3. Potencia
HbA1C
Estilo de vida
Metformina
Insulina
Sulfonilurea
(glicazidaglimepirida)
Repaglinida
Problemas
Ventajas
Insuficiencia renal.
Hipoxemia crónica.
Tolerancia gastrointestinal.
Para todos.
Vence resistencia
insulínica.
Pierde peso.
1-2%
1-2%
1,5-3,5%
1-2%
0,5-1,5%
Monitorización
frecuente. Más
pinchazos.
Ganancia peso.
Hipoglucemia.
Lo más rápido.
No límite de dosis.
No problemas con
insuficiencias de
órganos.
Mejora lípidos.
Hipoglucemia.
Ganancia de peso.
Interacciones
I.renal
Acción rápida.
Pierde utilidad con el
tiempo.
Ganancia de peso.
Múltiples tomas.
Hipoglucemia.
Acción rápida.
Glucemias
postprandiales
Ideal en Insuficiencia
renal y hepática.
6. Most current therapies for type 2 diabetes
have an insulin-dependent mechanism of
action
Sulphonylureas
Incretins
DPP4 inhibitors
Incretins
Slow gastric emptying
Stimulate
insulin secretion
↑ insulin secretion
↓ glucagon secretion
Metformin
Thiazolidinediones
↑ glucose metabolism
Thiazolidinediones
↑ glucose intake
↓ FFA release
Metformin
Thiazolidinediones
Suppress glucose production
DPP4 = Dipeptidyl peptidase 4; FFA = free fatty acids; Adapted from Tahrani AA, et al. Lancet 2011;378182-97.
All Disease Education materials must be reviewed in accordance with local review requirements
6
7. El riñón, protagonista de la homeostasis de la glucosa
Balance ~0 g/día
Disponibilidad de glucosa ~250
g/día
Ingesta por la dieta ~180 g/día
Producción glucosa ~70 g/día
Gluconeogénesis
Glucogenolisis
Consumo de glucosa ~250 g/día
Cerebro ~125 g/día
Resto del organismo ~125 g/día
−
+
El riñón filtra
la glucosa circulante
Glucosa filtrada
El riñón reabsorbe y
Glucosa reabsorbida
~
1
8
0
7
Wright, E. M, et al. J Intern Med 2007; 261: 32–43
g
8. La diabetes altera la homeostasis de la glucosa
Balance ~0
g/día
Disponibilidad de glucosa >280
g/día
Ingesta por la dieta >180 g/día
Producción de glucosa ~100 g/día
Gluconeogénesis*
Glucogenolisis
+
8
Consumo de glucosa >250 g/día
Cerebro ~125 g/día
Resto del organismo >125 g/día
−
Aumento de la reabsorción
C
o
n
c
e
Por encima del umbral renal
n
t
Glucosa filtrada
r
a
c
i
*La elevación en la producción de glucosa en pacientes con diabetes tipo 2 se atribuye a la gluconeogénesis hepática y renal
ó
Wright, E. M, et al. J Intern Med 2007; 261: 32–43
9. Continued glucose reabsorption even at high glucose
levels induces sustained hyperglycaemia in diabetics1,2
Paradoxically, SGLT2 reabsorbs glucose through an insulin-independent pathway,
even in the presence of hyperglycaemia
Filtered glucose
Rate of glucose filtration /
reabsorption / excretion (mmol/min)
No excretion
Excretion
threshold
3
Excreted glucose
Reabsorbed glucose (diabetes)
2
Reabsorbed glucose (normal)
Saturation
threshold
1
0
0
8.3
13.3
25
mmol/L
0
149.6
239.6
450.5
Plasma glucose
mg/dL
Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; Marsenic O. Am J Kidney Dis 2009;53:875-883; Nairs S, et al. J Clin Endocrinol Metab
2010;95:34-42.
All Disease Education materials must be reviewed in accordance with local review requirements
9
10. All Disease Education materials must be reviewed in accordance with local review requirements
10
11. Other conditions associated
with altered glucose transport
Transporter
SGLT2
GLUT2
SGLT1
GLUT1
Condition leading
to defective glucose transport
Symptoms of condition
Familial renal glucosuria
Most patients do not develop significant
clinical problems over time
Fanconi–Bickel syndrome
Numerous symptoms, including
enlarged liver, abdominal bloating and
vitamin
D-resistant rickets
Glucose–galactose
malabsorption syndrome
De Vito disease
Severe diarrhoea
Numerous symptoms, including
microcephaly and delayed mental and motor
development
Adapted from Bays H. Curr Med Res Opin 2009;25:671–
681.
All Disease Education materials must be reviewed in accordance with local review requirements
11
12. SGLT2 and GLUT2 mechanism of transport
Basolateral membrane
Tubular
lumen
Interstitial
space
SGLT2
GLUT2
Na+
Glucose
Glucose
Glucose
Na+
Na+
K+
K+
Na+/K+
pump
Tight
junction
Lateral intercellular space
Adapted from Wright EM, et al. Physiology 2004;19:370–376;
All Disease Education materials must be reviewed in accordance with local review requirements
12
13. El 90% de la glucosa se reabsorbe en el túbulo
proximal mediante los cotransportadores SGLT2
180 g glucosa
filtrada cada día
Glomérulo
Túbulo
proximal
S1
Túbulo
colector
S2
Filtración
de glucosa
SGLT2
90%
Túbulo
distal
SGLT1
10%
S3
Reabsorción
de glucosa
Hasta un ~90% de la
Hasta un ~90% de la
glucosa
glucosa
se reabsorbe
se reabsorbe
en los segmentos S1/S2
en los segmentos S1/S2
~10% de la glucosa
~10% de la glucosa
se reabsorbe
se reabsorbe
en el segmento S3
en el segmento S3
Asa de
Henle
SGLT1: Cotransportador sodio-glucosa tipo 1; SGLT2: Cotransportador sodio-glucosa tipo 2
13
Bailey CJ. Trends in Pharmacological Sciences 2011;32 (2):63-71
Mínima
excreción
de glucosa
14. FORXIGA® (dapagliflozina) reduce la reabsorción renal
de glucosa y produce su excreción por la orina1
Disminución de
la reabsorción de
la glucosa
FORXIGA
SGLT2
®
Túbulo
proximal
FORXIG
A®
SGLT2
Excreción urinaria
del exceso de
glucosa (≈ 70 g/día
equivalentes a
280 kcal/día*) 1
Filtración
Glucosa
de la
glucosa
Dapagliflozina actúa mediante un mecanismo independiente de la insulina 2
Actúa con independencia de la funcionalidad de las células β 2-6
Complementa los mecanismos de acción basados en la insulina 2-6
*Los incrementos del volumen de orina observados en sujetos con diabetes mellitus tipo 2 tratados con
dapagliflozina 10 mg se mantuvieron a las 12 semanas y ascendieron a aproximadamente 375 ml/día.
