This document discusses SGLT2 inhibitors as a treatment option for type 2 diabetes mellitus. It provides background on normal glucose homeostasis and the pathophysiology of hyperglycemia in diabetes. SGLT2 inhibitors work by inhibiting glucose reabsorption in the kidneys, causing it to be excreted in the urine. Clinical trial data shows SGLT2 inhibitors like dapagliflozin provide glycemic control as monotherapy or add-on therapy with other oral agents or insulin, with additional benefits of weight loss and blood pressure reduction. Long-term studies over 4 years show sustained glycemic control with dapagliflozin compared to other oral antidiabetic drugs.

1. 1
SGLT2 Inhibitors- A Therapeutic
Option Across the Continuum of
T2DM
Aizikovich Alex MD

2. 2

3. 3
SGLT2 Inhibitors- A Therapeutic
Option Across the Continuum of
T2DM

4. 4

5. 5

6. CORE - 6
SGLT2
Inhibitors
TZDs
Metformin
Site of Action: Oral Antidiabetic Agents
Increased
HGP
Hyperglycemia
ETIOLOGY OF T2DM
DEFN75-3/99
Decreased Glucose
Uptake
Impaired Insulin
Secretion
Increased Lipolysis
HYPERGLYCEMIA
Metformin
TZDs
GLP-1 RA
GLP-1 RA
TZDs
DPP4i
SU
GLP-1 RA
GLP-1 RA
DPP4i
GLP-1 RA
AGIs
TZDs
GLP-1 RA
TZDs
DPP4i
SU
GLP-1 RA
AGIs
TZDs

7. 7
Multiple pathophysiological failures contribute
to hyperglycaemia - The "Ominous Octet"
Adapted from: DeFronzo RA. Diabetes 2009;58:773–95. Wolters Kluwer Health
Islet α-cell
Increased
lipolysis
Increased glucose
reabsorption
Increased glucagon
secretion
Increased
hepatic glucose
production
Neurotransmitter dysfunction
Decreased
glucose uptake
Islet β-cell
Decreased incretin effect
Impaired insulin
secretion
Hyper-
glycaemia

8. 8
Normal glucose homeostasis1,2
1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18.
2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50.
• Brain ~125 g/day
• Rest of the body ~125 g/day
Glucose uptake ~250 g/day:
• Dietary intake ~180 g/day
• Glucose production ~70 g/day
• Gluconeogenesis
• Glycogenolysis
+ −
Net balance ~0 g/day
Glucose input ~250 g/day:
The kidney reabsorbs
and recirculates glucose
Glucose reabsorbed
~180 g/day
Glucose filtered
~180 g/day
The kidney filters
circulating glucose

9. 9
Glucose handling in Type 2 diabetes1,2
*Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis.2
1. Gerich JE. Diabet Med 2010;27:136–42; 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:782–90.
• Dietary intake >180 g/day
• Glucose production ~100 g/day
• Gluconeogenesis*
• Glycogenolysis
Glucose input >280 g/day:
• Brain ~125 g/day
• Rest of the body >125 g/day
Glucose uptake >250 g/day:
−Increased
reabsorption and
recirculation of
glucose
Average blood glucose
concentration 150 mg/dL
Kidney filters all
circulating glucose
Above the renal threshold for
glucose (~200 mg/dL), glucose is
excreted in the urine (glucosuria)
+
Glucose filtered
~270 g/day

10. The kidneys filter and reabsorb 180 g of glucose
per day in the nephrons by active transport
10Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246;
Washburn WN. J Med Chem 2009;52(7):1785‐1794
Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys
SGLT1
10%
Proximal tubule
S1
Glomerulus Distal tubule
Loop
of
Henle
Collecting duct
Glucose
filtration
Glucose
reabsorption
S3
~10% of glucose
is reabsorbed
from the S3 segment
180 g glucose
filtered
each day
Up to ~90% of glucose
is reabsorbed
from the S1 segments
Minimal
glucose
excretion
SGLT2
90%
Volume of plasma kidneys filter/day = 180 L
Normal glucose concentracion = 1000 mg/L (100 mg/dl)
Glucose filtered/day = (180 L/day) (1000 mg/L) = 180 G

