Part 10

FPG (mg/dL)

Baseline Day 8 Day 15

Vehicle (n=6)0.01 mg/kg (n=6)0.1 mg/kg (n=6)1 mg/kg (n=6)10 mg/kg (n=6)

0

100

200

300

400

*P<0.05; †P<0.0001 vs vehicle. ZDF=Zucker diabetic fatty.

Han S, et al. Diabetes. 2008;57:1723-1729; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P.

Effects of Dapagliflozin on Fasting Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF RatsPlasma Glucose in ZDF Rats

*

*

*

†

†* †

Hep

atic Glu

cose P

rod

uctio

n(m

g/kg

• min

)G

luco

se I

nfu

sio

n R

ate

(mg

/kg

• m

in)

0

1.0

2.0

3.0

4.0

0

2.0

4.0

6.0

8.0

CON DAPA CON DAPA

P<0.01

P<0.01

CON=controls; DAPA=dapagliflozin.

Han S, et al. Diabetes. 2008;57:1723-1729.

Effect of Dapagliflozin on Insulin-Stimulated Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Glucose Disposal and Hepatic Glucose Production in ZDF RatsProduction in ZDF Rats

Dapagliflozin-Induced GlucosuriaDapagliflozin-Induced GlucosuriaReduces HbAReduces HbA1c1c: A Dose-Ranging Trial: A Dose-Ranging Trial

Study designStudy design

• 12 week, double-blind, placebo-controlled12 week, double-blind, placebo-controlled

– Dapagliflozin: 2.5, 5, 10, 50 mg/dayDapagliflozin: 2.5, 5, 10, 50 mg/day

– Metformin XR: 1500 mg/dayMetformin XR: 1500 mg/day

– PlaceboPlacebo

PatientsPatients• 389 drug-naive T2DM patients

• HbA1c >7.0%

MeasurementsMeasurements • FPG, PPG, HbA1c

List JF, et al. Diabetes Care. 2009;32:650-657.

Baseline HbA1c (%) 7.7 8.0 8.0 7.8 7.9 7.7

All comparisons vs placebo; no statistical comparisons with metformin were made.

List JF, et al. Diabetes Care. 2008;2009;32:650-657.

P<0.01 P<0.01

P<0.01

Effect of Dapagliflozin on HbAEffect of Dapagliflozin on HbA1c1c

Δ HbA1c (%)

P<0.01 -1

-0.8

-0.6

-0.4

-0.2

0DAPA

2.5DAPA

5DAPA

10DAPA

50PBO MET MET

XRXR15001500

Dapagliflozin: Glucosuric and Dapagliflozin: Glucosuric and Metabolic EffectsMetabolic Effects

GlucosuriaGlucosuria ↑ 52-85 g/day52-85 g/day

FPGFPG ↓ 16-30 mg/dL

PPGPPG ↓ 23-29 mg/dL

Body weightBody weight ↓ 2.2-3.2 kg (↓ 2.5%-3.4%)

Urine volumeUrine volume ↑ 107-470 mL/day

List JF, et al. Diabetes Care. 2009;32:650-657.

Adverse Events With DapagliflozinAdverse Events With Dapagliflozin

PBO(n=54)

Met 1500 mg QD(n=56)

Dapa 2.5 mg QD(n=59)

Dapa 5 mg QD(n=58)

Dapa 10 mg QD(n=47)

Dapa 20 mg QD(n=59)

Dapa 50 mg QD(n=56)

Hypoglycemia, n (%)

2 (4) 5 (9) 4 (7) 6 (10) 3 (6) 4 (7) 4 (7)

UTIs, n (%) 3 (6) 5 (9) 3 (5) 5 (9) 5 (11) 7 (12) 5 (9)

Genital infection, n (%)

0 (0) 1 (2) 2 (3) 1 (2) 1 (2) 4 (7) 4 (7)

Hypotensive event, n (%)

1 (2) 2 (4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)

UTI=urinary tract infection.

List JF, et al. Diabetes Care. 2009;32:650-657.

Investigational SGLT2 InhibitorsInvestigational SGLT2 Inhibitors

AgentAgent ManufacturerManufacturer

Phase IIIPhase III DapagliflozinDapagliflozin AstraZeneca/Bristol-Myers Squibb

Phase IIPhase II AVE-2268 sanofi-aventis

BI 10773 Boehringer Ingelheim

JNJ-28431754 Johnson & Johnson

Remogliflozin

Sergliflozin

GSK/Kissei

TS-033 Taisho

YM-543 Astellas/Kotobuki Pharmaceuticals

Phase IPhase I CSG-452A Chugai/Roche

SAR-7226 sanofi-aventis

TA-7284 Mitsubishi Tanabe/Johnson & Johnson

• Highly specific for the kidney and SGLT2 transporter

• ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1

• Marked reduction in FPG, PPG, and HbA1c in all three species

• No changes in plasma or urine electrolytes

Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR.

ISIS 388626 – A Specific SGLT2ISIS 388626 – A Specific SGLT2Antisense OligonucleotideAntisense Oligonucleotide

Unanswered Questions About Unanswered Questions About SGLT2 InhibitionSGLT2 Inhibition

DurabilityDurabilityThe efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range

Safety and Safety and tolerabilitytolerability

The long-term safety of this class remains to be proven

Risk of nocturia and genitourinary infections may limit use in some patients

Renal Renal impairmentimpairment

SGLT2 inhibition may not be effective in patients with renal impairment

SGLT2 Inhibition: Meeting UnmetSGLT2 Inhibition: Meeting UnmetNeeds in Diabetes CareNeeds in Diabetes Care

WeightManagement

Type 2Diabetes

Multiple Defects in Type 2

Diabetes

Adverse Effectsof Therapy

Hyperglycemia

CVD Risk(Lipid and

HypertensionControl)

Improvements inImprovements inGlucose and WeightGlucose and Weight

Support OtherSupport OtherCVD InterventionsCVD Interventions

ComplementsAction of Other

AntidiabeticAgents

PromotesPromotesWeight LossWeight Loss

Corrects a NovelCorrects a NovelPathophysiologicPathophysiologic

DefectDefectNo HypoglycemiaNo Hypoglycemia

ImprovesImprovesGlycemicGlycemicControlControl

ConclusionsConclusions

• SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes

• Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity

– Restores normoglycemia– Improves -cell function and insulin sensitivity

ConclusionsConclusions

• Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans

• Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes

Overall ConclusionsOverall Conclusions

• Understanding of the pathophysiology of type 2 diabetes is an evolving process

• As new concepts emerge, there is potential for new treatment modalities

• Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis