Les inhibiteurs de SGLT2
Jean-François Gautier,Jean-François Gautier,Service de Diabétologie,
Hôpital Saint-Louis,INSERM URMS 872 (équipe 8), CRC,
ParisLiens d’intérêt: AZ-BMS, lilly, Novartis, Novo Nordisk, GSK, MSD, Sanofi-Aventis, Servier
The Ominous Octet: Role of the Kidney in Glucose Balance
Production de glucose (mg/min/kg)
2
Glycogénolyse
Néoglucogenèse
2
Foie (75%)
Reins (25%)
1
0
Foie (75%)
Reins (25%)
1
0
Post-absorptive Post-prandial
Utilisation du glucose
Utilisation de glucose(mg/min/kg)
Cerveau (50%)
2 10
5
Utilisation de glucose(mg/min/kg)
Muscles (35%)
Cerveau (10%)
Rein (10%)
1
0
Muscles (20%)
Autres (20%)
Postabsorptive Post-prandial
5
0
GI (10%)Rein (15%)
GI (30%)
Autres (10%)
Rôle du rein dans l’homéostasie glucidique
• 3 fonctions principales :– Production de glucose– Utilisation de glucose– Filtration et réabsorption de glucose
• Chaque jour les reins produisent 70 g de glucose via • Chaque jour les reins produisent 70 g de glucose via la néoglucogenèse et utilisent 30 g de glucose
• Chaque jour, 180 litres de plasma sont filtrés par le rein. Lorsque la glycémie moyenne est proche de la normale, 180 g de glucose sont filtrés chaque jour par le rein et est réabsorbé au niveau rénal
Gerich JE. Diabetes Med.,2009
La réabsorption rénale du glucose
Le rein n’a pas seulement la capacité de produire et d’utiliser leglucose. Il influence l’homéostasie glucidique en réabsorbant leglucose qu’il filtre.
Chaque jour, 180 litres de plasma sont filtrés par le rein.Lorsque la glycémie moyenne est proche de la normale, 180 gde glucose sont filtrés chaque jour par le rein, mais l’urine necontient pas de glucose. Tout le glucose est donc réaborbé auniveau rénal.
Chaque jour les reins produisent 70 g de glucose via lanéoglucogenèse et utilisent 30 g de glucose. Donc en termed’économie glucidique la réabsorption rénale de glucose a unrôle considérable
Glucose filtré Glucosurie
Glucose filtré,excrété, réabsorbé
(mg/min)
400
600
L’excrétion urinaire de glucose chez le non-diabétique
Tm : Transport max
Glucose réabsorbé
Glycémie (mg/dl)200 300 400
200
0
170 mg/dl
1000
350 mg/min
400
600
Glu
cose
(m
g/m
in)
• Complete glucose reabsorption until plasma glucose concentrations exceed ~180 - 200 mg/dL
• This is known as the Transport
Virtually All Filtered Glucose is Reabsorbed in Non -diabetic State
Urinary
Glucose
Tubular
Reabsorption
Filtered by
Glomerulus
Normal plasma glucose
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038.
0
200
0 200 400 600 800
Plasma Glucose (mg/dL)
Threshold
8
Glu
cose
(m
g/m
in)
the Transport Maximum for Glucose (TmG)
• When TmG is exceeded, glucose is excreted in the urine
TmG
11070
La réabsorption rénale du glucose
La réabsorption rénale du glucose a lieu dans le tubecontourné proximal. Elle s’effectue grâce à des co-transporteurs (glucose/Na+), les SGLTs (sodium-glucosecotransporters).
Environ 90% du glucose est réaborbé par SGLT2 (hautecapacité, basse affinité pour le glucose) localisé à lasurface luminale des cellules épithéliales des segments S1et S2 du tubule proximal. Le reste du glucose (10%) estréabsorbé par SGLT1 (haute affinité, basse capacité)localisé à la surface luminale du segment S3 du tubuleproximal.
Glucose Reabsorption Occurs in the Proximal Tubule
Glucose
S1 segment of proximal tubule
• ~90% glucose reabsorbed
• Facilitated by SGLT2
Glomerulus filters
Proximal tubule
reabsorbs
No glucosein filtrate
Collecting
duct
• Facilitated by SGLT2
Distal S3 segment of proximal tubule
• ~10% glucose reabsorbed
• Facilitated by SGLT1
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038. Bakris GL, et al. Kidney Int. 2009;75:1272-1277.
SGLT: sodium glucose transporter
Le glucose réabsorbé est ensuite libéré dans la circulationsanguine par un transporteur de diffusion facilité GLUT2localisé sur la membrane basolatérale des segments S1 et S2
La réabsorption rénale du glucose
localisé sur la membrane basolatérale des segments S1 et S2ou GLUT1 localisé sur la membrane basolatérale du segment 3
SGLT and GLUT Transporters Facilitate Insulin Independent Reabsorption of Filtered Glucose
SGLT2• low-affinity• high-capacity• insulin
independent
SGLT1 • high-affinity• low-capacity• insulin
independent
Adapted from: 1. Wright EM, et al. J Int Med. 2007;261:32-43. 2. Isaji M. Curr Opin Investig Drugs. 2007;8:285-292. 3. Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
Glucose Transporters in the Proximal Tubules
• Sodium-glucose cotransporters (SLGTs) – Transport glucose across the renal tubule membrane
out of the urine– Represents an active process against a concentration
gradient via sodium pump
• Glucose transporters (GLUTs)
1. Wright EM, et al. J Int Med. 2007;261:32-43. 2. Isaji M. Curr Opin Investig Drugs. 2007;8:285-292. 3. Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
• Glucose transporters (GLUTs) – Mediate passive movement of glucose out of the tubular
cell across the basolateral cell membrane– Passive process along a concentration gradient
(glucose moves from a higher concentration to one that is lower)
Sodium-Glucose Cotransporters (SGLTs)
• SGLT2– Found primarily in the brush-border membrane of the S1
segment of proximal renal tubule– Accounts for ~90% of glucose reabsorption in the kidney
• SGLT1– Located in the S3 segment of the proximal tubule– Located in the S3 segment of the proximal tubule– Accounts for ~10% of renal glucose reabsorption
• Blocking the reabsorption of glucose has become an intriguing therapeutic strategy for type 2 diabetes mellitus (T2DM)
• Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting SGLT2– Developed as an insulin-independent treatment approach for
T2DM
Bakris GI, et al. Kidney Int. 2009;75:1272-1277. Bays H. CMRO. 2009;25:671-681. Komoroski BJ, et al. Clin Pharmacol Ther. 2009;85:520-526.
Normal physiology of renal glucose homeostasis
SGLT2 SGLT1
Proximal tubule
S1
Glomerulus Distal tubule Collecting duct
Glucosefiltration
S3SGLT2
Loop of Henle
Glucosereabsorption
Minimalglucose
excretion
SGLT2 inhibitors reduce renal glucose reabsorption
Proximal tubule
SGLT2 SGLT1
S1
S3
Glomerulus Distal tubule Collecting duct
Glucosefiltration
Loop of Henle
Reduced glucosereabsorption
Increasedglucose
excretion
DapagliflozinSGLT2 inhibitor
Ultrafiltrat primitif
Na/KATPase
K+
Sang
K+
Membranebordure en brosse
Membranebasolatérale
Réabsorption rénale du glucose (segment S1et S2)
SGLT2
Na+
glucose
ATPase
GLUT-2 glucoseglucose
Na+Na+
Cellule tubuleproximal
SGLT2 : Km= 10 mmol/l
Ultrafiltrat primitif
Na/K
K+
Sang
K+
Membranebordure en brosse
Membranebasolatérale
Réabsorption rénale du glucose (segment S3)
SGLT1
Na+
glucose
Na/KATPase
GLUT1 glucoseglucose
Na+Na+
Cellule tubuleproximal
SGLT1 : Km= 0,2 mmol/l
1- La néoglucogenèse rénale est augmentée à l’état post-absorptif, comme la néoglucogenèse hépatique.
2- La néoglucogenèse rénale est moins freinée par l’insuline àl’état post-prandial, comme la néoglucogenèse hépatique.
Anomalies de l’homéostasie du glucose dans le rein des diabétiques
l’état post-prandial, comme la néoglucogenèse hépatique.
3- Le captage rénal de glucose est augmenté en périodepostabsorptive comme en période post-prandiale (x 2-3). Lecaptage rénal de glucose peut alors excéder la productionrénale de glucose.
La réabsorption rénale de glucose est augmentée chez le patient diabétique
Le Tm du glucose est augmenté (de 350 à 420 mg/min) et la glucosurie ne commence qu’à une glycémie plus élevéeCeci est du à une augmentation de l’expression de SLGT2 et de GLUT2
Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
4- La réabsorption rénale de glucose est augmentée. Laglucourie des diabétiques ne se produit qu’à des glycémiessupérieures (220 mg/dl) à celles qui produiraient uneglucosurie chez les non-diabétiques (170 mg/dl).
Anomalies de l’homéostasie du glucose dans le rein des diabétiques
Le Tm du glucose est augmenté (de 350 à 420 mg/min) et laglucosurie ne commence qu’à une glycémie plus élevée. Ceciest du à ce que les expressions de SLGT2 et de GLUT2 sontaugmentées chez le diabétique (hyperglycémie…..).
Upregulation of SGLT2 Transporter and Enhanced Cellular Glucose Uptake in Type 2 Diabetes
7
Transporter Protein Expression
3
5
4
6
Nor
mal
ized
Lev
els
P
419,1
380
400
420
440
423,9420
440
TmG increased in Type 1 Diabetes TmG increased in Type 2 Diabetes
Patients with Diabetes Demonstrate High Reabsorption of Filtered Glucose
(mg/
min
)
(mg/
min
)
*
352,2
300
320
340
360404,0
380
400
Tm
(mg/
min
)
Tm
(mg/
min
)
Nondiabetic(n=9)2
Type 2 diabetes(n=12)2
Nondiabetic(n=9)1
Type 1 diabetes(n=10)1
*P
Glucose filtré
Glucose réabsorbé
Glucose filtré,excrété, réabsorbé
(mg/min)
600
420 mg/min
400
L’excrétion urinaire de glucose chez le diabétique
Glycémie (mg/dl)
Glucosurie
200 300 400
200
0
220 mg/dl
1000
400
Hyperglycemia – A Vicious Cycle
Type 2diabetes
• Hyperglycemia is a vicious cycle that will continue to escalate if not interrupted
• Continued reabsorption of
Continued reabsorption of
glucose
glucose by the kidney sustains and accelerates the cycle
25
Hyperglycemia produces glucotoxicity, which can increase insulin resistance, impair insulin secretion, and increase hepatic glucose production
Patients with Type 2 Diabetes Demonstrate High Reabsorption of Filtered Glucose
423,9420
440
(mg/
min
)
• TmG Tm was increased in patients with Type 2 diabetes
26
404,0
380
400Tm
(mg/
min
)
Nondiabetic(n=9)
Type 2 diabetes(n=12)
Farber SJ, et al. J Clin Invest. 1951;30(2):125-129.
Familial Renal Glucosuria (FRG) as a Model for Glucose Reabsorption Inhibition
• FRG is a rare inherited disorder characterized by urinary glucose excretion at normal plasma glucose levels due to an isolated defect in glucose reabsorption1,2
• Majority of cases are due to mutations in the SGLT2 gene2,3
• Clinical manifestations are rarely observed1-4
– Clinically insignificant renal histological changes and normal renal function
– No increase in the incidence of CRF, UTI, or diabetes– Hypoglycemia and hypovolemia are rare
271. Brodehl J, et al. Pediatr Nephrol, 1987; 1:502-508. 2. Ehrenkranz JRL, et al. Diabetes Metab Res Rev. 2005;21:31-38. 3. Wright EM, et al. J Intern Med. 2007;261:32-43; 4. Francis J, et al. Nephrol Dial Transplant. 2004;19:2893-2895.
SGLT2 inhibitors reduce renal glucose reabsorption
Proximal tubule
SGLT2 SGLT1
S1
S3
Glomerulus Distal tubule Collecting duct
Glucosefiltration
Loop of Henle
Reduced glucosereabsorption
Increasedglucose
excretion
DapagliflozinSGLT2 inhibitor
La glucosurie familiale:Preuve que SGLT2 est une bonne cible pour
traiter le diabète• Maladie héréditaire autosomale récessive liée à une
mutation du gène codant SGLT2• Glycémie normale, test de tolérance au glucose
normal mais glucosurie persistante et sévère (130 g/jour)g/jour)
• Perte d’électrolytes due à la polyurie
Mais: Pas d’anomalie de la fonction rénalePas d’augmentation des infections urinaires
29
Brodehl J, et al. Pediatr Nephrol, 1987; 1:502-508Ehrenkranz JRL, et al. Diabetes Metab Res Rev. 2005;21:31-38
Wright EM, et al. J Intern Med. 2007;261:32-43Francis J, et al. Nephrol Dial Transplant. 2004;19:2893-2895
Les inhibiteurs de SGLT
Les inhibiteurs non sélectifsPhlorizine et ses dérivés : Effets spectaculaires sur la
glycémie et l’HbA1c chez les rongeurs diabétiques, maisrapidement abandonnés car inhibent SGLT1 et inhibentl’absorption intestinale de glucose.l’absorption intestinale de glucose.
Les inhibiteurs sélectifs de SGLT2 (glucosides)Prodrugs administrées par voie oraleOligonucléotides antisens
Une douzaine d’inhibiteurs décrits
Glucose Lowering Improves Insulin Sensitivity and ß-cell DysfunctionIn Partially Pancreatectomized Rats
med
iate
d G
luco
se M
etab
olis
m(m
g/kg
/min
)
3
4
5
6
Pla
sma
Insu
lin R
espo
nse
(ng/
mL/
min
/g p
ancr
eas)
*
8
12
16
20
Control Diabetic Phlorizin treated
31
• Phlorizin treatment restored whole body glucose metabolism to normal 2
• Insulin sensitivity was restored in skeletal muscle, heart, skin, and brown adipose tissue 2
• Incremental plasma insulin response per gram of pancreatic tissue 1
• Phlorizin treatment normalized ß-cell response 1
Insu
lin-
med
iate
d G
luco
se M
etab
olis
m(m
g/kg
/min
)
0
1
2
First Phase Second Phase
Pla
sma
Insu
lin R
espo
nse
(ng/
mL/
min
/g p
ancr
eas)
*P
Résultats obtenus avec l’inhibiteur le plus avancé, le Dapagliflozin
Administré une fois par jour par voie orale. Effet dose-dépendantEffet dose-dépendant
Phase II, 14 jours, 12 semainesPhase III 24 semaines
Hardman 2011
Dapagliflozin Monotherapy in Type 2 Diabetic Patients with Inadequate Glycemic Control by Diet and Exercise: A Randomized, Double-blind, Placebo-controlled, Phase III Trial
MB102013
Ele Ferrannini, Silvia Jimenez Ramos, Afshin Salsali, Weihua Tang, James F List
Diabetes Care 2010;33:2217–24.