11. The kidneys filter and reabsorb 180 g of glucose
per day in the nephrons by active transport
11Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246;
Washburn WN. J Med Chem 2009;52(7):1785‐1794
Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys
SGLT1
10%
Proximal tubule
S1
Glomerulus Distal tubule
Loop
of
Henle
Collecting duct
Glucose
filtration
Glucose
reabsorption
S3
~10% of glucose
is reabsorbed
from the S3 segment
180 g glucose
filtered
each day
Up to ~90% of glucose
is reabsorbed
from the S1 segments
GLUCOSE
SGLT2
90%
Volume of plasma kidneys filter/day = 180 L
Normal glucose concentracion = 1000 mg/L (100 mg/dl)
Glucose filtered/day = (180 L/day) (1000 mg/L) = 180 G
SGLT2i

13. SLGT2 Inhibitors - Regulatory Status
•Dapagliflozin, Canagliflozin and Empagliflzoin are EMA and FDA approved
•Dapagliflozin FORXIGA is approved in MEUHEDET

16. 16
A Thorough and Extensive Clinical Development Program:
11,801 Patients Treated
Mono-
therapy
Add-on to
Oral agents
Add-on to
Insulin
Active
Comparator
Overweight/
Obesity CVD
Dapagliflozin Clinical Development Program
92-012
Japan
Open Label
N=728
009
Add-on to
Insulin
N=75
045
Insulin
Sensitivity
N=44
035
Renal
Function
N=75
054
China
MonoTx
N=393
92-006
Japan
MonoTx
N=261
008
MonoTx
N=389
018
Pts with
CVD+HTN
N=922
019
Pts with
CVD
N=965
013
MonoTx
N=558
032
Low dose
N=282
014
Add-on to
Metformin
N=546
90-005
Add-on to
SU
N=596
030
Add-on to
TZD
N=420
010
Add-on to
DPP4i
N=451
90-006
Add-on to
Insulin
N=807
92-005
Japan
MonoTx
N=279
Glycemic Efficacy
MoA
Phase 2b/
Dosing
Relevant
Co-morbidities
Regional
Studies
073
HTN
ACEi/ARB
N=944
077
HTN
ACEi/ARB
+add’l
anti-HTN
N=582
034
Dapa 10mg
Init Comb
with Met
and vs Met
N=638
021
Dapa 5mg
Init Comb
with Met
N=598
004
Add-on to
Met vs SU
N=814
Renal
Impairment
029
Moderate
Renal
Impairment
N=252
90-012
DXA / Body
Composition
N=182
Hypertension
Study D1691C00003 not included as it was not completed on time for the submission.
Study MB102-072 not included as it was studying a different indication.

17. Consistent reductions in HbA1c across a broad range
of commonly prescribed treatments
*Statistically significant versus placebo using Dunnett’s correction (p<0.0001); †Statistically significant versus placebo (p<0.0001); ‡p<0.001.
OAD, oral antidiabetic drug.
1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928–38; 4. Jabbour SA, et al.
Diabetes Care 2014;37:740–50; 5. Wilding JPH, et al. Ann Intern Med 2012;156:405–15.
Dapagliflozin
Placebo
(24 weeks)

18. Consistent reductions in HbA1c across a broad range of
treatments in patients with baseline HbA1c ≥9%
NR, not reported.
1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Katz A, et al. Diabetes 2014;63(Suppl. 1):A284.
(24 weeks)
Dapagliflozin
Placebo

19. FORXIGA delivers the additional benefit of weight loss
across a broad range of treatments
*Statistically significant versus placebo using Dunnett’s correction (p<0.0001); †Statistically significant versus placebo after sequential testing procedure (p<0.0001); ‡Statistically
significant versus placebo (p<0.0001); §p<0.001. Adjusted mean change from baseline using analysis of covariance, excluding data after rescue (last observation carried forward).
1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928–38; 4. Jabbour SA, et al.
Diabetes Care 2014;37:740–50; 5. Wilding JPH, et al. Ann Intern Med 2012;156:405–15; 6. FORXIGA®. Summary of product characteristics, 2014.
FORXIGA is not indicated for the management of obesity.6 Weight change was a secondary endpoint in clinical trials.2,6
(24 weeks)
Dapagliflozin
Placebo

20. 20
Significant Systolic Blood Pressure Reduction at Week 12
SourceTopline73/77.pptx–Slide35/41;Table7.2.1-1
-10.4
-7.3
-14
-12
-10
-8
-6
-4
-2
0
-11.9
-7.6
-14
-12
-10
-8
-6
-4
-2
0
AdjustedMean∆SeatedSBP
(mmHg)with95%CI
AdjustedMean∆SeatedSBP
(mmHg)with95%CI
Studies in Hypertensive Patients with Diabetes, -073 and -077
•Significant P-value. Repeated measures mixed model analysis
Weber, et al. Circulation 2013;128:A13144.
Weber, et al. Circulation 2013;128:A13165
Placebo
N=224
151.0 151.3
Study 073 Study 077
Dapa 10mg
N=225
BL (mmHg) 149.8 149.5
+ ACEi/ARB +add’l anti-HTN
Placebo
N=311
Dapa 10mg
N=302
+ ACEi/ARB
Diff vs Pbo (95% CI) -3.1 (-4.9, -1.2) -4.3 (-6.5, -2.0)
P-value 0.0010* 0.0002*

21. 21
BL 4 8 12 16 20 24
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
∆HbA1cwith95%CI
Study Week
BL 4 8 12 16 20 24
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
MET XR 2000mg
Dapa
10mg
Dapa 10mg + MET XR
Dapa 10mg MET XR 2000mg Dapa 10mg + MET XR
N 216 203 202
BL HbA1c (%) 9.03 9.03 9.10
Dapa + Metformin Superior to Individual Monotherapies
Dapa 10mg Initial Combination with Met and vs Met, -034
-1.98
-1.45
-1.44
Combination vs
Monotherapies
* Significantly superior to monotherapy.
Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF)
Henry et al. Int J Clin Pract, May 2012, 66, 5, 446–456.
R:CSR-034final
-0.53*
-0.54*

22. 22
Dif. −0.30%
(95% CI: −0.51, −0.09)
Dapagliflozin: glycaemic control over 4 years
vs glipizide
0.2
−1.0
−0.4
0.0
−0.6
−0.8
−0.2
0.4
ChangeinHbA1C(%)*
0 6 12 18 28 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208
Study week
Rescue therapy availableRescue therapy NOT available
Sample size (including data after rescue), n
DAPA + MET 400 321 233 79
GLIP + MET 401 315 208 71
DAPA + MET
GLIP + MET
0.20%
(95% CI: 0.05, 0.36)
−0.10%
(95% CI: −0.25, 0.05)
Week 208 values
Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions,
Chicago, USA; 21–25 June 2013: Abstract 62-LB.
DAPA, dapagliflozin; GLIP, glipizide; MET, metformin.
*Data are adjusted mean change from baseline ± 95% CI derived from a longitudinal repeated-measures mixed model.
Add-on to Metformin Compared to SU (Glipizide) Plus Metformin, -004

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1 4 8 12 16 20 24 32 40 48 52 65 78 91 104
-8
-4
0
4
8
12
16
20
24
∆MeanInsulinDose(IU/day)with95%CI
Study Week
Dapa 10mg + INS Placebo + INS
BL
Dapa + MET
Pbo + MET
Insulin Doses Remain Stable on Dapa Over 2 Years
Source:Study006Figure4,Table11.2.6.1.1
Add-on to Insulin, 90-006
Sample Size Per Time Point
Dapa 10mg+INS 189 185 180 177 175 173 166 145 146 144 142 140
Placebo+INS 185 176 170 168 164 158 157 121 118 114 110 104
Difference vs comparator
-19.2 ( -25.5, -12.9)
Repeated measures mixed model analysis, including data after insulin up-titration.
Wilding et al. Diabetes, Obesity and Metabolism16: 124–136, 2014
Baseline Insulin dose 77 IU/day

