Son todos los Inhibidores de DPP4 IGUALES ... - Aveso

Son todos los
Inhibidores de DPP4
IGUALES ?
Farmacología de la eficacia
_____________
Caracas 2012
Dra. Lisette Aponte Marín
Medico Endocrinólogo HUC-UCV
Unidad Farmacología Clínica UCV
Director Medico IPP-UCV
Caracas.

INSULINA
CONTROL DE LA HOMEOSTASIS GLUCÉMICA
GENÉTICA
Célula ß fuerte o débil
• MODYs
• TCF7L2
• KCNJII
E
AMBIENTE
Feto /adultos
• Malnutrición
• Sedentarismo
• Estrés
• IR
• Inflamación
•Glucolipotoxicidad
• EO/ROS
•AGEs
R
Normoglucemia TGA Diabetes Mellitus
Gagliardino, 2010
NID IRCM IRS

La fisiopatología de la diabetes tipo 2 comprende
tres defectos principales
Deficiencia de
insulina
Islote
Glucagon en exceso
Páncreas
Células
alfa
Producen
glucagon
en
exceso
Células
beta
Producen
menos
insulina
Menos
insulina
Hígado Liver
Menos insulina
Hiperglucemia
Músculo y
tejido adiposo
Liberación excesiva de
glucosa
Resistencia a la insulina
(disminución de la captación
de glucosa)
Adaptado de 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.

La Función de la Célula β
Se Encuentra Alterada en DM2
Insulina
(pmol/L)
Anomalías funcionales:
• Pérdida 1ª fase secreción insulina
• Liberación de insulina pulsatil
anormal
• Respuesta anormal de 2ª fase
de secrecion insulínica
• Perdida progresiva de la masa
funcional de células β
• Niveles de Glucagon
• Niveles de Incretinas GLP-1 GIP
Comida mixta *
50
0
400
300
200
100
0
*
Tiempo (min)
Sujetos normales
Diabéticos tipo 2
0 60 120 180
*p

Elevación de los niveles de GLP-1 es el objetivo
para la disfunción del Islote
Physiological levels of GLP1 – multiple effects on plasma glucose
Insulin
resistance
Inadequate
glucagon
suppression (-cell
dysfunction)
Acute
β-cell
function
Chronic
β-cell
function
• Improves glucose
uptake in fat and
muscle tissue
• Suppresses
glucagon
secretion
• Improves
insulin secretion
• Increases insulin
biosynthesis*
• Promotes β-cell
differentiation*
• Decreases β-cell
apoptosis*
*Preclinical data.
GLP1=glucagon-like peptide-1.
Adapted from Drucker. Diabetes Care 2003;26:2929–40

SECRETION
INCRETIN
INTESTINAL
INSULIN
INSULINA
70%
Diabetes Research and clinical practice 90(2010)131-140

Incretinas
• Péptidos intestinales que incrementan de
manera glucosa dependiente la secreción de
insulina
• Son: GLP-1 y GIP. El 50-60% de la secreción
postprandial de insulina se explica por acción
de las incretinas
• El 80% de la actividad incretínica postprandial
es atribuible a GLP-1.
Stuart Ross .Clinical Review vol 56:july 2010;639-648

GLP1 degraded in vivo via DPP4
● GLP1 (green) released into intestinal capillaries is immediately exposed
to DPP4 (red) 1
● >50% of secreted GLP1 is already
degraded before it reaches the
general circulation 1
● >40% of circulating GLP1 is already
degraded before it reaches β-cells 2
DPP4=dipeptidyl peptidase 4.
Histochemistry by C. Ørskov, Panum Institute, Copenhagen.
Copyright © 1999, The Endocrine Society.
1
Hansen et al. Endocrinology 1999;140:5356–63;
2
Deacon et al. Am J Physiol 1996;271:E458–64

DPP4 inhibition rationale in T2DM treatment
Oral glucose
or mixed
meal GLP1 (9-36)
inactive
Intestinal wall
L-cell
DPP4
>80% of total pool
GLP1
actions
GLP1 (7-36)
agonist
Deacon et al. Diabetes 1995;44:1126–31;
Deacon, Holst. Biochem Biophys Res Commun 2002;294:1–4;
Demuth et al. Biochem Biophys Res Commun 2002;296:229–32;
Ahren et al. Diabetes Care 2003; 26: 2860-2864;
Drucker. Diabetes Care 2003;26:2929–40

INHIBIDORES DPP4

Inhibidores DPP4 Farmacocinética
DPP4 Inh.
Función
Cel B
U. recept
t 1/2
Ruta
metabólica
Interacción
Medic.
Efectos
colaterales
VILDAGLIPTINA
Incrementa
HOMA B
proinsul / ins
U covalente
90 min -4 h 85%
hepático
23% renal
no
transaminasas
SITAGLIPTINA
U Competitiva
10-12 h 79% exc.
renal
no
Aumento de
Infec. resp
SAXAGLIPTINA
U. Covalente
2.5- 3.1 h CYP3A4/5
Exc. renal
si
Disminuye
La cuenta de
linfocitos
LINAGLIPTINA
U Covalente
184 h 7% exc.
Renal
no
Promueve
cicatrización
heridas
PHARMACOLOGY THERAPEUTHICS 125 (2010) 328-361
Diabetes Research and clinical practice 90(2010)131-140

