DPP-4 is a serine protease of the prolyl oligopeptidase enzyme family that exists in 2 forms– Membrane-bound– Soluble
Evans DM. I Drugs. 2002;5:577–585; Drucker DJ. Expert Opin Investig Drugs. 2003;12:87–100;Adapted from Rasmussen HB et al. Nat Struct Biol. 2003;10:19–25.
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Inhibition of DPP-4 Increases Levels ofIntact Biologically Active GLP-1
IntestinalGLP-1
Release
GLP-1 (9–36)
GLP-1 (7–36)Active
Mixed Meal
DPP-4
DPP-4 Inhibitor
• Acute GLP-1 actions – Augments glucose-induced
insulin secretion– Inhibits glucagon secretion
and hepatic glucose production
– Increases glucose disposal
Longer term GLP-1 actions• Increases insulin biosynthesis• Promotes beta-cell
differentiation
Drucker DJ. Diabetes Care. 2003;26:2929–2940.
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DPP-4 Inhibition Increases Levels of Biologically Active GLP-1 and GIP
Intestinal GIP and GLP-1
release
GIP and GLP-1 actions
GIP and GLP-1 actions
GIP (1–42)GLP-1 (7–36)Active
GIP (1–42)GLP-1 (7–36)Active
GIP (3–42)GLP-1 (9–36)GIP (3–42)GLP-1 (9–36)
Rapid inactivation(≤2 min)
MealMealDPP-4
enzymeDPP-4
enzyme DPP-4 inhibitorDPP-4 inhibitor
Deacon CF et al. Diabetes. 1995;44:1126–1131; Kieffer TJ et al. Endocrinology. 1995;136:3585–3596; Ahrén B. Curr Diab Rep. 2003;3:365–372; Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952–957; Weber AE. J Med Chem. 2004;47:4135–4141.
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DPP-4 Inhibitor Restored Pancreatic Islet Beta Cells in Diabetic Mice
Diabetic mouseDiabetic mouse +
DPP-4 inhibitor Lean control mouse
Green: Insulin-producing beta cellRed: Glucagon-producing alpha cell
Zhang BB et al. Poster presented at the 64th Scientific Session of the American Diabetes Association, Orlando, Florida. June 2004.
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Vildagliptin Therapy Significantly Lowered HbA1c Over the Course of 1 Year
6.8
7.2
7.6
8.0
8.4
–4 0 4 8 12 16 20 24 28 32 36 40 44 48 52Week
Vildagliptin/MET (extension, ITT n=42)PBO/MET (extension, ITT n=29)Vildagliptin/MET (core, ITT n=56)PBO/MET (core, ITT n=51)
HbA
1c (%
)
p<0.0001
p<0.0001∆–1.1 ± 0.2%
MET=metformin; PBO=placebo; ITT=intent to treat.Adapted from Ahrén B et al. Diabetes Care. 2004; 27:2874–2880.
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BID Dose-Range Finding StudySitagliptin Significantly Reduced HbA1c in
12-Week Study of Patients With Type 2 Diabetes
5 mgBID
(n=125)
12.5 mgBID
(n=123)
25 mgBID
(n=123)
50 mgBID
(n=124)
–0.38*
–0.64* –0.66*–0.77*
–1.0*
Glipizide5–20 mg(n=125)
Sitagliptin
0
Plac
ebo-
subt
ract
ed c
hang
efr
om b
asel
ine
in H
bA1c
(%)
–0.2
–0.4
–0.6
–0.8
–1.0
–1.2
*p<0.001 vs placebo.Adapted from Scott RS et al. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005; Athens, Greece.
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BID Dose-Range Finding StudySitagliptin Had Neutral Effect on Body Weight
Week 12 change in body weight
0.9*1.0
–0.3
0.8
0.6
Wei
ght (
kg)
0.4
0.2
0
–0.4
–0.2
–0.4
–0.6Glipizide 5–20 mg
QD(n=125)
Sitagliptin 5–50 mgBID
(n=495)Placebo(n=125)
QD=once daily.*p<0.001 vs placebo and sitagliptin groups.Adapted from Scott RS et al. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005; Athens, Greece.
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Add-On Therapy to Metformin StudySitagliptin Improved 24-Hour Glucose Profile vs
Metformin Alone Period 1 Results
Treatment difference: –32.8 mg/dL (p<0.001)*
Metformin ≥1500 mg/day (n=13)Sitagliptin 50 mg BID + metformin ≥1500 mg/day (n=15)
Breakfast Lunch Dinner240
Glu
cose
(mg/
dL)
8:00 Day 1
13:00 19:00
Dose 17:30
Dose 218:30
220
200
180
160
140
120
100
0:00Day 2
7:30
*Least-squares mean difference in weighted mean glucose.Adapted from Brazg RL et al. Poster presented at the 65th Annual Scientific Sessions of the American Diabetes Association; June 10–14, 2005; San Diego, Calif.
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GLP-1R Agonists vs DPP-4 InhibitorsGLP-1R Agonists DPP-4 Inhibitors
Administration Injection Orally Available
GLP-1 concentrations Pharmacological Physiological
Mechanisms of actionActivation of portal glucose sensor
GLP-1
No
GLP-1 + GIP
Yes
↑ Insulin secretion +++ +
↓ Glucagon secretion ++ ++
Gastric emptying Inhibited +/-
Weight loss Yes No
Expansion of beta-cell mass
In preclinical studies Yes Yes
Nausea and vomiting Yes No
Potential immunogenicity Yes No
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