The document summarizes diabetes statistics and information in the United States. It states that in 2011 there were 25.8 million people in the US with diabetes, including 18.8 million diagnosed cases and 7 million undiagnosed cases. Diabetes is the seventh leading cause of death. The total annual cost of diagnosed diabetes in the US is estimated at $174 billion.

2. 2011 U.S Diabetes Statistics
• Diabetes affects 25.8 million people in the US (8.3%
of the U.S. population)
– 18.8 million diagnosed, 7.0 million undiagnosed
• 10.9 million (26.9%) of those aged ≥65 have diabetes
• 215,000 people <20
• 79 million US adults >20 years estimated to have had
prediabetes in 2010
• 7th leading cause of death in the U.S.
www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

3. Percentage of U.S. Adults With Diagnosed
Diabetes
1994 2000
No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%
2009
www.cdc.gov/diabetes/statistics

4. Cost of Diabetes
• Total (direct and indirect) estimated diabetes costs in
the US in 2007 = $174 billion
– Medical expenses for people with diabetes are more than
two times higher than for people without diabetes
• A 50 year old with diabetes dies, on average, 6 years
earlier than someone without diabetes
Emerging Risk Factors Collaboration. NEJM. 2011; www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

5. Type 2 Diabetes Pathophysiology
1Bergenstal RM, et al. Endocrinology. 2001; 2DeFronzo RA. Diabetes. 1988; 3Poitout V, et al. Endocrinology. 2002.
Gluco-
lipotoxicity
 Production of glucose
in the liver1,2
Acquired/genetic factors (obesity)1,2
 FFA1-3
Type 2 DM1
Inherited/acquired factors
 Glucose uptake1,2
Insulin deficiency,
inappropriate glucagon
secretion1,3
Insulin resistance1
Hyperglycemia1-3
FFA=free fatty acid
Decreased Incretin
Effect

6. Current Therapeutic Targets
Dopamine Analogs
Pramlintide
BRAIN PANCREAS
Insulin
GLP-1 Agonists
DPP-4 Inhibitors
Sulfonylureas
Pramlintide (α cells only)
Meglitinides
LIVER
Metformin
Thiazolidinediones (TZD)
GI TRACT
GLP-1 Agonists
Alpha Glucosidase
Inhibitors
MUSCLE/FAT
Metformin
Thiazolidinediones
(TZD)
?? KIDNEY ??

7. Updated ADA/EASD Consensus Algorithm
Nathan DM, et al. Diabetes Care. 2009.
At Diagnosis:
Lifestyle
+
Metformin Lifestyle + Metformin
+
Sulfonylurea
Lifestyle + Metformin
+
Basal Insulin
Lifestyle +
Metformin +
Intensive Insulin
Lifestyle + Metformin
+
Pioglitazone
No hypoglycemia,
edema/CHF, bone loss
Lifestyle + Metformin
+
GLP-1 agonist
No hypoglycemia,
weight loss,
nausea/vomiting
Lifestyle + Metformin
+
Basal Insulin
Lifestyle + Metformin
+
Pioglitazone
+
Sulfonylurea
STEP 1 STEP 2 STEP 3
Tier 2: Less well-validated therapies
Tier 1: Well-validated therapies

8. AACE/ACE DIABETES ALGORITHM
FOR GLYCEMIC CONTROL
American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control.
Available at https://www.aace.com/publications.

9. Risks of Current Therapies: Weight Gain
Met-
formin
DPP-4
Inhib-
itor
GLP-1
Agonist
SU Glinide TZD AGI Insulin
Pram-
lintide
Weight Gain
Met-
formin
DPP-4
Inhib-
itor
GLP-1
Agonist
SU Glinide TZD AGI Insulin
Pram-
lintide
Hypoglycemia
Neutral
Benefits
Causes