Mercury
ID: 732H
Q11N
P051
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
24-week Monotherapy Study: Changes from Baseline at Week 24 in Efficacy Parameters and Vital Signs (Main Pat ient Cohort)
Placebo (n=75)
Dapagliflozin dose
2.5 mg QAM 5 mg QAM 10 mg QAM(n=65) (n=64) (n= 70)
HbA1c (SE), %*† –0.23 (0.10) –0.58 (0.11) –0.77 (0.11)ǁ –0.89 (0.11)¶
Fasting plasma glucose (SE), mg/dL*† –4.1 (3.9) –15.2 (4.2) –24.1 (4.3)ǁ –28.8 (4.0) ¶
Weight (SE), kg*† –2.2 (0.4) –3.3 (0.5) –2.8 (0.5) –3.2 (0.4)
Mercury ID
: 732HQ
11NP
051
Weight (SE), kg*† –2.2 (0.4) –3.3 (0.5) –2.8 (0.5) –3.2 (0.4)
Urinary glucose:creatinine (SE), g/g‡§ 0.96 (2.87) 12.12 (2.98) 17.68 (3.28) 33.80 (3.08)
Vital signs
Seated systolic BP (SE), mmHg‡ –0.9 (1.8) –4.6 (1.8) –2.3 (1.9) –3.6 (1.9)
Seated diastolic BP (SE), mmHg‡ –0.7 (1.0) –2.8 (1.1) –1.7 (1.1) –2.0 (1.1)
Data are mean (standard error) unless noted otherwise
*Assessed in patients with non-missing baseline and week-24 values with last observation carried forward. †Mean value after adjusting for baseline value. ‡Assessed in patients with non-missing baseline and week-24 values. §Ratio from morning, fasting spot urine test
ǁp
24-week Monotherapy Study: Changes from Baseline at Week 24 in Laboratory Parameters (Main Patient Coho rt)
Placebo (n=75)
Dapagliflozin dose
2.5 mg QAM 5 mg QAM 10 mg QAM(n=65) (n=64) (n= 70)
Sodium (SE), mmol/L* –0.1 (0.3) –0.1 (0.3) –0.9 (0.4) –0.4 (0.4)
Potassium (SE), mmol/L* –0.03 (0.06) –0.05 (0.05) 0 (0.05) –0.01 (0.06)
Calcium (SE), mmol/L* 0.01 (0.01) 0.03 (0.02) 0 (0.02) 0.03 (0.01)
Magnesium (SE), mmol/L* –0.25 (0.18) 0 (0.20) 0.50 (0.26) 0 (0.26)
Mercury ID
: 732HQ
11NP
051
Inorganic phosphorus (SE), mmol/L* –0.01 (0.02) 0.01 (0.02) 0.04 (0.03) 0.05 (0.02)
Serum creatinine (SE), mmol/L* –0.4 (0.9) –0.6 (1.3) –2.0 (1.4) –1.1 (1.0)
Serum albumin (SE), g/L* –0.1 (0.3) 0.6 (0.4) 0.3 (0.4) 0.9 (0.3)
Cystatin C (SE), mg/L* -0.014 (0.012) –0.009 (0.014) 0.005 (0.014) –0.003 (0.016)
Hematocrit (SE), %* –0.38 (0.25) 1.60 (0.33) 1.74 (0.40) 2.38 (0.44)
Serum uric acid (SE), mmol/L*† –11.9 (5.6) –39.3 (6.0) –50.6 (6.1) –51.7 (5.8)
Blood urea nitrogen (SE), mmol/L* 0.2 (0.2) 0.6 (0.2) 0.6 (0.2) 0.4 (0.2)
Data are mean (SE) unless noted otherwise
*Assessed in patients with non-missing baseline and week-24 values. †Mean value after adjusting for baseline value
Ferrannini E, et al. Diabetes Care. 2010;33:2217–2224.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
24-week monotherapy study: adjusted mean change fro m baseline in HbA1c over time* (main patient cohort)
Placebo (n=75)DAPA 2.5 mg QAM (n=65)DAPA 5 mg QAM (n=64)DAPA 10 mg QAM (n=70)
HbA1c (%)Adjusted –0.4
–0.2
0.0 Week 24 value (95% CI)
- 0.23 (-0.43 to – 0.02)
Mercury ID
: 732HQ
11NP
051
*Excluding data after rescue. Last Observation Carried Forward
(%)Adjusted Mean Change From Baseline –0.8
–0.6
–0.4
0 4 8 12 16 20 24Study Week
–1.0
-0.58 (-0.80 to -0.36)
-0.77 (-0.99 to -0.55)
-0.89 (-1.10 to -0.67)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Ferrannini E, et al. Diabetes Care. 2010;33:2217–2224.
24-week monotherapy study: adjusted mean change fro m baseline in fasting plasma glucose over time* (main patient coh ort)
FPG (mg/dL) Adjusted
–20
–10
0.0
Placebo (n=75)DAPA 2.5 mg QAM (n=65)DAPA 5 mg QAM (n=64)DAPA 10 mg QAM (n=70)
Week 24 value (95% CI)
- 4.1 (-11.8 to 3.5)
-15.2 (-23.5 to -7.0)
Mercury ID
: 732HQ
11NP
051
Adjusted Mean Change From Baseline
0 4 8 12 16 20 24
Study Week
–40
–30
–50
*Excluding data after rescue. Last Observation Carried Forward
-24.1 (-32.5 to -15.5)
-0.28.8 (-36.8 to -20.9)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Ferrannini E, et al. Diabetes Care. 2010;33:2217–2224.
24-week monotherapy study: adjusted mean change fro m baseline in body weight over time* (main patient cohort)
Total Body Weight (kg)
–1
0
1
Placebo (n=75)DAPA 2.5 mg QAM (n=65)DAPA 5 mg QAM (n=64)DAPA 10 mg QAM (n=70)
Week 24 value (95% CI)
Mercury ID
: 732HQ
11NP
051
Weight (kg) Adjusted Mean Change From Baseline –4
–3
0 4 8 12 16 20 24
Study Week
–5
–2
*Excluding data after rescue. Last Observation Carried Forward
Week 24 value (95% CI)
- 2.2 (-3.3 to -1.3)
-3.3 (-4.2 to -2.3)
-2.8 (-3.8 to -1.9)
-3.2 (-4.0 to -2.3)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Ferrannini E, et al. Diabetes Care. 2010;33:2217–2224.
24-week Monotherapy Study: Adverse Events (Main Patient Cohort)
Placebo (n=75)
Dapagliflozin dose
2.5 mg QAM 5 mg QAM 10 mg QAM(n=65) (n=64)§§§§ (n=70) §§§§
At least one AE 45 (60.0) 41 (63.1) 37 (57.8) 48 (68.6)
At least one serious AE 3 (4.0) 0 1 (1.6) 1 (1.4)
Discontinuation for AE 1 (1.3) 2 (3.1) 3 (4.7) 5 (7.1)
Discontinuation for serious AE 0 0 1 (1.6) 0
Most common AEs ( ≥10% in any group) by MedDRA preferred term, n (%)
Mercury ID
: 732HQ
11NP
051
Most common AEs ( ≥10% in any group) by MedDRA preferred term, n (%)
Nasopharyngitis 4 (5.3) 7 (10.8) 3 (4.7) 2 (2.9)
Diarrhea 1 (1.3) 4 (6.2) 1 (1.6) 1 (1.4)
Headache 5 (6.7) 5 (7.7) 3 (4.7) 4 (5.7)
Events by special interest category
Hypoglycemia* 2 (2.7) 1 (1.5) 0 2 (2.9)
Events suggestive of UTI† 3 (4.0) 3 (4.6) 8 (12.5) 4 (5.7)
Events suggestive of GI‡ 1 (1.3) 5 (7.7) 5 (7.8) 9 (12.9)
Hypotensive events 1 (1.3) 0 0 1 (1.4)
Data shown include data after rescue. *None of the hypoglycemic events led to discontinuation from study and none was a majorepisode. †These events included signs, symptoms, and other reports suggestive of urinary tract infections. ‡These events included signs, symptoms, and other reports suggestive of genital infections. §Not placebo-controlled AE = adverse event; GI = gastrointestinal; UTI = urinary tract infection Ferrannini E, et al. Diabetes Care. 2010;33:2217–24.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Effect of Dapagliflozin in Patients with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control with Metformin: A Randomized, Double-blind, Placebo-controlled trial
MB102014
Clifford J. Bailey, Jorge L. Gross, Anne Pieters, Arnaud Bastien, James F. List
Lancet 2010;375:2223-2233.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)
These slides are provided in response to an unsolicited Medical Information request – For Medical Use only
Mercury
ID: 732H
Q11N
P051
Perte de poids(Kg)
Baisse d’HbA1c en %
0
2,5 mg 5 mg 10 mg
Baisse d’HbA1c et perte de poids en 24 semaines.Diabétiques en échec de Metformine
0
Dapagliflozine
- 0,5
- 1 - 3
- 1
- 2
Bailey (2010) Lancet 375: 2223
Add-on to Metformin Study: Objectives and Methods
� Objective– To evaluate the efficacy and safety of dapagliflozin when added to metformin
� Patients– Aged 18–77 years – Type 2 diabetes mellitus– HbA1c 7%–10%– C-peptide ≥0.34 nmol/L
Mercury ID
: 732HQ
11NP
051
– C-peptide ≥0.34 nmol/L– Body mass index ≤45 kg/m2
– Stable metformin dose ≥1500 mg/d for ≥8 weeks prior to enrollment
� Study design– Randomized, double-blind, 4-arm parallel-group, placebo-controlled trial – 2-week, single-blind placebo lead-in period; 24-week treatment phase– Patients were randomized to once-daily dapagliflozin 2.5 mg, 5 mg, 10 mg,
or placebo before the morning meal in addition to open-label therapy with their usual metformin dose
Bailey CJ, et al. Lancet 2010;375:2223–2233
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Add-on to Metformin Study: Assessments
� Primary end point– Change from baseline in HbA1c percentage at week 24
� Key secondary end points– Change from baseline in FPG at week 24– Change from baseline in total body weight at week 24– Proportion of patients achieving HbA1c
Add-on to Metformin Study: Patients
546 randomly assigned to study drug plus stable dose of metformin (≥1500 mg
16 not randomized 1 adverse event 7 no longer met study criteria 3 poor compliance or not compliant4 withdrew consent1 lost to follow-up
915 patients enrolled 353 did not complete qualification
332 no longer met study criteria 4 poor compliance or not compliant
11 withdrew consent 3 lost to follow-up 3 other
562 entered lead-in period
Mercury ID
: 732HQ
11NP
051121 completed study
14 did not complete study
3 adverse events2 withdrew consent 5 lost to follow-up 2 no longer met
study criteria 1 administrative
reason of sponsor1 other
122 completed study
15 did not complete study
1 lack of efficacy2 adverse events5 withdrew consent 4 lost to follow-up 2 poor compliance
or not compliant1 other
121 completed study
16 did not complete study
3 adverse events4 withdrew consent 3 no longer met
study criteria 4 lost to follow-up 1 administrative
reason of sponsor 1 other
119 completed study
18 did not complete study
2 lack of efficacy4 adverse events6 withdrew consent5 lost to follow-up 1 administrative
reason of sponsor
daily)
132 included in analysis of primary endpoint
133 included in analysis of primary endpoint
135 included in analysis of primary endpoint
134 included in analysis of primary endpoint
137 assigned to receive dapagliflozin 5 mg once daily
137 assigned to receive placebo once daily
135 assigned to receive dapagliflozin 10 mg once daily
137 assigned to receive dapagliflozin 2.5 mg once daily
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Demographic and Baseline Characteristics
Placebo + Metformin
(N=137)
Dapagliflozin2.5 mg + Metformin
(N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin (N=135)
Age, years 53.7 (10.3) 55.0 (9.3) 54.3 (9.4) 52.7 (9.9)
Men 76 (55%) 70 (51%) 69 (50%) 77 (57%)
Body mass index, kg/m2 31.8 (5.3) 31.6 (4.8) 31.4 (5.0) 31.2 (5.1)
Type 2 diabetes mellitus duration, 5.8 (5.1) 6.0 (6.2) 6.4 (5.8) 6.1 (5.4)
Mercury ID
: 732HQ
11NP
051
Type 2 diabetes mellitus duration, years
5.8 (5.1) 6.0 (6.2) 6.4 (5.8) 6.1 (5.4)
HbA1c, % 8.11 (0.96) 7.99 (0.90) 8.17 (0.96) 7.92 (0.82)
FPG, mmol/L 9.19 (2.57) 8.96 (2.39) 9.39 (2.72) 8.66 (2.15)
Seated systolic blood pressure, mm Hg
127.7 (14.6) 126.6 (14.5) 126.9 (14.3) 126.0 (15.9)
Seated diastolic blood pressure, mm Hg
80.9 (9.0) 79.5 (8.7) 80.8 (8.5) 79.0 (10.2)
Total daily metformin dose during trial, mg
1861 (423) 1792 (410) 1854 (389) 1800 (392)
Data are mean (SD) or n (%). FPG = fasting blood glucose.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: HbA1c (%) Adjusted Mean Change from Baseline*
Week 24 value (95% CI)
7.79% (7.59 to 7.99)
7.34% (7.18 to 7.50)
PlaceboDapagliflozin 2.5 mgDapagliflozin 5 mgDapagliflozin 10 mg
7.6
7.8
8.0
8.2
8.4
HbA1c (%)
Mercury ID
: 732HQ
11NP
051*Randomized subjects, excluding data after rescue, last observation carried forwardANCOVA model with treatment group as effect and baseline value as covariate.
