Les inhibiteurs de SGLT2 - ACTUALITÉS … · Rôle du rein dans l’homéostasie glucidique • 3...

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 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


Distal S3 segment of proximal tubule

• ~10% glucose reabsorbed


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


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


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<0.05

P<0.05

Glucose Uptake by Tubular Cells

1500

2000

2500

AM

G*

Upt

ake

(CP

M) P<0.05

Healthy (n=4) Type 2 Diabetes (n=4)

1

0

3

2

SGLT2 GLUT2

Nor

mal

ized

Lev

els

P<0.05

500

1000

0A

MG

* U

ptak

e (C

PM

)

*Uptake of alpha-methyl-glucose (AMG) is Na+ dependentand is a measure of transport by SGLTs rather than GLUTs

22Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

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<0.05

1. Mogensen CE. Scand J Clin Lab Invest. 1971 Sep;28(1):101-109. 2 Farber SJ, et al J Clin Invest. 1951;30(2):125-129.

Glucose filtré

Glucose 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


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<0.01 vs untreated diabetic rats

0

4

8

1. Rosetti L et al. J Clin Invest. 1987;80:1037-1044. 2. Lisato G et al. Diabetologia. 1992;35:310-315. 3. Del Prato S. Diabet Med. 2009;26(12):1185-1192.

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.

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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)

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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<0.001; ¶p<0.0001 (α=0.019 [2-sided] applying Dunnett’s adjustment; secondary endpoints tested using a sequential procedure)

Ferrannini E, et al. Diabetes Care. 2010;33:2217–2224.


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)

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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



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)

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*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)



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


Week 24 value (95% CI)

- 4.1 (-11.8 to 3.5)

-15.2 (-23.5 to -7.0)

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Adjusted Mean Change From Baseline

0 4 8 12 16 20 24

Study Week

–40

–30

–50


-24.1 (-32.5 to -15.5)

-0.28.8 (-36.8 to -20.9)



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



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Weight (kg) Adjusted Mean Change From Baseline –4

–3

0 4 8 12 16 20 24

Study Week

–5

–2



- 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)



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 (%)

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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.


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

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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

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– 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


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 <7.0% at week 24

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– Proportion of patients achieving HbA1c <7.0% at week 24– Change from baseline in HbA1c percentage at week 24 for patients

with a baseline HbA1c ≥9%– Change from baseline in FPG at week 1

FPG = fasting plasma glucose.



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


1 lack of efficacy2 adverse events5 withdrew consent 4 lost to follow-up 2 poor compliance

or not compliant1 other

121 completed 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


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




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



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)


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.



Add-on to Metformin Study: HbA1c (%) Adjusted Mean Change from Baseline*


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

(%)



Add-on to Metformin Study: HbA1c

Placebo + Metformin

(N=137)

Dapagliflozin 2.5 mg +

Metformin (N=137)


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† <0.0001† <0.0001†

Patients with HbA1c <7.0% at week 24

n/N§ 33/134 46/135 47/133 58/132

Proportion of patients (%) 25.9 (19.1 to 32.6)

33.0 (25.4 to 40.6)

37.5 (30.0 to 45.1)

40.6 (32.9 to 48.3)

P value 0.1775 0.0275‡ 0.0062§

Data are mean (SD) or mean (95% CI). *Number of randomized patients with week 24 (LOCF) values. †Significant versus placebo at α=0.019 applying Dunnett’s adjustment. ‡Significant after sequential testing procedure at α=0.05. §No. of responders/no. of randomized patients with week 24 (LOCF) values.

Bailey CJ, et al. Lancet 2010;375:2223–2233.


Mercury

ID: 732H

Q11N

P051

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)


Metformin (N=137)


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.