SGLT2: Cotransportador sodio-glucosa tipo 2
14
1. Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
2.Bailey CJ, et al. Lancet. 2010;375:2223–2233. 3.Ferrannini E, et al. Diabetes Care. 2010; 2010;33:2217–2224. 4.Strojek K et al. Diabetes Obes Metab
2011; 13:928-938. 5. Nauck MA, et al. Diabetes Care 2011;34:2015–22; 2. 6.Wilding J.P.H et al Ann Intern Med. 2012;156:405-415.
15. Development of SGLT2 inhibitors
The search for a potent, selective
SGLT2 inhibitor….from apple trees
to candidate drugs
All Disease Education materials must be reviewed in accordance with local review requirements
15
16. Discovery of phlorizin
by French chemists in the early 1800s
Isolated from apple tree bark
(1835)
Glycosuric effect revealed
(1865)
Renal effects identified in rat
(1903) and man (1933)
Antidiabetic effect discovered
(1987)
Found to inhibit SGLT1
and SGLT2
Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:31–38.
All Disease Education materials must be reviewed in accordance with local review requirements
16
17. In the 1880s-1890s,
phlorizin was shown to induce glycosuria
In 1886, Von Mering observed that dogs
receiving doses of phlorizin above 1.0 g developed
glycosuria
“In a diabetic with 2.857 g of glucose per litre
of blood, the injection of 50 mg of phlorizin
was also followed by a slight decrease,
to 2.706 g, while glycosuria increased by
115 to 140 g…” (Émile) Charles Achard, 1899
Cited in Joel RL, et al. Diabetes Metab Res Rev 2005;21:31–38.
All Disease Education materials must be reviewed in accordance with local review requirements
17
18. Dapagliflozin - a potent and selective SGLT2
inhibitor in vitro and in vivo
pharmacokinetic characteristics
1 Good oral bioavailability independent of food intake 1
2 Half-life consistent with once-daily dosing1
3 Low risk of drug-drug interactions1-5
4 1200-fold selectivity for SGLT2 vs. SGLT16
Komoroski BJ, et al. Clin Pharmacol Ther 2009;85:520–526. 2Obermeier M, et al. Drug Metab Dispos 2010;38:405–414; 3Kasichayanula S, et al. Diabetes
Obes Metab 2011;13:47–54; 4Kasichayanula S, et al. AAPS 2010, Diabetes Obes Metab 2011;13:770-773; 5Wilcox, et al. ASN 2010, Denver, CO [Poster
4509]; 6Han S, et al. Diabetes 2008;57:1723–1729
1
All Disease Education materials must be reviewed in accordance with local review requirements
18
19. Dapagliflozin – An extensive clinical program
14 Phase 3 double-blind, randomised, controlled clinical trials
>5000 randomised patients
Studies up to 4 years in duration
>30% of patients originating from Europe
Early disease
Advanced Disease
Treatment-naive
patients
Add-on after initial
treatment failure
to:
Monotherapy
versus placebo
Combination with
metformin as initial therapy
Special at-risk
populations
Versus placebo - added
• Metformin
• Sulphonylurea (SU)
• Insulin
• TZD
• DPP4 inhibitor
(SITAGLIPT)
Versus SU - added to:
• Metformin
Safety and efficacy
versus placebo:
• Patients with moderate
renal insufficiency
• Patients at increased risk
of CV events
All Disease Education materials must be reviewed in accordance with local review requirements
19
20. Efficacy comparisons across
Phase 3 dapagliflozin studies
All Disease Education materials must be reviewed in accordance with local review requirements
20
21. Descenso mantenido de HbA1c en TODOS los
estudios, semana 24
Monotherapy1
Add-on
to Met2
Add-on
to Glim3
Add-on
to Pio4
Add-on
to Ins5
Dapa
+ Met XR6
7.92
8.06
8.11
8.37
8.53
9.05
Baseline
HbA1c
Primary endpoint for 24-week
adjusted ∆ from baseline HbA1c (%)
10
m
g
o
eb
ac
Pl
10
m
g
o
eb
ac
Pl
10
m
g
o
eb
ac
Pl
10
m
g
o
eb
ac
Pl
10
m
g
o
eb
ac
Pl
10
m
g
o
eb
ac
Pl
-0.13
-0.23
-0.3
-0.3
-0.42
-0.89
*
-0.84
*
-0.82
*
-0.97
*
-0.9
*
-1.44
-1.98
*p <0.001 compared with placebo
*
Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2Bailey CJ, et al. Lancet 2010;375:2223-33. 3Strojek K, et al. Diabetes Obes Metab 2011;13:928-38.
4
Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P. 5Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract
0078-OR. 6Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
1
All Disease Education materials must be reviewed in accordance with local review requirements
21
22. Descenso mantenido de glucemia en Ayunas,
semana 24 (21-30 mg/dL)
Monotherapy1
mmol/L mg/dL
10
m
g
o
eb
c
la
P
Add-on to Met2
10
g
m
o
eb
c
la
P
Add-on to Ins3
10
g
m
o
eb
c
la
P
10
m
g
o
eb
c
la
P
3.3
0.28
FPG adjusted mean change from baseline
Add-on to Pio4
0.00
0.28
-4.1
-5.94
0.56
-6
0.83
1.11
1.39
1.67
-23.4
-21.7
-28.8
-30
1.94
Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22
[Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P];
1
All Disease Education materials must be reviewed in accordance with local review requirements
22
23. Descenso de Glucemia Postprandial
dapagliflozin (39-67mg/dL)
Mean change in PPG levels (24 weeks)
Time (min)
Mean change in PPG levels (12 weeks)
Time (min)
30
60
90
120
150
Placebo
2.5 mg/d
5 mg/d
10 mg/d
60
90
120
150
-40
-60
-20
180
Placebo
5 mg/d
10 mg/d
-40
-60
-90
Monotherapy (12 weeks)
(Phase 2)
Add-on to pioglitazone
(24 and 48 weeks)
Dapagliflozin mg/d
Dapagliflozin mg/d
Placebo
2.5
5
10
Placebo
0
5
10
0
-10
2.5
-10
-20
Adjust
ed
mean
chang
e
in 2-h
PPG
levels
(mg/d
L)
Adjusted mean change
in 2-h PPG levels (mg/dL)
30
0
-20
-90
0
180
Mean change
PPG levels (mg/dL)
Mean change in
PPG levels (mg/dL)
0
0
-20
-30
-30
-40
-50
-40
24 weeks
-50
48 weeks
Add-on to glimepiride (24 and 48 weeks)
Salsali A, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June [Poster 1104-P].