7.34% (7.18 to 7.50)
7.42% (7.26 to 7.58)
7.13% (6.97 to 7.29)
6.8
7.0
7.2
7.4
0 4 8 12 16 20 24
Study Week
(%)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: HbA1c
Placebo + Metformin
(N=137)
Dapagliflozin 2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin10 mg +
Metformin(N=135)
HbA1c at week 24 (%)
n* 134 135 133 132
Baseline 8.11 (0.96) 7.99 (0.90) 8.17 (0.96) 7.92 (0.82)
Week 24 7.79 (1.18) 7.34 (0.93) 7.42 (0.94) 7.13 (0.94)
Change from baseline –0.30 –0.67 –0.70 –0.84 Change from baseline –0.30 (–0.44 to –0.16)
–0.67 (–0.81 to –0.53)
–0.70 (–0.85 to –0.56)
–0.84 (–0.98 to –0.70)
P value 0.0002†
Add-on to Metformin Study: HbA1c at Week 24 in Patients with Baseline HbA1c ≥9.0%
Placebo + Metformin
(N=137)
Dapagliflozin2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin(N=135)
HbA1c at week 24 in patients with baseline HbA1c ≥9.0 (%)
n* 22 17 34 18
Baseline 9.70 (0.57) 9.69 (0.49) 9.50 (0.42) 9.42 (0.31)Baseline 9.70 (0.57) 9.69 (0.49) 9.50 (0.42) 9.42 (0.31)
Week 24 9.12 (1.26) 8.44 (1.30) 8.16 (1.01) 8.16 (0.96)
Change from baseline –0.53(–1.00 to –0.06)
–1.21 (–1.74 to –0.69)
–1.37(–1.74 to –1.00)
–1.32(–1.83 to –0.80)
P value NT 0.0068† 0.0290†
NT=not tested under sequential testing procedure if previously tested end point was not statistically significant. Data are mean (SD) or mean (95% CI). *Number of randomized patients with week 24 (LOCF) values. †Significant after sequential testing procedure at α=0.05.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Adjusted Mean Change from Baseline in Fasting Plasma Glucose*
Week 24 change (95% CI)
–0.33 (–0.62 to –0.04)
-0.6-0.4-0.20.00.20.4
Change from
PlaceboDapagliflozin 2.5 mgDapagliflozin 5 mgDapagliflozin 10 mg
*Randomized subjects, excluding data after rescue, last observation carried forwardANCOVA model with treatment group as effect and baseline value as covariate.
–0.99 (–1.28 to –0.69)–1.19 (–1.49 to –0.90)–1.30 (–1.60 to –1.00)
2-1.8-1.6-1.4-1.2-1.0-0.8-0.6
0 4 8 12 16 20 24
Week
from baselinein FPG (mmol/L)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Fasting Plasma Glucose
Placebo + Metformin
(N=137)
Dapagliflozin 2.5 mg + Metformin
(N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg + Metformin
(N=135)
FPG at week 24 (mmol/L)
n* 136 137 136 132
Baseline 9.19 (2.57) 8.96 (2.39) 9.39 (2.72) 8.66 (2.15)
Week 24 8.79 (2.48) 8.03 (1.88) 8.03 (2.11) 7.56 (1.88)
Change from baseline (CI) –0.33 –0.99 –1.19 –1.30 Change from baseline (CI) –0.33(–0.62 to –0.04)
–0.99(–1.28 to –0.69)
–1.19 (–1.49 to –0.90)
–1.30 (–1.60 to –1.00)
P value 0.0019†
Add-on to Metformin Study: Adjusted Mean Change from Baseline in Total Body Weight*
Week 24 change, kg (95% CI)
–0.9 (–1.4 to –0.4)
–2.2 (–2.7 to –1.8)-2
-1
0
1
Change from baseline in
PlaceboDapagliflozin 2.5 mgDapagliflozin 5 mgDapagliflozin 10 mg
*Randomized subjects, excluding data after rescue, last observation carried forwardANCOVA model with treatment group as effect and baseline value as covariate. Logistic regression with adjustment for baseline total body weight.
–2.2 (–2.7 to –1.8)
–3.0 (–3.5 to –2.6)
–2.9 (–3.3 to –2.4)
2-4
-3
-2
0 4 8 12 16 20 24
Week
baseline in body weight(kg)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Body Weight and Waist Circumference
Placebo +Metformin
(N=137)
Dapagliflozin 2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin(N=135)
Total body weight at week 24 (kg)
n* 136 137 137 133
Baseline 87.7 (19.2) 84.9 (17.8) 84.7 (16.3) 86.3 (17.5)
Week 24 86.8 (18.9) 82.7 (17.6) 81.7 (16.1) 83.4 (17.4)
Change from baseline –0.9 (–1.4 to –0.4)
–2.2 (–2.7 to –1.8)
–3.0 (–3.5 to –2.6)
–2.9 (–3.3 to –2.4)
P value
Add-on to Metformin Study: Adverse Events
Placebo + Metformin
(N=137)
Dapagliflozin 2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin(N=135)
1 or more adverse event 88 (64) 89 (65) 95 (69) 98 (73)
1 or more drug-related adverse event
22 (16) 22 (16) 25 (18) 31 (23)
Adverse event leading 5 (4) 3 (2) 3 (2) 4 (3)Adverse event leading to discontinuation
5 (4) 3 (2) 3 (2) 4 (3)
1 or more serious adverse event 5 (4) 4 (3) 4 (3) 4 (3)
Deaths 0 0 0 0
Data are number (%) of patients and include data after rescue.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Most Common Adverse Events ( ≥5% in Any Treatment Group)
Preferred termPlacebo + Metformin
(N=137)
Dapagliflozin 2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin(N=135)
Headache 6 (4) 4 (3) 10 (7) 11 (8)
Back pain 7 (5) 5 (4) 3 (2) 10 (7)
Diarrhea 7 (5) 3 (2) 5 (4) 10 (7)
Urinary tract infection 7 (5) 4 (3) 7 (5) 9 (7)Urinary tract infection 7 (5) 4 (3) 7 (5) 9 (7)
Influenza 10 (7) 13 (9) 13 (9) 8 (6)
Nasopharyngitis 11 (8) 12 (9) 4 (3) 8 (6)
Hypertension 6 (4) 9 (7) 4 (3) 5 (4)
Upper respiratory tract infection
10 (7) 5 (4) 4 (3) 3 (2)
Cough 7 (5) 4 (3) 4 (3) 1 (
Add-on to Metformin Study: Adverse Events of Special Interest
Placebo + Metformin
(N=137)
Dapagliflozin 2.5 mg +
Metformin (N=137)
Dapagliflozin 5 mg +
Metformin (N=137)
Dapagliflozin 10 mg +
Metformin(N=135)
Hypoglycemia*† 4 (3) 3 (2) 5 (4) 5 (4)
Events suggestive of urinary tract infection‡
11 (8) 6 (4) 10 (7) 11 (8)
Events suggestive of 7 (5) 11 (8) 18 (13) 12 (9)Events suggestive of genital infection*§
7 (5) 11 (8) 18 (13) 12 (9)
Hypotension or syncope* 1 (
Add-on to Metformin Study: Laboratory Parameters
Placebo + Metformin
Dapagliflozin 2.5 mg +
Metformin
Dapagliflozin 5 mg +
Metformin
Dapagliflozin 10 mg +
Metformin
Serum creatinine (SE), µmol/L* Change at week 24
n=120–0.7 (0.7)
n=1190.4 (0.7)
n=122–1.2 (0.9)
n=122–0.1 (0.7)
Cystatin-C (SE), µmol/L*Change at week 24
n=1190.002 (0.006)
n=1160.021 (0.008)
n=1160.006 (0.010)
n=1150.025 (0.008)
Serum uric acid (SD), µmol/L†Change at week 24
n=136–4.2 (4.2)
n=137–30.9 (4.2)
n=136–36.3 (4.2)
n=132–47.6 (4.3)
Blood urea nitrogen (SE), mmol/L*Change at week 24
n=1200.2 (0.1)
n=1190.6 (0.1)
n=1220.6 (0.1)
n=1220.7 (0.1)
Hematocrit (SE), %*Change at week 24
n=118–1.1 (0.2)
n=1181.0 (0.2)
n=1211.3 (0.2)
n=1191.7 (0.2)
Alanine aminotransferase (SE), U/L*Change at week 24
n=120–3.7 (1.2)
n=118–5.0 (0.4)
n=122–5.1 (1.5)
n=122–6.0 (1.0)
Total bilirubin (SE), µmol/L*Change at week 24
n=1200.3 (0.3)
n=119–0.2 (0.2)
n=1220.2 (0.3)
n=1201.0 (0.3)
n=number of treated patients with week 24 values. *Data are mean change from baseline at week 24 (SE), including data after rescue. †Data are adjusted mean change from baseline at week 24 (SD) based on ANCOVA model with treatment group as an effect and baseline value as a covariate (LOCF), excluding data after rescue.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Laboratory Parameters (c ont)
Placebo + Metformin
Dapagliflozin 2.5 mg +
Metformin
Dapagliflozin 5 mg +
Metformin
Dapagliflozin 10 mg +
Metformin
Total cholesterol (SE), mmol/L*Percent change at week 24
n=1232.7 (1.3)
n=1232.9 (1.3)
n=1262.2 (1.3)
n=1214.2 (1.3)
LDL cholesterol (SE), mmol/L*Percent change at week 24
n=1213.5 (2.3)
n=1235.0 (2.3)
n=1263.1 (2.3)
n=1209.5 (2.4)
HDL cholesterol (SE), mmol/L*Percent change at week 24
n=1230.4 (1.4)
n=1231.8 (1.4)
n=1263.3 (1.4)
n=1214.4 (1.5)
Triglycerides (SE), mmol/L* n=123 n=123 n=126 n=121Triglycerides (SE), mmol/L*Percent change at week 24
n=1232.1 (3.6)
n=123–2.4 (3.4)
n=126–6.2 (3.2)
n=121–6.2 (3.3)
Urinary glucose/creatinine ratio (SE), g/g†
Change at week 24n=118
–0.7 (3.4)n=115
10.8 (3.4)n=123
32.2 (3.3)n=118
31.2 (3.4)
n=number of treated patients with week 24 values. LDL = low-density lipoprotein. HDL = high-density lipoprotein. *Data are adjusted mean percent change (SE) from baseline at week 24, based on ANCOVA of the logarithms of the post treatment to baseline ratios with treatment group as an effect and log of baseline value as a covariate (LOCF), excluding data after rescue. †Data are adjusted mean change from baseline (SE) at week 24 based on ANCOVA model with treatment group as an effect and baseline value as a covariate (LOCF). Measures for urinary glucose/creatinine ratio were derived from a urinary spot-check performed in the morning fasting state.
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Add-on to Metformin Study: Change in Blood Pressure , and Patients with Hypertension who Achieved Goal Blood Pressure at Week 24
Placebo + Metformin
Dapagliflozin 2.5 mg +
Metformin
Dapagliflozin 5 mg +
Metformin
Dapagliflozin 10 mg +
Metformin
Seated blood pressure, mm Hg n=119* n=119* n=122* n=122*
Systolic
Baseline† 127.7 (14.6) 126.6 (14.5) 126.9 (14.3) 126.0 (15.9)
Mean change at week 24‡ –0.2 (1.2) –2.1 (1.1) –4.3 (1.3) –5.1 (1.3)
Diastolic
Baseline † 80.9 (9.0) 79.5 (8.7) 80.8 (8.5) 79.0 (10.2)Baseline 80.9 (9.0) 79.5 (8.7) 80.8 (8.5) 79.0 (10.2)
Mean change at week 24‡ –0.1 (0.7) –1.8 (0.9) –2.5 (0.8) –1.8 (0.8)
Patients with hypertension §§§§ at baseline, who achieved goal at week 24
x/n=5/57ǁ x/n=18/61ǁ x/n=18/59ǁ x/n=18/48ǁ
Proportion of patients (%) 8.8 29.5 30.5 37.5
Difference versus placebo (%)¶
Confidence interval of difference (%)20.7
(6.7 to 34.8)21.7
(7.3 to 36.1)28.7
(12.7 to 44.3)
*n=number of treated patients with week 24 values (LOCF), including data after rescue. †Data are mean (SD). ‡Data are mean (SE). §Goal blood pressure of
Add -on to Metformin Study: S ummary and Conclusions
� Dapagliflozin can improve glycemic control in patients inadequately controlled with metformin alone
� Safety parameters and tolerability were favorable
� Dapagliflozin– Acts independently of insulin– Acts independently of insulin– Lowers weight– Not associated with risk for hypoglycemia
� Dapagliflozin provides an important new therapeutic option for type 2 diabetes
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Bailey CJ, et al. Lancet 2010;375:2223–2233
Efficacy and Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus and Inadequate Glycaemic Control on Glimepiride Monotherapy
D1690C00005
Krzysztof Strojek, Veronika Hruba, Martina Elze, Anna-Maria Langkilde, Shamik Parikh
Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)
These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Add-on to Sulfonylurea Study: Background and Aims
� Progressive deterioration of glycemic control in patients with T2DM often requires treatment intensification with additional drug therapy
� Dapagliflozin, a selective inhibitor of sodium-glucose co-transporter 2:transporter 2:– inhibits renal glucose reabsorption– reduces hyperglycemia and body weight in patients with T2DM without
a significantly increased risk of hypoglycemia
� We assessed efficacy, safety and tolerability of dapagliflozin as add-on to glimepiride in patients with uncontrolled T2DM.
Strojek K, et al. Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Add -on to Sulfonylurea Study: Study Design
Dapagliflozin 2.5 mg (n=154)
Dapagliflozin 5 mg (n=145)
Dapagliflozin 10 mg (n=151)
Ran
dom
ized
(n=
597)
Patients entering on
ClinicalTrial.gov identifier: NCT00680745
Dapagliflozin 10 mg (n=151)
Placebo (n=146)
Open-label glimepiride 4 mg/day
Ran
dom
ized
(n=
597)
Patients entering onglimepiride 4 mg/dayproceed directly to
randomization
Enrolment Qualification period
Lead-in period
Double-blindtreatment period
Double-blindextension period
Follow-up
Study Week
-12 -10 -9 -5 -1 0 1 4 8 12 16 20 24 32 40 48 51
• Patients with T2DM• HbA1c 7.0%–10.0%• At least half maximal
SU monotherapy
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Strojek K, et al. Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Add -on to Sulfonylurea Study: Assessments
� Primary endpoint– HbA1c change from baseline at 24 weeks
� Secondary endpoints– Change in body weight from baseline at week 24– Change in 2-hour post-challenge plasma glucose (PPG) as a response
to an oral glucose-tolerance test (OGTT) change from baseline at week 2424
– Proportion of patients achieving a therapeutic glycemic response, defined as HbA1c
−0.13
-0.5
-0.4
-0.3
-0.2
-0.1
0
Placebo+ glimepiride
(n=145)
Dapagliflozin 2.5 mg+ glimepiride
(n=154)
Dapagliflozin 5 mg+ glimepiride
(n=142)
Dapagliflozin 10 mg+ glimepiride
(n=151)
HbA1c (%), adjusted absolute mean change from
Add -on to Sulfonylurea Study: Changes in HbA1c at 24 Weeks
Baseline HbA 1c (%), mean (SD) 8.15 (0.74) 8.11 (0.75) 8.12 (0.78) 8.07 (0.79)
Week 24 (LOCF) absolute change from baseline in HbA 1c(%), adjusted mean (SE)
−0.13 (0.063) −0.58 (0.060) −0.63 (0.063) −0.82 (0.061)
p versus placebo*
Add -on to Sulfonylurea Study: Changes in Body Weight at 24 Weeks
Placebo+ glimepiride
(n=145)
Dapagliflozin 2.5 mg+ glimepiride
(n=154)
Dapagliflozin 5 mg+ glimepiride
(n=142)
Dapagliflozin 10 mg+ glimepiride
(n=151)
Body weight (kg), adjusted absolute mean change from
−0.72
−1.18
−1.56-1.5
-1.0
-0.5
0.0
Baseline BW (Kg), mean (SD) 80.9 (15.8) 81.9 (19.0) 81.0 (18.6) 80.6 (17.9)
Week 24 (LOCF) absolute change from baseline in BW (kg), adjusted mean (SE)
−0.72 (0.23) −1.18 (0.22) −1.56 (0.23) −2.26 (0.22)
p versus placebo* NS
Add -on to Sulfonylurea Study: Changes in OGTT Plasma Glucose Response at 24 weeks
+ glimepiridePlacebo
(n=145)
Dapagliflozin 2.5 mg+ glimepiride
(n=154)
Dapagliflozin 5 mg+ glimepiride
(n=142)
Dapagliflozin 10 mg+ glimepiride
(n=151)
OGTT plasma glucose response (mg/dL),
adjusted mean change
−6.0
-25
-20
-15
-10
-5
0
Baseline OGTT (mg/dL), mean (SD) 158.6 (58.75) 140.4 (68.18) 151.2 (64.21) 157.3 (69.03)
Week 24 (LOCF) absolute change from baseline in OGTT (mg/dL), adjusted mean (SE)
−6.0 (5.02) −37.5 (4.68) −32.0 (4.84) −34.9 (4.56)
p versus placebo* NT
Add -on to Sulfonylurea Study: Glycemic Response at 24 Weeks
Adjusted proportion of patients (%) with HbA1c
Add -on to Sulfonylurea Study: Changes in Blood Pressure at 24 Weeks
Placebo+ glimepiride
(n=145)
Dapagliflozin 2.5 mg+ glimepiride
(n=154)
Dapagliflozin 5 mg+ glimepiride
(n=142)
Dapagliflozin 10 mg+ glimepiride
(n=151)
−1.2−1.4
−1.1
−1.7
-1
0
Blood pressure(mm Hg),
mean change from baseline at week 24
−4.7
−4.0
−5.0
−2.8
-6
-5
-4
-3
-2
seated systolic blood pressure
seated diastolic blood pressure
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Strojek K, et al. Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Add -on to Sulfonylurea Study: Safety Results
Patients with adverse events
Placebo+ glimepiride
(n=146)
Dapagliflozin 2.5 mg
+ glimepiride(n=154)
Dapagliflozin 5 mg
+ glimepiride(n=145)
Dapagliflozin 10 mg
+ glimepiride(n=151)
All adverse events 47% 52% 48% 50%
Hypoglycaemic events 4.8% 7.1% 6.9% 7.9%
Events suggestive of UTI 6.2% 3.9% 6.9% 5.3%
Events suggestive of genital
� Frequency of drug-related AEs similar across all treatment groups
� No kidney infections were reported
� No genital tract infections led to study discontinuation
� No clinically meaningful changes from baseline in serum creatinine or electrolytes were observed
Events suggestive of genital infection
0.7% 3.9% 6.2% 6.6%
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Strojek K, et al. Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Add -on to Sulfonylurea Study: Conclusions
� significantly improved mean HbA1c
Dapagliflozin as add-on therapy to glimepiride in patients with T2DM poorly controlled with sulphonylurea monotherapy:
� reduced weight
� was well-tolerated
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Strojek K, et al. Diabetes Obes Metab 2011 Jun 15 (ahead of print)
Dapagliflozin vs Glipizide in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: 52-week Results of a Double-blind, Randomized, Controlled trial
D1690C00004
Michael Nauck, Stefano Del Prato, Katja Rohwedder, Martina Elze, Shamik Parikh
Nauck M et al. Diabetes Care 2011 Aug 4 (online only).
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)
These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Sulfonylurea Comparator Study: Background and Aims
� Glipizide is commonly used as an add-on to metformin, but is associated with weight gain and hypoglycemia
� Dapagliflozin is a selective inhibitor of sodium-glucose cotransporter 2 that– inhibits renal glucose reabsorption in an insulin-independent manner– inhibits renal glucose reabsorption in an insulin-independent manner– is a potential therapy to reduce hyperglycemia in T2DM– and has been associated with weight loss
� Tested the efficacy, safety and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with T2DM
Nauck M et al. Diabetes Care 2011 Aug 4 (ahead of print).
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Down-titrated if medically indicated
Double-blind treatment (52 weeks)
Dapagliflozin no further 2.5–10 mg/day up-titration(n=406) allowed
Metformin R
Open-label metformin
Patients with T2DM≥18 yearsHbA 6.5–10%
Stable metformin
Variable
Single-blind
placebo
ClinicalTrials.gov identifier: NCT00660907
Sulfonylurea Comparator Study: Study Design
-13 -11 -10 -2 0 3 6 9 12 15 18 26 34 42 52Study Week
Enrolment Stabilization Lead-in Up-titration* Maintenanc e
Glipizide no further5–20 mg/day up-titration (n=408) allowed
Metformin stabilization
Open-label metformin
HbA1c 6.5–10%
Other OAD discontinuedMetformin up-titrated to
1500, 2000, or 2500 mg/day as nearest dose
metformin± other
OAD
placebo
*Until FPG
Sulfonylurea Comparator study: A ssessments
� Primary endpoints– change from baseline in HbA1c at 52 weeks– tested for non-inferiority of dapagliflozin versus glipizide
with a pre-defined margin of 0.35%
� Secondary endpoints– Change in body weight– Change in body weight– Proportion of patients reporting hypoglycemic episodes– Proportion of patients with weight loss of ≥5%
� No pre-planned statistical analyses for otheradverse events
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Nauck M et al. Diabetes Care 2011 Aug 4 (ahead of print).
Sulfonylurea Comparator Study: C hange in HbA1c at 52 Weeks
-0.2
-0.1
0
Dapagliflozin*+ metformin
(n=400)
Glipizide †
+ metformin(n=401)
Mean baseline HbA1c 7.72%
-0.7
-0.6
-0.5
-0.4
-0.3Change in HbA1c (%)‡
*86.9% receiving maximum 10 mg dose at end of titration period†72.5% receiving maximum 20 mg dose at end of titration period‡Data are adjusted mean change from baseline ± 95% CI
Non-inferior mean difference, 0.0%; 95% CI −0.11% t o 0.11%
−0.52 −0.52
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Nauck M et al. Diabetes Care 2011 Aug 4 (ahead of print).
1.41
2
33.3%
25%
30%
35%
Dapagliflozin + metformin (n=400) Glipizide + metformin (n=401)
Weight Proportion
Difference−4.7 kg
95% CI: −5.1 to −4.2p
Sulfonylurea Comparator Study: Other Changes From Baseline with Dapagliflozin Compared with Glipizide
� ↓ Systolic blood pressure (nominal p
30%
40%
50%
Proportion of patients
40.8%
p
Sulfonylurea Comparator Study: Adverse Events
Adverse eventsDapagliflozin
(n=406)Glipizide(n=408)
Serious adverse events 8.6% 11.3%
Actively solicited events
Suggestive of UTI 10.8% 6.4%
Mercury ID
: 732HQ
11NP
051
Suggestive of genital infections 12.3% 2.7%
Men 5.3% 0.4%
Women 21.1% 5.4%
Patients discontinuing due to UTI 1 1
Patients discontinuing due to genital infections 3 0
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Nauck M et al. Diabetes Care 2011 Aug 4 (ahead of print).