10. The Kidneys Play an Important Role in the
Handling of Glucose
Wright EM, et al. J Intern Med. 2007.
• Total glucose stored in body ~450 g
• Glucose utilization ~250 g/day
• Brain ~125 g/day
• Rest of body ~125 g/day
• Glucose in Western diet ~180 g/day
• Renal glucose production (gluconeogenesis + ~70 g/day
glycogenolysis)
• Renal glucose filtration and reabsorption ~180 g/day
• Urinary glucose 0 g

11. Sodium-Glucose Cotransporters
SGLT1 SGLT2
Site Mostly intestine with some kidney Almost exclusively kidney
Sugar specificity Glucose or galactose Glucose
Affinity for glucose
High
Km = 0.4 Mm
Low
Km = 2 Mm
Capacity for glucose
transport
Low High
Role
Dietary glucose absorption
Renal glucose reabsorption
Renal glucose reabsorption
Lee YJ, et al. Kidney Int Suppl. 2007.

12. Altered Renal Glucose Control in Diabetes
• Renal gluconeogenesis is increased in
patients with Type 2 DM
• Renal contribution to hyperglycemia
• 3-fold increase relative to patients without
diabetes
• Glucose reabsorption
• Increased SGLT2 expression and activity in renal
epithelial cells from patients with diabetes vs.
normoglycemic individuals
Marsenic O. Am J Kidney Dis. 2009; Bakris GL, et al. Kidney Int. 2009;
Rahmoune H, et al. Diabetes. 2005.

13. Rationale for SGLT2 Inhibitors
• The SGLT2 is a glucose transporter responsible for 90% of
glucose reabsorption
• Selective SGLT2 inhibitors could reduce blood glucose levels due
to increased renal excretion of glucose
• Mutations in the SGLT2 transporter linked to hereditary renal
glycosuria, a relatively benign condition in humans
• Selective SGLT2 inhibition would cause urine loss of the calories
from glucose (200-300 kcal/day), also potentially leading to
weight loss
Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J Clin Endocrinol Metab. 2010.

14. Effects of SGLT2 Inhibitors
Inhibition of renal tubular Na+-glucose cotransporter
Reversal of hyperglycemia
Reduction of “glucotoxicity”
Insulin sensitivity in muscle and liver
Gluconeogenesis
Improved beta cell function
Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J Clin Endocrinol Metab. 2010.

15. SGLT2 Inhibitors in
Phase 3 Development
• Dapagliflozin
• Canagliflozin
• Empagliflozin
• Ipragliflozin
• Tofogliflozin

16. Empagliflozin: Change in A1C
N = 408
Baseline A1C = 7.9%
*P<.001 vs. placebo
†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
-0.8
-0.6
-0.4
-0.2
0
0.2
*
*
*
*
5 mg 25 mg10 mg Metformin
Placebo
ChangeinA1C(%)
Ferrannini E, et al. Abstract 877. EASD 2010.
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin†

17. Empagliflozin: Change in FPG
N = 408
*P<.001 vs. placebo
†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
Ferrannini E, et al. Abstract 877. EASD 2010.
-35
-30
-25
-20
-15
-10
-5
0
5
*
**
*
Placebo
5 mg 10 mg 25 mg Metformin
ChangeinFPG(mg/dl)
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin†

18. Empagliflozin: Change in Weight
*
N = 408
Baseline BMI = 29 kg/m2
*P<.001 vs. placebo
†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
Ferrannini E, et al. Abstract 877. EASD 2010.
-2.5
-2
-1.5
-1
-0.5
0
*
*
*
Placebo 5 mg 10 mg 25 mg Metformin
Changeinweight(%)
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin†

19. Empagliflozin: Safety Considerations
Side effects:
– Polyuria (3.3% vs. 0% in placebo), thirst (3.3% vs. 0% in
placebo), and nasopharyngitis (2% vs. 1.2% in placebo)
were the most frequently reported side effects
– UTI 1.2% vs. 1.2% in placebo and 1.3% in metformin
Ferrannini E, et al. Abstract 877. EASD 2010.
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin†

