Part 10. FPG (mg/dL) BaselineDay 8Day 15 Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg...
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Transcript of Part 10. FPG (mg/dL) BaselineDay 8Day 15 Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg...
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