Sulfonylurea Comparator Study: Conclusions
� was non-inferior to glipizide in improving HbA1C after 52 weeks of treatment
In patients with T2DM inadequately controlled with OADs including metformin, the addition of dapagliflozin:
Mercury ID
: 732HQ
11NP
051
� produced significantly greater weight loss and fewer hypoglycaemic episodes compared with glipizide
� was generally well-tolerated but more UTI and genital infections were reported compared with glipizide
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Nauck M et al. Diabetes Care 2011 Aug 4 (ahead of print).
Dapagliflozin in Patients With Type 2 Diabetes Poorly Controlled on Insulin Therapy —Efficacy of a Novel Insulin-independent Treatment (24 weeks)
D1690C00006
John Wilding, Vincent Woo, Norman Soler, Andrea Pahor, Jennifer Sugg, Shamik Parikh
Diabetes. 2010;59(suppl 1):A21-A22. Abstract 0078-OR
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)
These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Mercury
ID: 732H
Q11N
P051
Add-on to Insulin Study (24 weeks): Objectives and Methods
� Objective– To determine the efficacy and safety of dapagliflozin in patients with type 2
diabetes poorly controlled with insulin
� Patients (N=807)– Mean baseline insulin dose: 77 IU/d– Mean baseline HbA1c: 8.5%
Mercury ID
: 732HQ
11NP
051
� Study design– Patients received once-daily placebo or dapagliflozin 2.5, 5, or 10 mg in
addition to their unchanged background insulin therapy with or without concomitant oral antidiabetic drugs
� Primary end point– Change from baseline in HbA1c at week 24 (last observation carried forward)
Wilding J, et al. Diabetes. 2010;59(Suppl 1):A21–A22. Abstract 0078-OR
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Add-on to Insulin Study (24 weeks): Efficacy Parameters
Adjusted Mean Change From Baseline (SE)at Week 24
Placebo + Insulin(n=193)
Dapagliflozin 2.5 mg + Insulin(n=202)
Dapagliflozin 5 mg + Insulin
(n=211)
Dapagliflozin 10 mg + Insulin
(n=194)
HbA1c (SE), % –0.30 (0.05) –0.75 (0.05)* –0.82 (0.05)* –0.90 (0.05)*
Body weight (SE), kg 0.02 (0.18) –0.98 (0.18)* –0.98 (0.17)* –1.67 (0.18)*
Insulin dose (SE), IU/d 5.08 (0.94) –1.80 (0.92)* –0.61 (0.90)* –1.16 (0.94)*
Mercury ID
: 732HQ
11NP
051
Insulin dose (SE), IU/d 5.08 (0.94) –1.80 (0.92)* –0.61 (0.90)* –1.16 (0.94)*
Fasting Plasma Glucose (SE), mg/dL
3.3 (3.4) –12.5 (3.2)† –18.8 (3.1) –21.7 (3.3)*
P value (vs Placebo + insulin), *P≤0.0001; †P=0.0008
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Wilding J, et al. Diabetes. 2010;59(Suppl 1):A21–A22. Abstract 0078-OR
Add-on to Insulin Study (24 weeks): Adverse Events
� Adverse events, serious adverse events, and study discontinuations were similar across all groups
� No clinically relevant increase in hypoglycemia was observed with dapagliflozin
� In the dapagliflozin treatment groups active solicitation revealed increased reports of signs and symptoms suggestive of
Mercury ID
: 732HQ
11NP
051
increased reports of signs and symptoms suggestive of – Urinary tract infections (8.4% vs 4.1% for placebo)– Genital infections (7.2% vs 2.0% for placebo)
� Urinary tract and genital infections responded to routine management
� Trend of small mean decreases in systolic blood pressure, without orthostatic hypotension, in the dapagliflozin groups
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Wilding J, et al. Diabetes. 2010;59(Suppl 1):A21–A22. Abstract 0078-OR
Add-on to Insulin Study (24 weeks): Conclusions
� Once-daily dapagliflozin therapy improved glycemic control and body weight in patients with type 2 diabetes poorly controlled with insulin therapy
Mercury ID
: 732HQ
11NP
051
Dapagliflozin is an investigational compound that has not been approved by the European Medicines Agency (EMA)These slides are provided in response to an unsolicited Medical Information request – For Medical use only
Wilding J, et al. Diabetes. 2010;59(Suppl 1):A21–A22. Abstract 0078-OR
• AvantagesPerte de poids (300 kcal/j, environ 3 kg en 16
semaines)Pas d’hypoglycémiesBaisse de la PA (≈ 4-5 mmHg, mais activation du
Systéme Rénine Angiotensine Aldostérone)
Inhibiteurs de SGLT-2 et diabète
Systéme Rénine Angiotensine Aldostérone)Effet indépendant de l’insuline L’inhibition de la réabsorption sodium devrait théoriquement protéger de la néphropathie diabétique
• QuestionsPolyurie (400ml/j): augmentation de l’Ht et de l’urée, pertes d’ électrolytes (Na)Infections urinaires et mycoses génitales
Les inhibiteurs de SGLT2 actuellement disponibles ont un effet limité carils ne bloquent que 40% de l’activité SGLT2 chez le diabétique. Orl’efficacité dépend du degré d’inhibition. Des doses plus élevées nepermettent pas de résoudre ce problème. Chez les personnes souffrant deglucosurie génétique, l’inhibition de réabsorption rénale du glucose est de90%.
Problème lié à l’efficacité des inhibiteurs
90%.
Spéculation : Ces molécules n’accèdent pas efficacement à SGLT2 dans le rein et l’hyperglycémie contrecarre les effets de l’inhibiteur.
Utilisation d’oligonucléotides antisens de SGLT2 qui réduisent l’expression de SGLT2 de près de 75% chez les primates (ISIS Pharm, Phase 1)
Conclusions
� Le rein joue un rôle central dans le métabolisme du glucose et larégulation de la glycémie
� Le SGLT2 rénal a un rôle clé dans le transport actif de glucose encontrôlant la réabsorption de glucose
� L’inhibition spécifique de SGLT2 est donc une cible pharmacologique� L’inhibition spécifique de SGLT2 est donc une cible pharmacologiquepotentielle pour le traitement du diabète
� Dans les modèles animaux, les inhibiteurs de SGLT2 ont un effetantidiabétique avec excrétion urinaire de glucose, diminution de laglycémie à jeun et postprandiale, sans modification de la sécrétiond’insuline et donc sans hypoglycémie. On observe également unediminution de l’insulinorésistance
Conclusions
� Plusieurs inhibiteurs spécifiques de SGLT2 sontactuellemnt en développement clinique (phase 2 et 3).� Les résultats obtenus confirment les effets observés surl’homéostasie glucidique dans les modèles animaux�. Ce traitement s’accompagne d’une perte de poids
� Des études cliniques de longue durée sont nécessaires:o Tolérance au long courso Efficacité au long courso Positionnement dans la stratégie thérapeutique
Summary
• Multiple organ systems contribute to sustaining hyperglycemia in type 2 diabetes
• The kidney plays an active role in glucose balance; it is not merely a “victim” – Production– Utilization– Utilization– Filtration and reabsorption
• The kidney contributes to the pathophysiology of type 2 diabetes by continually reabsorbing glucose into the bloodstream through an insulin-independent mechanism
91
Glucose filtréGlucosurie SGLT2
Glucosurie DT2
Glucose filtré,excrété, réabsorbé
(mg/min)
600
420 mg/min
400
L’excrétion urinaire de glucose chez le diabétique traité par
Glycémie (mg/dl)200 300 400
200
0
220 mg/dl
1000
400
150 mg/dl