Mercury

ID: 732H

Q11N

P051


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


*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)


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Fasting Plasma Glucose

Placebo + Metformin

(N=137)

Dapagliflozin 2.5 mg + Metformin

(N=137)


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† <0.0001† <0.0001†

FPG at week 1 (mmol/L)

n* 126 120 121 115

Baseline 9.22 (2.61) 9.00 (2.40) 9.32 (2.76) 8.65 (2.16)

Week 1 9.22 (2.52) 8.69 (1.77) 8.57 (2.12) 7.87 (1.54)

Change from baseline 0.07 (–0.14 to –0.28)

–0.33 (–0.55 to –0.12)

–0.67(–0.88 to –0.45)

–0.92(–1.14 to –0.69)

P value NT <0.0001† <0.0001†

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.


Mercury

ID: 732H

Q11N

P051


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


*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)


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Body Weight and Waist Circumference

Placebo +Metformin

(N=137)


Metformin (N=137)


Metformin (N=137)


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 <0.0001† <0.0001† <0.0001†

Patients with body weight reductions ≥5% compared to placebo

Proportion of patients (%) 18.1(9.9 to 26.3)

19.5(11.2 to 27.9)

22.1(13.5 to 30.6)

Waist circumference (cm)

Change from baseline –1.3(–2.3 to –0.4)

–1.7(–2.5 to –0.9)

–2.7(–3.5 to –1.9)

–2.5(–3.3 to –1.6)

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.



Add-on to Metformin Study: Adverse Events

Placebo + Metformin

(N=137)


Metformin (N=137)


Metformin (N=137)


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.


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Most Common Adverse Events ( ≥5% in Any Treatment Group)

Preferred termPlacebo + Metformin

(N=137)


Metformin (N=137)


Metformin (N=137)


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 (<1)

Data are number (%) of patients and include data after rescue.


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Adverse Events of Special Interest

Placebo + Metformin

(N=137)


Metformin (N=137)


Metformin (N=137)


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 (<1) 0 2 (1) 0

Data are number (%) of patients and include data after rescue. *None led to discontinuation from study. † None was a major event, defined as a symptomatic episode requiring third party assistance due to severe impairment in consciousness or behavior, with a capillary or plasma glucose value <3 mmol/L (54 mg/dL), and prompt recovery after glucose or glucagon administration. ‡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.


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Laboratory Parameters

Placebo + Metformin


Metformin


Metformin


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.


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Laboratory Parameters (c ont)

Placebo + Metformin


Metformin


Metformin


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.


Mercury

ID: 732H

Q11N

P051


Add-on to Metformin Study: Change in Blood Pressure , and Patients with Hypertension who Achieved Goal Blood Pressure at Week 24

Placebo + Metformin


Metformin


Metformin


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 <130/80 mm Hg. ǁx/n=number of patients achieving blood pressure goal at week 24/number of patients with a history of hypertension and not at blood pressure goal at baseline. ¶Data are percent difference versus placebo (95% CI), based on a post hoc analysis.


Mercury

ID: 732H

Q11N

P051


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


Mercury

ID: 732H

Q11N

P051


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)


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)


Mercury

ID: 732H

Q11N

P051

Add -on to Sulfonylurea Study: Study Design

Dapagliflozin 2.5 mg (n=154)

Dapagliflozin 5 mg (n=145)


Ran

dom

ized

(n=

597)

Patients entering on

ClinicalTrial.gov identifier: NCT00680745


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


Mercury

ID: 732H

Q11N

P051


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 <7%, at 24 weeks

� Exploratory endpoints– Seated systolic/diastolic blood pressure change from baseline at 24

weeks

� Safety data were also collected


Mercury

ID: 732H

Q11N

P051


−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)


(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* <0.0001 <0.0001 <0.0001

*Primary endpoint tested at α=0.019 applying Dunnett’s adjustment; SD = standard deviation; SE = standard error.