All Disease Education materials must be reviewed in accordance with local review requirements
23
24. Sustained long-term efficacy of dapagliflozin
as add-on to metformin (1)
Mean change from baseline in HbA1c (102 weeks)
Week 24
Week 50
Week 102
0.0
Adjusted mean change
from baseline in HbA1c (%)
0.2
Adjusted mean
change from baseline
at week 102 (95% CI)
0.02 (-0.20,0.23)
-0.2
-0.4
-0.48 (-0.68, -0.29)
-0.6
-0.58 (-0.77, -0.39)
-0.8
-0.78 (-0.97, -0.60)
-1.0
Placebo
2.5 mg/d
-1.2
0
16
32
48
64
Time (weeks)
80
96
11
2
Bailey CJ, et al. Lancet 2010;375:2223–2233.
Bailey CJ et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
All Disease Education materials must be reviewed in accordance with local review requirements
5 mg/d
10 mg/d
24
25. Eficacia a largo plazo en Dapa+Metformina (102
semanas)
Percentage of patients with HbA1c <7.0%*
PBO + MET (n = 137)
DAPA 2.5 mg + MET (n = 137)
DAPA 5 mg + MET (n = 137)
45
DAPA 10 mg + MET (n = 135)
40
35
30
25
20
15
10
5
0
Week 24
Week 50
Week
76
Week 102
* Excluding data after rescue
Bailey CJ, et al. Lancet 2010;375:2223–2233.
Bailey CJ et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract # 988-P].
All Disease Education materials must be reviewed in accordance with local review requirements
25
26. Weight loss comparisons across
phase 3 dapagliflozin studies
All Disease Education materials must be reviewed in accordance with local review requirements
26
27. Consistent reductions in body weight with
dapagliflozin
24-wk
Monotherapy
Baseline
24-wk add-on
to Met2
52-wk add-on
to Met3
24-wk add-on
to Glim4
24 wk-add-on
to Ins5
24-wk add-on
to Pio6
24-wk Dapa
+ Met XR7
90.2kg
88kg
85.9kg
81.1kg
93.8kg
86.3kg
81.1kg
Weight
m
24- and 52-week adjusted ∆ from
baseline weight (kg)
10
g
Pl
bo
ce
a
10
m
g
o
eb
c
la
P
a
ap
D
et
m
+
lip
G
et
m
+
10
m
g
o
eb
ac
Pl
10
m
g
Pl
o
eb
ac
10
m
g
Pl
o
eb
ac
10
m
1.64
1.44
g
o
eb
ac
Pl
0.02
-0.14
*
-0.72
-0.89
-1.36
-1.67
-2.19
-2.26
-2.86
-3.16
NS
*
-3.22
*
*
*
*p <0.001 vs. comparator
NS: not significant
-3.33
*
Ferrannini E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Nauck MA, et al. Diabetes Care 2011;34:2015-2022;
4
Strojek K, et al. Diabetes Obes Metab 2011;13:928-938 5Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA
Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P]; 7Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
1
All Disease Education materials must be reviewed in accordance with local review requirements
27
28. Sustained body weight reduction of add-on dapagliflozin
vs. add-on glipizide in patients on metformin
Baseline weight
DAPA + MET : 88.4 kg
GLIP + MET : 87.6 kg
Change in total body weight (kg)
3.0
Week 104 weight
2.0
+1.36 kg (0.88, 1.84)
1.0
-0.0
GLI + MET (n = 401)
-1.0
Between-group difference:
−5.06 kg
(95% CI; −5.73, −4.4)
DAPA + MET (n =
400)
-2.0
-3.0
-3.70kg (-4.16, -3.24)
-4.0
-5.0
0
6
12
18
26
34
42
52
65
78
91
104
Nauck M, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 40-LB].
All Disease Education materials must be reviewed in accordance with local review requirements
28
29. Dapagliflozin reduces total body weight
and fat mass at week 24
DXA: dual X-ray absorptiometry
Langkilde A.M, Study D1690C00012. Internal Presentation January, 2011.
All Disease Education materials must be reviewed in accordance with local review requirements
29
30. Effects on Blood Pressure Comparisons across Phase 3
Dapagliflozin Studies
All Disease Education materials must be reviewed in accordance with local review requirements
30
31. FORXIGA® (dapagliflozina) ofrece el beneficio
adicional
de una reducción de la presión arterial sistólica
FORXIGA® (dapagliflozina) consigue una reducción significativa de la presión arterial
sistólica a las 52 semanas de tratamiento
Diferencia PAS
5,1
mmHg
Diferencia PAD
1,2
31
*Diferencia vs glipizida+metformina -5,0 mmHg (IC 95% -6,7; -3,4); ** Diferencia vs glipizida+metformina -1,2 mmHg (IC 95% 2,3; -0,2)
PAS: Presión arterial sistólica; PAD: Presión arterial diastólica
Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
mmHg
32. FORXIGA® (dapagliflozina) ofrece el beneficio
adicional
de una reducción de la presión arterial sistólica
FORXIGA® (dapagliflozina) consigue una reducción significativa de la presión arterial
sistólica a las 52 semanas de tratamiento
Diferencia PAS
5,1
mmHg
Diferencia PAD
1,2
32
*Diferencia vs glipizida+metformina -5,0 mmHg (IC 95% -6,7; -3,4); ** Diferencia vs glipizida+metformina -1,2 mmHg (IC 95% 2,3; -0,2)
PAS: Presión arterial sistólica; PAD: Presión arterial diastólica
Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
mmHg
33. Safety Comparisons across
Phase 3 Dapagliflozin Studies
All Disease Education materials must be reviewed in accordance with local review requirements
33
34. FORXIGA® (dapagliflozina): Resultados de seguridad en
1.193 pacientes en 12 estudios controlados con placebo
*Notificadas en ≥ 2% de los sujetos tratados con dapagliflozina 10 mg y con una frecuencia ≥ 1% mayor que en los sujetos tratados con placebo.