24. 24
Low Intrinsic Propensity to Cause Hypoglycemia
n / N (%) of Patients
Placebo-controlled studies Dapa 10mg Placebo
Total Patients with Event* 309 / 2360 (13.1) 242 / 2295 (10.5)
Major Episode* 2 / 2360 (0.1) 1 / 2295 (<0.1)
Monotherapy 2 / 70 (2.9) 2 / 75 (2.7)
Add-on to Met 5 / 135 (3.7) 4 / 137 (2.9)
Add-on to TZD 0 / 140 (0.0) 1 / 139 (0.7)
Add-on to DPP4i 5 / 225 (2.2) 3 / 226 (1.3)
Add-on to SU 11 / 151 (7.3) 7 / 146 (4.8)
Add-on to Insulin 83 / 196 (42.3) 69 / 197 (35.0)
n / N (%) of Patients
Active comparator studies Dapa 10mg Control
Dapa vs. SU (Add-on to Met) 14 / 406 (3.5)** 162 / 408 (40.8)**
Dapa vs. Met 2 / 219 (0.9) 6 / 208 (2.9)
* Placebo-controlled Pool
** Adjusted percent using modified logistic regression analysis
Source:30MUTable37;CSR004Table30;CSR034Table8.6.1
ST – 30MU

25. 25
Urinary Tract and Genital Infections*
Source:rl-ae-saeutilt23,30MUTables38,41,42
Number (%) of Patients
Dapa 10mg
N=2360
Placebo
N=2295
Infections of the Urinary Tract 110 (4.7) 81 (3.5)
Genital Infections 130 (5.5) 14 (0.6)
Dapa Total
N=5936
Control
N=3403
Pyelonephritis 7 (0.1) 7 (0.2)
Infections of the Urinary Tract SAEs 8 (0.1) 6 (0.2)
Genital Infection SAEs 1 (<0.1) 0
Placebo-controlled Pool, ST
All Phase 2b/3 Pool, ST + LT
30MU
*Based on prespecified lists of Preferred Terms

26. 26
Renal Function: Stable Over Time
Placebo-controlled Pool, ST + LT – 30MU
Source:rt-lb-gfrchgltplac,30MUAppendix273
MDRD = Modification of Diet in Renal Disease
Ptaszynska et al. Presented at the 74th Scientific Sessions of the American Diabetes Association (ADA), San Francisco, CA, USA, June 13–17, 2014
Number of Patients
Dapa 10mg 2026 1697 1655 1777 1600 1663 712 692 656 627
Placebo 1955 1629 1570 1671 1513 1558 605 585 551 521
Change in Estimated GFR (by MDRD)
BL
1 4 8 16 24 37 50 63 76 89 102
-15
-10
-5
0
5
10
15
eGFR(mL/min/1.73m2)
MeanChangefromBaseline
Dapa 10mg Placebo
Baseline Mean 81.0 80.7
(mL/min/1.73m2)

27. Dapagliflozin is not associated with an
increased of risk CV events
• A meta-analysis of CV events among 21 Phase IIb/III trials, showed no increase in the primary CV composite endpoint
of CV death, stroke, MI and hospitalisation for unstable angina with FORXIGA1,2
CV events were adjudicated by an independent committee.
CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; UA, unstable angina.
1. EMDAC background document. Available at:
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Last accessed September 2014;
2. FORXIGA®. Summary of product characteristics, 2014.
Dapagliflozin
Control

28. 28

29. 29

30. 30

31. 31
Dapagliflozin: Indication
Indication
Forxiga is indicated in adults aged 18 years and older with type 2 diabetes mellitus to
improve glycaemic control as:
Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for
whom use of metformin is considered inappropriate due to intolerance.
Add-on combination therapy
In combination with other glucose-lowering medicinal products including insulin, when
these, together with diet and exercise, do not provide adequate glycaemic control
Limitations of use
• Based on its mechanism of action, dapagliflozin is not recommended to be initiated in
patients with moderate renal impairment (eGFR <60 mL/min/1.73m2)
Dosing
10mg, orally once daily
Dapagliflozin is currently approved in 44 countries including the European Union
(since Oct 2012), Australia and the United States (since Dec 2013)