−0.58−0.63

−0.82

-0.9

-0.8

-0.7

-0.6

-0.5mean change from baseline ±±±± SE at

week 24



Mercury

ID: 732H

Q11N

P051

Add -on to Sulfonylurea Study: Changes in Body Weight at 24 Weeks


(n=145)


(n=154)


(n=142)


(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 <0.01 <0.0001

*Secondary endpoints tested following a sequential procedure at alpha=0.05; BW = body weight; NS = not significant; SD = standard deviation; SE = standard error

mean change from baseline ±±±± SE at

24 weeks

−1.56

−2.26

-2.5

-2.0

-1.5


Mercury

ID: 732H

Q11N

P051


Add -on to Sulfonylurea Study: Changes in OGTT Plasma Glucose Response at 24 weeks

+ glimepiridePlacebo

(n=145)


(n=154)


(n=142)


(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 <0.01 <0.0001

*Secondary endpoints tested following a sequential procedure at alpha=0.05; NT= not tested; OGTT = oral glucose tolerance test;SD = standard deviation; SE = standard error

adjusted mean change from baseline ±±±± SE at

week 24

−37.5

−32.0

−34.9

-40

-35

-30

-25


Mercury

ID: 732H

Q11N

P051


Add -on to Sulfonylurea Study: Glycemic Response at 24 Weeks

Adjusted proportion of patients (%) with HbA1c <7% at week

Placebo Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapaglif lozin 10 mg+ glimepiride

(n=145)+ glimepiride



(n=151)

26.8

30.331.7

20

25

30

35

40

*Secondary endpoints tested following a sequential procedure at alpha=0.05; CI = confidence interval; NT= not tested

1c24 ±±±± 95% CI

13.0

5

10

15

Week 24 (LOCF) adjusted proportion of patients (%) with HbA1c <7%

13.0 26.8 30.3 31.7

95% confidence interval 7.6 to 18.4 20.2 to 33.3 23.4 to 37.1 24.7 to 38.7

p versus placebo* NT <0.01 <0.0001


Mercury

ID: 732H

Q11N

P051


Add -on to Sulfonylurea Study: Changes in Blood Pressure at 24 Weeks


(n=145)


(n=154)


(n=142)


(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


Mercury

ID: 732H

Q11N

P051


Add -on to Sulfonylurea Study: Safety Results

Patients with adverse events


(n=146)

Dapagliflozin 2.5 mg

+ glimepiride(n=154)

Dapagliflozin 5 mg


Dapagliflozin 10 mg


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%


Mercury

ID: 732H

Q11N

P051


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


Mercury

ID: 732H

Q11N

P051


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).



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).


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 <6.1 mmol/L or maximum tolerated dose reached


Mercury

ID: 732H

Q11N

P051


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


Mercury

ID: 732H

Q11N

P051


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


Mercury

ID: 732H

Q11N

P051


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<0.0001

p<0.0001

Sulfonylurea Comparator Study: W eight Changes at 52 Weeks

−3.2

-4

-3

-2

-1

0

2.5%0%

5%

10%

15%

20%

25%Weight change

(kg)*

Proportionof patientswith weightreduction ≥5%†

*Data are adjusted mean change from baseline

†Data are adjusted percent


Mercury

ID: 732H

Q11N

P051


Sulfonylurea Comparator Study: Other Changes From Baseline with Dapagliflozin Compared with Glipizide

� ↓ Systolic blood pressure (nominal p<0.0001)

� ↓ Diastolic blood pressure

� ↑ HDL (nominal p<0.0001)

Mercury ID

: 732HQ

11NP

051

� ↑ HDL (nominal p<0.0001)



30%

40%

50%

Proportion of patients

40.8%

p<0.0001

Sulfonylurea Comparator Study: H ypoglycemia by 52 Weeks

Mercury ID

: 732HQ

11NP

051

*Data are adjusted percent

0%

10%

20%

30%with ≥1 episode of

hypoglycemiaby 52 weeks*

3.5%

Dapagliflozin+ metformin

(n=400)

Glipizide+ metformin

(n=401)



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



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 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



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


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



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



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



• 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


(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

Les inhibiteurs de SGLT2 - ACTUALITÉS … · Rôle du rein dans l’homéostasie glucidique • 3...

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Transcript of Les inhibiteurs de SGLT2 - ACTUALITÉS … · Rôle du rein dans l’homéostasie glucidique • 3...