20. Canagliflozin: Change in A1C
*P<.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.
N = 451
-0.22%
-0.79% -0.76%
-0.7%
-0.92% -0.95%
-0.74
-1
-0.8
-0.6
-0.4
-0.2
0
PBO 50 mg 100 mg 200 mg 300 mg 300 mg BID SITA 100 mg
ChangeinA1C(%)
*
**
*
Mean Baseline A1C (%) 7.71 8.01 7.81 7.57 7.70 7.71 7.62
*
*
Canagliflozin add-on to metformin, double-blind, placebo-
controlled, dose-ranging study (Phase 2)

21. Canagliflozin: Change in FPGChangeinFPG(mg/dl)
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
N = 451
Baseline FGP 162 mg/dl)
*P<.001 vs. placebo calculated using LS means
-16.2
-25.2
-32.4 -32.4
-30.6
-18
-35
-30
-25
-20
-15
-10
-5
0
50 mg 100 mg 200 mg 300 mg 300 mg BID SITA 100 mg
*
*
* * *
*
Canagliflozin add-on to metformin, double-blind, placebo-
controlled, dose-ranging study (Phase 2)

22. Canagliflozin: Change in Weight
N = 451
Baseline weight 87 kg
*P<.01 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.
-1.1
-2.3%
-2.6% -2.7%
-3.4% -3.4%
-0.6%
-4
-3
-2
-1
0
PBO 50 mg 100 mg 200 mg 300 mg 300 mg BID SITA 100 mg
Changeinweight(%)
Mean Baseline Weight (kg) 85.5 87.5 87.7 87.7 87.8 86.3 87
*
* *
* *
Canagliflozin add-on to metformin, double-blind, placebo-
controlled, dose-ranging study (Phase 2)

23. Canagliflozin: Safety Considerations
Side effects:
– Mild-to-moderate, transient
– Non dose-dependent increase in symptomatic genital
infections: 3-8% in canagliflozin vs. 2% in placebo and 2% in
sitagliptin
– UTI: 3-9% in canagliflozin (no dose-dependency) vs. 6% in
placebo and 2% in sitagliptin
– Hypoglycemia: 0-6% in canagliflozin (no dose dependency)
vs. 2% in placebo and 5% in sitagliptin
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Canagliflozin add-on to metformin, double-blind, placebo-
controlled, dose-ranging study (Phase 2)

24. Effects of Canagliflozin on
Vulvovaginal Candida Colonization (VCC)
– Relative to PBO/SITA, CANA treatment increased
conversion to positive vaginal Candida culture and
VVC events
– Incidence of VVC in female subjects was 2.9% and
3.7% with PBO and SITA, respectively, and 10.4%
with CANA
– None of the VVC events were serious or led to
discontinuation; most were treated with topical or
oral antifungals, and resolved without study drug
interruption
Nyirjesy P, et al. Abstract 0032-LB. ADA 2011.

25. Bacteria or UTI Incidence with
Canagliflozin
– At Week 12, CANA decreased A1C (0.45%-0.73% relative to PBO),
lowered weight (1.3%-2.3% relative to PBO), and increased urinary
glucose excretion (UGE) (35.4-61.6 mg/mg creatinine)
– Conversion from negative baseline urine bacterial culture to
positive culture did not differ in pooled CANA group vs pooled
PBO/SITA group (4.8% vs. 3.7%, respectively)
– UTI AEs (both symptomatic and positive post-baseline urine
culture reported as a UTI) occurred in 16 (5.0%) in pooled CANA
group and 5 (3.8%) in pooled PBO/SITA group
– All UTI AEs considered mild or moderate, and none led to
discontinuation
Nicolle L, et al. Abstract 0043-LB. ADA 2011.