Plasma DPP4 activity
(% of baseline)
Vildagliptina formulado para tener t ½ prolongado
N
N
N
H
H
N
O
N
N
R
R
R
H
N
DPP728 – July 1996 Vildagliptin – May 1998
O
N
N
HO
H
N
O
N
N
100
80
60
DPP728 Vildagliptin
hDPP4 in vitro
K i (nM) 2 3
t 1/2 complex 9 min 55 min
40
20
0
0 2 4 6 8 10 12 24
Hours after dose
HO
H
N
HN
O
N
DPP4 Catalytic Site
Villhauer et al. J Med Chem 2003;46:2774–89;
Burkey et al. Poster P0788 presented at EASD 2006
Hughes et. al. Biochemistry 1999; 38, 11597-11603
O
Serine 630
H - His

Vildagliptina formulado para mayor especificidad
a los DPP4
Protease
Binding
mode
K on
(103M-1s-1)
K off
(s-1)
E·I t ½
(min)
K i
(nM)
DPP2 none ND ND ND >20,000
DPP4 long & tight 70 2.5 X 10 -4 55 3.0 ± 0.3
DPP8 fast * *

vildagliptina and sitagliptina:
substrate-enzyme blocker (u covalente) vs a competitive
enzyme inhibitor
DPP4 Catalytic Site
DPP4 Catalytic Site
HO
H
N
O
N
N
Serine 630
O
H His
HO
H
N
HN
O
N
O
Serine 630
H - His
Sitagliptin – competitive
enzyme inhibitor
Off-rate kinetics comparison
Compound K off (s -1 )
Half-life of
enzymeinhibitor
(EI)
complex
Vildagliptin 2.5 X 10 -4 55 min §
Sitagliptin >1 X 10 -3 negligible €
§
Expected from a covalently bound inhibitor
€
Expected from a non-covalent competitive inhibitor
Potashman, Duggan. J Med Chem 2009;52:1231–46;
Davis et al. Indian J Pharmacol 2010;42:229–33
Ahren et al. Diabetes Obes Metab 2011; 13:775-783

RFU
UNION al DPP4:
vildagliptin (lento) vs sitagliptin (rapida) disociacion
Competitive
enzyme
inhibitor:
sitagliptin
Inhibitor
+
DPP4
K 1
K -
1
Inhibitor:
DPP4 complex
40000
Natural
substrate:
(GLP1)
Substrateenzyme
blocker:
(slow, tightbinding
vildagliptin)
Slow dissociation due to reversible covalent bond
HO
GLP1
+ +
+ Slow +
H
N
DPP4
HN
O
K 2
K 1
Fast
K -1
GLP1:DPP4
complex
K 2
K 1
K -1
Vildagliptin DPP4 Vildagliptin:
DPP4 complex
N
DPP4 Catalytic Site
O
Serine 630
H - His
Inactive
GLP1
Inactive
Vildagliptin
DPP4
DPP4
30000
20000
10000
0
VC
Sitagliptin
Vildagliptin
0 1000 2000 3000
Time (s)
The human recombinant DPP4 (10 ng) pre-incubated
without (VC) or with sitagliptin (500 nM) or vildagliptin
(50 nM) diluted more than 100-fold into 0.5 mM
H-Gly-Pro-AMC and the DPP4 activity measured.
Represents one experiment (n=3)
Davis et al. Indian J Pharmacol 2010;42:229–33
Ahren et al. Diabetes Obes Metab 2011; 13:775-783

Intact GLP-1 (pmol/L)
Niveles plasmaticos de GLP1 luego de
3 meses de tratamiento con vildagliptin o sitagliptin
30
25
Vildagliptin 50 mg
twice daily + metformin
Sitagliptin 100 mg
once daily + metformin
20
15
10
5
0
0 2 4 6 8 10 12 14 16
Breakfast Lunch Dinner
Time (hours)
*p

Plasma glucagon (mg/dL)
Vildagliptina demostró mejor control del glucagon durante
el día
90
80
70
60
50
40
30
20
Sitagliptina 100mg 1x/dia
Vildagliptina 50mg 2x/dia
** * * *
* * * * *
* * *
-20 0 15 30 60 90 120 180 -240 300 0 15 30 60 90 120 180 -240 300 0 15 30 60 90 120 180 -240 300 min
Desayuno Almuerzo Cena
Marfella R e cols. J Diab Complications 2009; epub ahead

MAGE (mg/dl)
MAGE (mg/dl)
Vildagliptin reduced 24-hr acute glucose
fluctuation (MAGE) compared to sitagliptin
A cross-sectional study of acute glucose fluctuation on pre- and post- treatment
Media de la amplitud de las oscilaciones de glicemia
100
Vildagliptin n=20
*p

RR de muerte en la UCO
La Variación Glicémica Predice la Mortalidad en la
Unidad Coronaria
*
*
*
● n = 5.828 pacientes Edad media:
65 años
Cuartil
Glicemia Media
(mg/dl)
MAGE
(mmol/hora)
1 < 125 < 0.39
2 125 - 137 0.39 - 0.60
3 137 - 160 0.60 - 0.87
4 > 160 > 0.87
La Alta variabilidad glicémica es un fuerte predictor de mortalidad.
La Baja variabilidad glicémica parece ser protectora
Hermanides J et al. Diabetes 2009; Suppl 1: A71

No. of Events
No. of Events
Change in HbA 1c (%)
Vildagliptin add-on to insulin: significant reduction in
HbA 1c and fewer hypoglycemic events
Duration: 24 weeks
Add-on to insulin:
vildagliptin
vs placebo
0.0
n =
Overall Mean BL = 8.4%
≥65 Years Mean BL = 8.4%
140 149 42 41
–0.2
–0.4
–0.6
–0.8
200
150
100
–0.5
*
No. of Events
*
185
113
–0.2
200
200
150 160
100
–0.1
Vildagliptin 50 mg bid +
insulin
Placebo + insulin
–0.7
**
No. of Severe Events
*
6
50
0
50
0
0
*p

(pmol/L)
Synergy between vildagliptin and metformin on
prandial GLP1
● Vildagliptin increases active GLP1
levels by 2–4x through inhibition of the
DPP4 enzyme 1–7
● Metformin raises GLP1 levels,
presumably through increasing GLP1
synthesis and not through DPP4
inhibition 5–7
● Vildagliptin and metformin are known
to have synergy to maximise levels of
intact GLP1 8,9
Active GLP1 AUC 0-2hr
30
25
20
15
10
5
0
Effect of vildagliptin on prandial
active GLP1 levels in drug-naïve
versus metformin-treated patients
Vildagliptin
in drug-naïve
patients
(n=5)
*
Vildagliptin in
patients on
metformin
(n=12)
*p

Intact GLP1 (pM)
Intact GLP1 (pM)
Synergy between vildagliptin and metformin on
fasting GLP1
Fasting levels of intact GLP1 at baseline and
at 3 months
Vilda group
Placebo
n = 20 20 19 19
14
14
Fasting levels of intact GLP1 in vildagliptin
subgroups at 3 months
Vilda only
7
Vilda + met
13
12
12
**
10
8
*
10
8
6
6
4
4
2
2
0
BL
3 months BL 3 months
0
3 months 3 months
*p

HbA 1c (%)
Vildagliptin add-on to metformin:
Significantly lowers HbA 1c over 52 Weeks
Duration: 52 weeks
Vilda add-on to met
8.4
Vilda 50 mg daily + met (extension, ITT n=42)
PBO + met (extension, ITT n=29)
Vilda 50 mg daily + met (core, ITT n=56)
PBO + met (core, ITT n=51)
8.0
7.6
p

Mean HbA 1c (%)
Incidence (%)
Body weight (kg)
No. of events
No. of events
Vildagliptin: as effective as glimepiride when added to metformin
at 52 weeks – no weight gain and low incidence of hypoglycemia
Add-on treatment to metformin
(~1.9 g mean daily)
Patients with
1 hypos (%)
Number of
hypoglycemic
events
7.5
7.3
7.1
6.9
6.7
Vildagliptin 50 mg twice daily + metformin
Glimepiride up to 6 mg once daily + metformin
Duration: 52 weeks
Add-on to metformin: vildagliptin vs glimepiride
NI=non-inferiority
Time (weeks)
NI: 97.5%
CI (0.02, 0.16)
−0.5%
−0.4%
6.5
–8 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
20
15
10
5
0
91.0
90.5
90.0
89.5
89.0
88.5
88.0
n=
1.7
1389 1383
18.2
600
554
500
400
300
200
100
0
n=
1389 1383
39
−1.8 kg
difference
87.5
–8 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (weeks)
Ferrannini et al. Diabetes Obes Metab 2009;11:157–66
Data on file, Novartis Pharmaceuticals
12
10
8
6
4
2
0
0

conclusión
• Los Inhibidores de DPP4 representan una importante
contribución para el tratamiento de la diabetes tipo 2
• Se diferencian de otros ADO por su bajo riesgo de
hipoglucemia, efecto neutral en la ganancia de peso
• Estudios experimentales y clínicos sugieren que los DPP4
pueden preservar y posiblemente prevenir la disfunción de la
célula B pancreática
• Sin embargo, se requieren estudios a largo plazo para
demostrar estos hallazgos

Grandes mentes tienen un
propósito
Los demás solo
Deseos
Prof. Gill’ Adi
______________