**Notificadas en ≥ 0,2% de los sujetos y un ≥ 0,1% más veces y en al menos 3 sujetos más tratados con dapagliflozina 10 mg independientemente
del tratamiento de rescate glucémico en comparación con placebo.
34
Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
35. La mayoría de las infecciones fueron leves o moderadas
y se resolvieron con un único ciclo de tratamiento
estándar
La mayoría de las infecciones genitales e infecciones del tracto urinario fueron de tipo
leve a moderado, raramente llevaron a una interrupción del tratamiento y
generalmente se resolvieron con un único ciclo de tratamiento estándar
Infecciones del tracto urinario (24 semanas)
Placebo
3,7%
FORXIGA® 10 mg
4,3%
Infecciones genitales (24 semanas)*
Placebo
0,9%
35
FORXIGA® 10 mg
4,8%
Análisis conjunto de 12 ensayos controlados con placebo
*
Las infecciones genitales incluyen los siguientes términos de preferencia, que aparecen listados por orden de frecuencia de aparición: infección
vulvovaginal micótica, infección vaginal, balanitis, infección genital por hongos, candidiasis vulvovaginal, vulvovaginitis, balanitis por cándida, candidiasis
genital, infección genital, infección genital masculina, infección peneana, vulvitis, vaginitis bacteriana, absceso vulvar
Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
36. FORXIGA® (dapagliflozina) disminuye en más de 10 veces los
episodios de hipoglucemia en comparación con una SU
Pacientes con ≥1 episodio hipoglucémico a 1 año (criterio de valoración secundario)
*Diferencia vs. GLIP + MET, -37,2% (IC 95% de la diferencia -42,3 a -21,2; p< 0,0001)
SU: Sulfonilurea; GLIP: Glipizida; MET: Metformina
36
Nauck MA, et al. Diabetes Care 2011;34:2015–22
37. Genital infections summary of pooled data up to 24 weeks
The rate of clinically diagnosed
vaginitis and other related genital
infection was higher in
the 10 mg dapagliflozin group than
with placebo
10
Placebo
DAPA 10 mg
8
6.9
Events were more frequently
6
4.8
Perce
ntage
of
subje
cts
with
clinic
al
diagn
osis
of
genit
al
infect
ion
experienced by women
than by men
All events were mild to moderate in
intensity
4
2.7
Most events did not recur with time
Most events responded to the initial
2
1.5
0.9
0.3
course of standard therapy
0
Tota
l
Women
Men
List J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Poster # 985-P].
All Disease Education materials must be reviewed in accordance with local review requirements
37
38. Urinary tract infections summary of pooled data up to 24 weeks
The rates of clinically diagnosed UTI were
in intensity
Most events did not recur with time
Placebo
DAPA 10 mg
10
clinical diagnosis of UTI
All events were mild to moderate
Percentage of subjects with
slightly higher in
the dapagliflozin 10 mg group
than with placebo and these
events were more frequent in women than
men
12
7.7
8
6
4.3
Most events responded to the initial course of
standard therapy
6.6
3.7
4
Upper UTI was rare and balanced between
groups
1.0
2
0.8
0
Tota
l
Women
Men
Parikh SJ, et al. 71st ADA Scientific Sessions, San Diego, June 24-28, 2011 [abstract 984-P].
All Disease Education materials must be reviewed in accordance with local review requirements
38
39. RESULTADOS:
Control de DM tipo 2: naïve o en asociación con otro antiDM
(excepto análogos de GLP1)
• Descenso de HbA1C.
• Descenso de Glucosa en ayunas y postprandial
• Útil en pacientes con HbA1C mayor del 9%: descenso de un 2,04% en
la semana 24 (solo Dapa) y de 1,32% Dapa+Met
Pérdida de peso, incluso en combinacion con Insulina: -2 a
-5kg (dependiendo de la combinación de fármacos).
Descenso de grasa visceral (medido por DEXA).
Descenso de TA sistolica y diastolica:-4,4mmHg y -2,1mmHg
Perfil lipídico…
All Disease Education materials must be reviewed in accordance with local review requirements
39
40. Resultados
No existe aumento del riesgo cardiovascular.
Pero: aumenta colesterol (frente a placebo,sem 24):
• Total: +1,4% vs -0,4%
• HDL: +5,5% vs 3,8%
• LDL:+2,7 vs -1,9%
Útil en pacientes con HbA1C mayor del 9%: desenso de un
2,04% en la semana 24 (solo Dapa) y de 1,32% Dapa+Met
Renal: menos efecto en Insuf Renal moderada. Descenso de
HbA1C: -0,44%.
All Disease Education materials must be reviewed in accordance with local review requirements
40
41. Efectos secundarios
Tumores: NO
Infecciones de mucosa genital: más frecuente (4% más)
Infecciones urinarias: más frecuente (0,6% más)
Aumento de Hematocrito (2,15%)
Aumento de creatinina inicial-meseta-normalización.
Aumento de PTH no asociado a pérdida ósea.
Descenso ácido úrico.
All Disease Education materials must be reviewed in accordance with local review requirements
41
42. Situaciones especiales:
Insuficiencia renal moderada –grave CrCL: menor 60ml/min).:
EVITAR
• Función renal al principio y una vez al año.
Insuficiencia hepática: Sí, incluso en estadios avanzados
(5mg)
Infecciones urinarias o genitales previas: EVITAR
Situaciones de depleción de volumen: EVITAR
• Uso con diuréticos de asa.
• Atención a IECAS ARA2.
• Situaciones aguda de depleción de volumen: GEA
• Ancianos. (No en mayores de 75 años)
All Disease Education materials must be reviewed in accordance with local review requirements
42
43. Situaciones especiales:
NO en embarazo , lactancia ni edad pediátrica.
Estudios de combinación con antiDM, excepto análogos de GLP1
No interacciona con CIT p450 ni CYP
No existe problemas de interacciones farmacológicas (digoxina,
sintrom, rifampicina, fenitoinas…)
Pioglitazona: tumores vejiga…mejor evitar combinación.
Bajar dosis de insulina, secretagogos cuando se añada Dapa
NO DM tipo 1…(¿)
All Disease Education materials must be reviewed in accordance with local review requirements
43
44. Situaciones especiales:
Sobredosis:
•
•
•
•
•
NO toxicidad en ingestas únicas de 500 mg (50 veces más).
NO alteraciones hidroelectroliticas.
No hipotensión arterial.
No alteraciones QTc.
No hipoglucemia.
All Disease Education materials must be reviewed in accordance with local review requirements
44
45. RESUMEN:
FORXIGA 10 MG AL DIA: 1 comprimido. 55,95 euros.
Independiente de hora y alimentos
Perdida de 70 gramos de glucosa /día en orina mantenido
Aumento de diuresis de 375mL al día
Pérdida de 280kcal al día.
Control de HbA1C con potencia intermedia (menos de 1,5%)
Efectos secundarios “clínicos”: infecciones genitourinarias
Efectos secundarios laboratorio: poco importantes.
No interacciones medicamentosas
Puede combinarse con CUALQUIER Antidiabético.
Ojo dosis Insulina y Sulfonilureas. No estudios con análogos GLP1.
45
46. FORXIGA® (dapagliflozina) – Indicaciones terapéuticas
Forxiga está indicado en adultos de 18 años de
edad o mayores con diabetes mellitus tipo 2
para mejorar el control glucémico en:
®
Monoterapia
Cuando la dieta y el ejercicio por sí solos no logran un control
glucémico adecuado en pacientes en los que no se considere
adecuado el uso de la metformina debido a la intolerancia
Tratamiento adicional en combinación
En combinación con metformina, iDPP4, sulfonilureas e insulina,
cuando estos, junto con dieta y ejercicio, no logren un control
glucémico adecuado
iDDP4: Inhibidores de la dipeptidil peptidasa tipo 4
Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
47. “Forxiga está indicado en adultos de 18
años de edad o mayores con DM tipo 2
para mejorar el control glucémico en
terapia doble con metformina cuando esta
solo con dieta y ejercicio no alcanza el
control glucémico adecuado y en lugar de
la asociación metformina con sulfonilurea
cuando esta última no se tolera o está
contraindicada”.
Notes de l'éditeur
The current therapies for type 2 diabetes mellitus target the following organs and tissues in the body:
Pancreas,
Liver,
Skeletal tissue,
Fatty tissue,
Intestinal tract.
With the exception of α-glucosidase inhibitors, insulin is a major mediator of the different antidiabetic treatments used so far, having an insulin-dependent mechanism of action.
Reference:
Tahrani AA, et al. Management of type 2 diabetes: new and future developments in treatment. Lancet 2011;378:182-97.
De los 450 gramos almacenados en el organismo, 250 gramos se renuevan cada día (aporte y consumo).
En condiciones normales:
Aporte de glucosa: aproximadamente 180 g por la dieta y unos 70 g mediante la gluconeogénesis hepática y renal.
Gasto de glucosa: 125g a nivel cerebral y los otros 125 g por el resto del organismo.
Importante: los riñones reabsorben la práctica totalidad de la glucosa ingerida (≈180 g), que se filtran en el glomérulo. La reabsorción se lleva a cabo gracias a la existencia de co-transportadores de sodio-glucosa en el túbulo contorneado proximal renal de la nefrona
Bibliografía:
Wright EM, et al. J Int Med 2007;261:32–43.
En la diabetes se produce un aumento del aporte de glucosa por el aumento de la gluconeogénesis.
Hasta un cierto punto, el organismo establece sistemas de compensación, como un aumento de la reabsorción en el tubo contorneado proximal.
Sin embargo, a partir de una concentración de glucosa ≈200 mg/dl, se satura el sistema y la glucosa se elimina por la orina (glucosuria).
En la siguiente diapositiva se muestra cómo ocurre.
Bibliografía:
Wright EM, et al. J Int Med 2007;261:32–43
In both healthy individuals and in patients with type 2 diabetes, the majority of glucose entering the kidneys is returned to the circulation.1,2
The high plasma glucose levels that are characteristic of uncontrolled type 2 diabetes exceed the maximum threshold of glucose reabsorption, saturating the SGLT receptors and resulting in an increased excretion of glucose in the urine.
Nevertheless, even in the presence of hyperglycaemia, renal SGLT2 continues to reabsorb glucose and its associated calories through an insulin-independent pathway, contributing to elevated plasma glucose levels.1,2
Renal tubular reabsorption is known to undergo adaptations in patients with uncontrolled diabetes through up-regulation of SGLT2; this is an important adaptation in diabetes permitting maintenance of renal tubular glucose reabsorption. Saturation and excretion thresholds are shifted in diabetic patients, probably due to an increased expression of SGLT2 cotransporters in diabetes.3,4
References:
Chao EC, et al. SGLT2 inhibition - a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010;9:551-559.
Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis 2009;53:875-883.
Nairs S, et al. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010;95:34-42.
Rahmoune H et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427-34.
Altered SGLT2 is associated with familial renal glucosuria; the majority of patients with this condition do not develop significant clinical problems over time.
Altered GLUT2 is associated with Fanconi–Bickel syndrome, the numerous symptoms characteristic of this condition including enlarged liver, abdominal bloating and vitamin D-resistant rickets.
Altered SGLT1 is associated with glucose–galactose malabsorption syndrome, the principal symptom of this condition being severe diarrhoea.
Altered GLUT1 is associated with De Vito disease, patients presenting with numerous symptoms including microcephaly and mental and motor developmental delays.
Reference:
Pichler, International Diabetes Federation, 2009.
More precisely, this slide shows the mechanism of glucose transport through the proximal tubule. Glucose is actively co-transported with sodium by SGLT2 from the tubular lumen and is released into the circulation via GLUT2, one of the major facilitated glucose transporters, which is also expressed in the kidneys.1,2
References:
Lee YJ, et al. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl 2007;106:S27–35.
Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol 2001;280:F10-8.
Wright EM. Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology 2004;19:370-6.
A nivel del túbulo contorneado proximal se produce la reabsorción de la glucosa, mediada por dos transportadores: SGLT1 y SGLT2.
El SGLT2 es el responsable del 90% de la reabsorción (a nivel de los segmentos S1 y S2 del túbulo) y el SGLT1 (segmento S3) del 10% restante.
A continuación se presenta el mecanismo de acción de la reabsorción.
Bibliografía:
Bailey CJ. Trends in Pharmacological Sciences 2011;32 (2):63-71
Explicar la inhibición del SGLT2 en el túbulo contorneado proximal y cómo ello tiene como consecuencia la excreción de la glucosa no reabsorbida a través de la orina.
Bibliografía:
Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
Bailey CJ, et al. Lancet 2010;375:2223–33
Ferrannini E, et al. Diabetes Care. 2010; 2010;33:2217–2224
Strojek K et al. Diabetes Obes Metab 2011; 13:928-938
Nauck MA, et al. Diabetes Care 2011;34:2015–22; 2
Wilding J.P.H et al Ann Intern Med. 2012;156:405-415
The main features of phlorizin are as follows:
Bitter white glycoside,
Identified by French chemists in the early nineteenth century,
Initially used to treat malaria and infectious diseases,
Glycosuria observed at high doses,
Widely used in physiology research,
Found to be an effective inhibitor of SGLT1 and SGLT2, accounting for the majority of glucose reuptake in the kidney.
Reference:
Ehrenkranz JRL, et al. Phlorizin: a review. Diabetes Metab Rev 2005;21:31-8.
The natural product phlorizin, an O-glucoside found in the root and bark of certain fruit trees, is a non-selective SGLT inhibitor.
The potential therapeutic value of phlorozin was described by Émile Achard, professor of internal medicine at the University of Paris, who identified its potential as a treatment for diabetes at the end of the nineteenth century.
However, phlorizin was not suitable for development as a drug candidate because of its low oral bioavailability and rapid clearance via the gut, liver and kidneys.
The finding that a defective SGLT1 transporter in the gut was responsible for glucose and galactose malabsorption disorders in humans suggested that the pursuit of specific SGLT2 inhibitors was preferable.
An overview of the most important pharmacokinetic characteristics of dapagliflozin is presented below. In the next few slides, we will examine these in more detail.
SGLT2 selectivity1:
Cell-based assays measuring glucose analogue uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitate glucose transport in human adipocytes.
Dapagliflozin exhibits a mean EC50 against hSGLT2 of 1.12 nmol/L, compared with 35.6 nmol/L for phlorizin. Against hSGLT1, dapagliflozin and phlorizin displayed mean EC50 values of 1,391 and 330 nmol/L, respectively, indicating that dapagliflozin has high (1,200-fold) selectivity for hSGLT2 vs. hSGLT1.
Reference:
Han S, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 2008;57:1723-9.
This slide and the next slide present the extensive dapagliflozin clinical development programme. Phase 3 trials assessed dapagliflozin in patients with early and advanced disease, as monotherapy and as an add-on to other antidiabetic medications. Investigations included special populations (renal insufficiency, high cardiovascular risk).
In a 24-week, double-blind, randomised, parallel-group, placebo-controlled phase 3 trial (85 sites: US, Canada, Mexico, Russia), dapagliflozin monotherapy was evaluated in treatment-naïve patients with newly diagnosed type 2 diabetes and inadequate glycaemic control by diet and exercise.1 Patients with an HbA1c 7.0-10% (n=485) were randomly assigned to one of seven treatment arms: once-daily placebo or dapagliflozin 2.5, 5 or 10 mg once-daily in the morning (main cohort) or evening (exploratory cohort). Patients with an HbA1c 10.1-12% (high-HbA1c exploratory cohort; n=73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of dapagliflozin 5 or 10 mg/day. Dapagliflozin lowered hyperglycaemia with a near absence of hypoglycaemia.
In a 24-week double-blind, randomised parallel-group, placebo-controlled, phase 3 trial (80 sites in the US, Canada, Argentina, Mexico, Brazil), dapagliflozin was tested as add-on to metformin in type 2 diabetic patients achieving inadequate glycaemic control with metformin alone.2 Patients (n=546) were randomised to placebo or dapagliflozin 2.5 mg, 5 mg or 10 mg once daily on top of their stable pre-study metformin regimen. Addition of dapagliflozin to metformin achieved greater glycaemic control than placebo, the incidence of hypoglycaemia being similar to that seen with placebo
In an 52-week, double-blind, randomised, active-controlled, multicentre, non-inferiority trial, dapagliflozin was compared to glipizide as add-on therapy in type 2 diabetic patients achieving inadequate glycaemic control with metformin alone.3 Patients (baseline mean HbA1c 7.7%) receiving metformin monotherapy were randomised to add-on dapagliflozin (n=406) or glipizide (n=408) up-titrated over 18 weeks, based on glycaemic response and tolerability, to ≤10 or ≤20 mg/day, respectively. While achieving similar 52-week glycaemic efficacy, dapagliflozin reduced weight and produced less hypoglycaemia than glipizide.
References:
1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
3. Nauck MA, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34:2015-22.
4. Dapagliflozin Is Effective as Add-on Therapy to Sitagliptin With or Without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Diabetes Care October 21, 2013
Steady and clinically relevant decreases from baseline HbA1c values with dapagliflozin 10 mg were observed across all studies, regardless of therapy combination, decreases in HbA1c from baseline ranging from 0.52-1.0%, or even up to -1.98% in combination with metformin extended release. All decreases were statistically significantly different from those seen with placebo.
References:
1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
3. Strojek K, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.
4. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 0986-P].
5. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract 0078-OR].
6. Henry RR, et al. Dapagliflozin, metformin-XR, or both together as initial therapy for T2DM. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
The results illustrated in this slide, obtained in four of the six phase 3 trials described in the previous slides, were calculated according to the Last Observation Carried Forward principle and exclude data obtained after recourse to rescue medication.
A dose-dependent decrease in FPG was seen across all studies, regardless of the therapeutic regimen (monotherapy or combination) assessed. With regard to dapagliflozin 10 mg, the adjusted mean decrease from baseline in FPG at 24 weeks ranged from 21.7 to 30.0 mg/dL. FPG was a secondary endpoint in these studies.
The references for the four studies illustrated are provided below.
References:
1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
3. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract # 0078-OR].
4. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract # 0986-P].
Plasma glucose: mg/dL=0.0555 mmol/L.
This slide illustrates the reduction in postprandial glucose (PPG) achieved by dapagliflozin as monotherapy, as an add-on to pioglitazone and as an add-on to glimepiride. Significant reductions in mean baseline PPG ranged from -39.3 to -67.5 mg/dL with dapagliflozin 5-10 mg over 24 weeks in three placebo-controlled Phase 3 studies. PPG was a secondary endpoint, where change in A1c was usually the primary endpoint in these studies.
Monotherapy (12 weeks)
Mean 2-hour PPG levels were numerically reduced in all dapagliflozin groups compared with placebo when dapagliflozin was administered as monotherapy for 12 weeks. In this study, the statistical significance of the mean change in 2-hour PPG levels was not evaluated. Both HbA1c and FPG levels were significantly reduced at all doses of dapagliflozin.
Add-on to glimepiride (24 and 48 weeks)
Statistically significant reductions in mean 2-hour PPG levels were observed with dapagliflozin (≥5 mg) following 24 weeks of treatment as an add-on to glimepiride compared with placebo. These reductions in PPG observed with dapagliflozin at 24 weeks were sustained for up to 48 weeks.
Add-on to pioglitazone (24 and 48 weeks)
Mean PPG levels were significantly reduced across all dapagliflozin groups when dapagliflozin was administered for 24 weeks to patients with type 2 diabetes inadequately controlled with pioglitazone alone. These reductions were statistically significant compared with placebo. The reductions in mean PPG levels observed with dapagliflozin as an add-on to pioglitazone at 24 weeks were sustained for up to 48 weeks.
Reference:
Salsali A, et al. Reduction in postprandial glucose with dapagliflozin in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Poster 1104-P].
This slide illustrates the sustained efficacy of dapagliflozin as an add-on to metformin up to 102 weeks in patients with type 2 diabetes inadequately controlled with metformin alone1 (results excluding data obtained after administration of rescue medication). This is the longest dapagliflozin treatment duration reported to date, comprising the initial 24-week treatment period of this phase 3 trial2 and the subsequent 78-week extension period.
The mean baseline HbA1c of the patients enrolled in this study was 8.13 in the placebo + metformin group, 7.99 in the dapagliflozin 2.5 mg + metformin group, 8.16 in the 5 mg dapagliflozin + metformin group and 7.95 in the 10 mg dapagliflozin + metformin group.
Dapagliflozin added to metformin achieved durable glycaemic control and reduced body weight over the entire 102-week treatment period without increasing the risk of hypoglycaemia.
During the additional 78-week extension period, the completion rate was lower in the placebo group (63.5%) than in the DAPA groups (68.3–79.8%). More patients in the placebo group (23.5%) withdrew during the extension period due to lack of efficacy compared to the dapagliflozin groups (13.3, 13.9 and 7.6% in the dapagliflozin 2.5, 5 and 10 mg groups, respectively).
The proportion of patients (%) having required rescue medication or having been withdrawn because of failure to achieve glycaemic targets was higher in the placebo group (83/137 [60.6%]) than in the dapagliflozin 2.5 mg (71/137 [51.8%]), 5 mg (63/137 [46.0%]), and 10 mg (57/135 [42.2%]) groups at week 102.
References:
1. Bailey CJ, et al. Long-term efficacy of dapagliflozin as add-on to metformin (MET) in T2DM inadequately controlled with MET alone. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
This slide illustrates the sustained efficacy of dapagliflozin as an add-on to metformin up to 102 weeks (initial 24-week treatment period1 plus the 78-week extension period2) in patients with type 2 diabetes inadequately controlled by metformin alone.
A dose-dependent increase in the percentage of patients achieving the target HbA1c (<7.0%, adjusted according to the baseline value) was observed with dapagliflozin + metformin compared to placebo + metformin throughout the 102-week treatment period (results excluding data obtained after administration of rescue therapy).
References:
1. Bailey CJ, et al. Long-term efficacy of dapagliflozin as add-on to metformin (MET) in T2DM inadequately controlled with MET alone. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
Early weight loss might be partly due to a mild osmotic diuresis caused by dapagliflozin. However, the gradual progressive reduction in body weight thereafter, seen in all studies,1-7 accompanied by a decrease in waist circumference as shown in the study evaluating dapagliflozin as an add-on to metformin,2 is consistent with a reduction of fat mass. This reduction is potentially attributable to the loss of excess energy through glucose excretion in the urine, an effect clearly evident at week 24, as shown by the increased urinary glucose/creatinine ratio in patients randomised to dapagliflozin.
References:
1. Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.
2. Bailey CJ, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
3. Nauck MA, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34:2015-22.
4. Strojek K, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.
5. Wilding JPH, et al. Dapagliflozin in patients with type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010;59(Suppl 1):A21-A22 [Abstract # 0078-OR].
6. Rosenstock J, et al. Dapagliflozin added-on to pioglitazone reduces HbA1c and mitigates weight gain with low incidence of hypoglycemia in type 2 diabetes. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract # 0986-P].
6. Henry RR, et al. Dapagliflozin, metformin-XR, or both together as initial therapy for T2DM. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR.
The mean changes in body weight shown in this slide were calculated on the basis of the number of subjects (N) in the full analysis set. At baseline, N corresponds to the number of subjects in the full analysis set with a non-missing baseline value and at least one post-baseline value.
Difference dapagliflozin + metformin vs. glipizide + metformin: -5.06 (95%CI: -5.73, -4.4)
This was a randomised, double-blind, parallel-group, active-controlled study. In addition to metformin, patients could be receiving one further oral antidiabetic drug at enrollment (but only up to half the maximum dose available). Eligible patients discontinued other oral antidiabetic drugs and were stabilised on ≥1500 mg of metformin daily, after which no further changes in metformin dose were allowed.
After a 2-week single-blind lead-in period, patients were randomised 1:1 to receive dapagliflozin or glipizide treatment. Patients commenced at dapagliflozin 2.5 mg or glipizide 5 mg and were then up-titrated over 18 weeks, on the basis of tolerability and glycaemic response, to a maximum dose of 10 mg and 20 mg, respectively. Treatment was subsequently maintained without further up-titration up to the primary analysis point at 52 weeks, although down-titration was allowed in the event of recurrent hypoglycaemia.
Patients then entered the long-term extension period 1 for a further 52 weeks of double-blind treatment, during which a single up-titration, if HbA1c was >7.0% (only until the subject reached the maximum dose), and down-titration, if medically indicated, was allowed. Patients with inadequate glycaemic control at maximum dose were withdrawn from the study on the basis of progressively stricter criteria (during the long-term extension period 1 if FPG was >200 mg/dL and HbA1c was ≥8%).
References:
Nauck M, et al. Long-term efficacy and safety of add-on dapagliflozin vs add-on glipizide in patients with T2DM inadequately controlled with metformin: 2-year results. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 40-LB].
The results presented include data obtained after the administration of rescue medication and were calculated according to the last observation carried forward (LOCF) principle.
Data are adjusted mean changes from baseline using ANCOVA, including data after rescue (LOCF).
En este estudio de no inferioridad frente a glipizida, FORXIGA® (dapagliflozina) reduce la presión arterial y esta reducción se mantiene a largo plazo.
Bibliografía:
Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
En este estudio de no inferioridad frente a glipizida, FORXIGA® (dapagliflozina) reduce la presión arterial y esta reducción se mantiene a largo plazo.
Bibliografía:
Nauck MA, et al. Diabetes Care 2011;34:2015–22 (supplementary data)
a.- [aplica a titulo de la gráfica] La tabla muestra los datos de 24 semanas (corto plazo) independientemente del tratamiento de rescate glucémico.
b.- [aplica a vulvovaginitis, balanitis e infecciones genitales relacionada, infecciones del tracto urinario, Depleción del volumen]. (Para más información consulte Ficha Técnica de Forxiga)
c.- [aplica a Vulvovaginitis, balanitis e infecciones genitales relacionadas] Vulvovaginitis, balanitis e infecciones genitales relacionadas incluyen, por ejemplo, los términos preferentes predefinidos: infección micótica vulvovaginal, infección vaginal, balanitis, infección fúngica genital, candidiasis vulvovaginal, vulvovaginitis, balanitis por Candida, candidiasis genital, infección genital, infección genital masculina, infección del pene, vulvitis, vaginitis bacteriana y absceso vulvar.c
d.- [aplica a poliuria] La poliuria incluye los siguientes términos preferentes: polaquiuria, poliuria, aumento de la diuresis.
e.- [aplica a la depleción del volumen] La depleción del volumen incluye, por ejemplo, los términos preferentes predefinidos: deshidratación, hipovolemia, hipotensión.
f.- [aplica a dislipidemia] El porcentaje medio de cambio desde el valor inicial para dapagliflozina 10 mg frente a placebo, respectivamente, fue de: colesterol total 1,4% frente a -0,4%; colesterol HDL 5,5% frente a 3,8%; colesterol LDL 2,7% frente a -1,9%; triglicéridos -5,4% frente a -0,7%.
g.- [aplica a aumento del hematocrito] La variación media del hematocrito respecto del valor inicial fue del 2,15% con dapagliflozina 10 mg frente al -0,40% con placebo.
* [aplica a reacciones adversas frecuentes] Notificadas en ≥ 2% de los sujetos tratados con dapagliflozina 10 mg y con una frecuencia ≥ 1% mayor que en los sujetos tratados con placebo.
** [aplica a reacciones adversas poco frecuentes] Notificadas en ≥ 0,2% de los sujetos y un ≥ 0,1% más veces y en al menos 3 sujetos más tratados con dapagliflozina
Bibliografía:
Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
Asumir que este tratamiento puede no ser adecuado en algunos tipos de paciente, como aquellos que sufran infecciones urinarias de repetición.
Bibliografía:
Ficha Técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013
A diferencia de otros tratamientos para la diabetes, FORXIGA® (dapagliflozina) se asocia a un bajo riesgo de episodios de hipoglucemia.
Criterios de hipoglucemia:
Hipoglucemia mayor definida como un episodio sintomático que necesitó de asistencia externa debido a una afectación grave de la consciencia o comportamiento, con una concentración capilar o plasmática inferior a 54 mg/dl (3 mmol/l) y una rápida recuperación después de la administración de glucosa o glucagón.
Hipoglucemia menor definida como un episodio sintomático con una concentración capilar o plasmática inferior a 63 mg/dl (3,5 mmol/l), con independencia de la necesidad de asistencia externa, o un episodio asintomático con una concentración capilar o plasmática de 63 mg/dl (3,5 mmol/l) no clasificada como hipoglucemia grave.
Otras hipoglucemias se definieron como un episodio con síntomas indicativos de hipoglucemia pero sin una medida que lo confirme.
Bibliografía:
Nauck MA, et al. Diabetes Care 2011;34:2015–22
Analysis of pooled study date showed higher rates of genital infections in all dapagliflozin groups than in the placebo group, particularly in women. All these events were mild or moderate in intensity and in general responded well to treatment. Most patients who experienced such an event had no recurrence during the102-week observation period (74.6% dapagliflozin vs. 77.8% placebo).
The table below presents the actual numbers of these events overall, according to sex and, in the case of women, in patients with a prior history of genital infections.
Reference:
List J, et al. Characterization of genital infections in the setting of pharmacologically induced glucosuria. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Poster 985-P].
Analysis of pooled study data showed higher rates of urinary tract infections in all dapagliflozin groups than in the placebo group, particularly in women. All events were mild or moderate in intensity and in general responded well to treatment. Most patients who experienced such an event had no recurrrence during the 102-week observation period (74.6% dapagliflozin vs. 86.4% placebo).
The table below presents the actual numbers of these events overall, according to sex and in patients with a prior history of urinary tract infections.
Indicación: en monoterapia tanto en combinación con otros antidiabéticos orales e insulina cuando no existe un control glucémico adecuado.
Bibliografía:
Ficha técnica de FORXIGA®. Disponible en la página web http://www.emea.europa.eu/. Acceso: Abril 2013