26. Dapagliflozin Phase 3 Studies:
Change in A1C
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Monotherapy
Met add-on
SU add-on
Insulin add-on
ChangeinA1C(%)
Placebo
Dapa
2.5mg
Dapa
5mg
Dapa
10mg
Wilding JPH, et al. Abstract 871. EASD 2010;
Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Baseline-
Monotherapy (N=591): 8.6%
Met add-on (N=546): 8%
SU add-on (N=597): 8.1%
Insulin add-on (N=808): 8.5%

27. ChangeinFPG(mg/dl)
Placebo
Dapa
2.5mg
Dapa
5mg
Dapa
10mg
Baseline-
Monotherapy (N=591): 179 mg/dl
Met add-on (N=546): 163.9 mg/dl
Insulin add-on (N=808): 178 mg/dl
Wilding JPH, et al. Abstract 871. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Dapagliflozin Phase 3 Studies:
Change in FPG
-35
-30
-25
-20
-15
-10
-5
0
5
Monotherapy
Met add-on
Insulin add-on

28. -3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
Monotherapy
Met add-on
SU add-on
Insulin add-on
Changeinweight(kg)
Placebo
Dapa
2.5mg
Dapa
5mg
Dapa
10mg
Baseline-
Monotherapy (N=591): 89.7 kg
Met add-on (N=546): 85.9 kg
SU add-on (N=597): 81.1 kg
Insulin add-on (N=808): 94 kg
Wilding JPH, et al. Abstract 871. EASD 2010;
Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Dapagliflozin Phase 3 Studies:
Change in Weight

29. Dapagliflozin, Metformin XR, or Both as
Initial Therapy
-3
-2
-1
0
-80
-60
-40
-20
0
-4
-3
-2
-1
0
M
E
T
D
A
P
A
5
m
g
D
A
P
A
+
M
E
T
D
A
P
A
+
M
E
T
D
A
P
A
1
0
m
g
M
E
T
M
E
T
D
A
P
A
5
m
g
D
A
P
A
+
M
E
T
D
A
P
A
+
M
E
T
D
A
P
A
1
0
m
g
M
E
T
M
E
T
D
A
P
A
5
m
g
D
A
P
A
+
M
E
T
D
A
P
A
+
M
E
T
D
A
P
A
1
0
m
g
M
E
T
Change in A1C Change in FPG
Change in Body Weight
Henry R, et al. Abstract 307-OR.
ADA 2011.

30. Dapagliflozin: Effect on BP and Lipids
HDL (% change)
– Placebo: +0.4
– Dapa 2.5mg: +1.8
– Dapa 5mg: +3.3
– Dapa 10mg: +4.4
Triglycerides (% change)
– Placebo: +2.1
– Dapa 2.5mg: -2.4
– Dapa 5mg: -6.2
– Dapa 10mg: -6.2
Systolic Blood Pressure (mmHg)
– Placebo: -0.2
– Dapa 2.5mg: -2.1
– Dapa 5mg: -4.3
– Dapa 10mg: -5.1
Diastolic Blood Pressure (mmHg)
– Placebo: -0.1
– Dapa 2.5mg: -1.8
– Dapa 5mg: -2.5
– Dapa 10mg: -1.8
Bailey CJ, et al. Lancet. 2010.

31. Dapagliflozin: Safety Considerations
Based on all trials (Monotherapy, metformin add-on,
sulfonylurea add-on, and insulin add-on)
Side effects:
– UTI*: 3.9-13.2% in dapagliflozin vs. 4-6.2% in placebo1-3
– Genital infections*: 3.9-12.9% in dapagliflozin vs. 0.7-5% in
placebo1-4
– Hypoglycemia: 0-7.9% in dapagliflozin vs. 2.7-4.8% in
placebo2-4
*Most occurred during the first 24 weeks, were generally mild, and responded to
routine management
1Wilding JPH, et al. Abstract 871. EASD 2010;
2Strojek K, et al. Abstract 870. EASD 2010;
3Ferrannini E, et al. Diabetes Care. 2010; 4Bailey CJ, et al. Lancet. 2010.

32. Dapagliflozin:
Sulfonylurea Comparator Study
Results
• Average A1C: 7.72%
• Change in A1C: -0.52% for dapagliflozin vs. -0.52% for glipizide
• Weight change: -3.2 kg for dapagliflozin vs. +1.4 kg for glipizide
• Hypoglycemic episodes: 3.5% for dapagliflozin vs. 40.8% with glipizide
• Significant reductions in diastolic and systolic blood pressure and
improvement in HDL with dapagliflozin vs. glipizide (P<.0001)
• Side effects:
• UTI: 10.8% with dapagliflozin vs. 6.4% with glipizide (actively solicited)
• Genital infection: 12.3% with dapagliflozin vs. 2.7% with glipizide (actively
solicited)
• Renal impairment: 5.9% with dapagliflozin vs. 3.4% with glipizide
Nauck MA, et al. Diabetes Care. 2011.
Randomized, double-blind, parallel-group, multicenter trial
comparing dapagliflozin to glipizide as add-on to metformin

33. Dapagliflozin + Insulin for 48 Weeks
Wilding J, et al. Abstract 0021-LB. ADA 2011.
• A1C reductions from baseline for PLA and DAPA 2.5, 5, and
10mg at 24 weeks were maintained at 48 weeks
– (−0.43%, −0.74%, −0.94%, −0.93%, respectively)
• 24 week body weight reductions with DAPA were maintained
at 48 weeks
– −1.5kg with DAPA 10mg vs. +0.9kg with PLA
• AEs, serious AEs, and discontinuations were balanced across
all groups
• Actively solicited s/sx suggestive of UTI and genital infections
(GI) were more with DAPA vs PLA
– UTI 7.9%-10.8% vs. 5.1%; GI 6.4%-10.7% vs. 2.5%
– most events were reported during the first 24 weeks, were of
mild/moderate intensity and responded to standard treatment
AE = Adverse events
s/sx = signs and symptoms

34. Dapagliflozin + Insulin for 48 Weeks:
Insulin Dose
Wilding J, et al. Abstract 0021-LB. ADA 2011.
15
10
5
0
-5
0 4 8 12 16 20 24 28 32 36 40 44 48
Timepoint (weeks)
PLA + INS
DAPA 2.5 mg + INS
DAPA 5 mg + INS
DAPA 10 mg + INS
Insulindose(IU/day)
Adjustedmeanchangefrombaseline±SE

35. Long-Term Efficacy of Dapagliflozin + Metformin
Week 102 Results
Adj. Mean ∆
From Baseline
PBO+MET
DAPA 2.5mg +
MET
DAPA 5mg +
MET
DAPA 10mg +
MET
A1C, % 0.02 -0.48 -0.58 -0.78
FPG, mg/dL -10.4 -19.3 -26.5 -24.5
Weight, kg -0.7 -2.2 -3.4 -2.8
% with ≥1
hypoglycemic
event
5.8 3.6 5.1 5.2
Bailey CJ, et al. Abstract 0988-P. ADA 2011.

36. Potential SGLT2 Safety Considerations???
• Evidence Demonstrates
• Urinary tract/genital infections
• Questions
• Hepatic toxicity?
• Breast and bladder cancer??
• Intravascular volume depletion due to osmotic diuresis??
• Nephrotoxicity (AGEs)??
• Drug-drug interactions??
• Evidence Does Not Demonstrate
• Electrolyte imbalance (Na+, K+, Ca++, PO4)
• Increased risk for hypoglycemia
• Nocturia

37. Dapagliflozin PDUFA Date
The FDA issued a Complete Response Letter to the makers
of dapagliflozin on January 19, 2012 requesting additional
information.

38. SGLT2 Inhibitors:
A New Era in Diabetes Treatment??
• In treatment-naive patients with newly-diagnosed
Type 2 DM, SGLT2 inhibitors resulted in:
• Clinically meaningful decreases in A1C and fasting
plasma glucose with no increased risk of hypoglycemia
• Also improved glycemic control in combination with a
variety of other antihyperglycemic agents
• Metformin, sulfonylureas, insulin
• Side effects generally appear to be mild and transient,
while avoiding increased risk of hypoglycemia or
weight gain