Meeting the Challenges of Type 2 Diabetes with

New & Emerging Therapies

Herbert Schuster M.D., Ph.D.

Professor of Medicine
Humboldt University Berlin, Berlin, Germany
 The challenges in future medicine

1. Genomics and biotech allow development of theories and

models in life sciences
2. To recognize health and disease as a process and not as
a condition
3. Molecular medicine will cause a shift from intervention to
prevention

2
 Historical development of healthcare systems
Birth Death

Palliative care lower pain

healthy sick

Interventional care increase life time

healthy sick

Preventive care shorten disease period

healthy years gained sick

3
 The future disease model

Drugs Dynamic network model of processes

Health

Genes
Attributes
Environment

Disease

Life style

4
Network model of cardiovascular disease mechanisms

Medical Clinical
Phenotypes Phenotypes

Hypertension

Hyperlipidemia Stroke

Diabetes MI

Thrombosis Heart failure

Obesity
Kidney failure

Atherosclerosis

5
Network model of cardiovascular disease mechanisms

Genotypes Molecular Biological Medical Clinical

Phenotypes Phenotypes Phenotypes Phenotypes

Blood pressure
Hypertension

Lipoproteines
Hyperlipidemia Stroke
Gene 1 Receptors
Glucose
Diabetes MI
Gene 2 Enzymes Clotting
Thrombosis Heart failure
Body weight
Gene 3 Hormones
Obesity
Kidney failure
Endothelial cells
Atherosclerosis
Muscle cells

6
Network model of cardiovascular disease mechanisms
Biology Medicine
healthy subclinial symptomatic
Threshold of signs
and symptoms

Genotypes Molecular Biological Medical Clinical

Phenotypes Phenotypes Phenotypes Phenotypes

Blood pressure
Hypertension

Lipoproteines
Hyperlipidemia Stroke
Gene 1 Receptors
Glucose
Diabetes MI
Gene 2 Enzymes Clotting
Thrombosis Heart failure
Body weight
Gene 3 Hormones
Obesity
Kidney failure
Endothelial cells
Atherosclerosis
Muscle cells

7
 Different cause-effect relationship models
Networks
a b c
Outcome

Condition Condition Condition

a) Linear response to change of conditions

b) Dramatic increase of response after reaching a critical condition

c) “Catastrophic shift of complex biological systems”

with point of no return after reaching a critical condition

8
 Current understanding of atherosclerosis
(staging and grading)
Threshold of signs & symptoms

Decades Decades/Years Minutes Months/Years

healthy subclinical clinical

Primary Secondary Tertiary

Prevention Prevention Prevention

Atherosclerosis - Disease (ICD 10 I170.9) Complications

Normal Endothelial Stable Instable Plaque Acute Coronary

Artery Dysfunction Plaque Plaque Rupture Syndrome
Thrombosis
Modified according to Ross R. N Engl J Med 1999;362:115–126 Infarction
9
“Molecular” therapy of atherosclerosis

NO
Adhesion molecules ß-Blocker
Proliferation factors ACE-Inhibitor
Oxidation AT1 Blocker
Proteasis
Cytokines Statins
Clotting Aspirin

10
 Atherogenesis and the renin system

Angiotensinogen

Renin

t-PA Angiotensin I

ACE Chymase
ACEI

Angiotensin II
Vasoconstriction ARB Cell proliferation
Aldosterone secretion Cell differentiation
Sympathic activiation Zellregeneration
Cardiac contractility AT1 AT2 Vasodilatation
Renal blood flow Bradykinine secretion
Vascular hypertrophy
Myocardial hypertrophy Bradykinin
11
Reduction in CVD mortality with Candesartan (CHARM)

% 30 CV death
HR 0.88 (95% CI 0.79-0.97), p=0.012
25 Adjusted HR 0.87, p=0.006

Placebo
20
Candesartan
15

10
Non-CV death
p=0.45
Candesartan
5
Placebo
0
Number at risk 0 1 2 3 3.5 years
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
Pfeffer et al., Lancet 2003 362: 759–66
12
 Reduction in new onset of type 2 diabetes
with Candesartan (CHARM)
10
Relative Risk Reduction - 40%, p=0.005
77 (7%)
8
Plazebo
Number of Patients in %

6
47 (4%)

4 Candesartan

HR 0.60 (0.41-0.86)
0
0 1.0 2.0 3.0 3.5 Years

Pfeffer et al., Lancet 2003 362: 759–66

13
 Identification of gastrointestinal peptides

GLP-1,GLP-2
 How DPP4 inhibitors work

Food
Intake

DPP4
Increases and Prolongs GLP-
GLP-1
Inhibitor And GIP Effects on Beta-
Beta-cells:
Beta--cells:
Beta Insulin Release

Stomach Net Effect:

Pancreas
Blood Glucose

GI Tract Incretins
Increases and Prolongs GLP-
GLP-1
Effect on Alpha-
Alpha-cells:
Alpha--cells:
Alpha
Glucagon secretion

Intestine

Adapted from Drucker and Nauck, 2006; Idris and Donnelly, 2007; Barnett, 2006 15
 Patients often not at goal and suffer many
safety / tolerability Issues
Percentage of patients not controlled
(relative to A1C Target of 7.0%) •Drawbacks of Key Classes
100
– Metformin
• GI Effects
80
69
– Sulfonylureas
64 • Weight Gain
Patients (%)

62
58 57
60
51 • Hypoglycemia
• Cardiac Effects
40
– TZDs
• Weight Gain
20
• Edema
• CHF Contra-Indication
0
U.S. U.K. France Ger. Italy Spain

Note: U.S. and EU percentage come from different studies and thus may not be entirely consistent —
EU data from physician chart review; U.S. data from NHANES 1999-2000
Source: BMS Market Research; BMS Outcomes Research 16
 The progressive nature of type 2 diabetes ultimately
overwhelms medications
Glycemic Control in an Illustrative Patient
Monotherapy Combination
Therapy
Potential
treatment
change
First
Agent
A1C

Goal*
A1C=<7

Normal**
A1C=5%

Time
Sources: ADOPT, UKPDS
(*) According to the ADA; (**) according to the NIH
17
 The effect of incretin, OGTT and iv infusion

Glucose (mg/dL) Insulin (pmol/L)

200 400

Oral
150 300 IV

100 200

50 100

0 0
-30 0 30 60 90 120 150 180 210 -30 0 30 60 90 120 150 180 210
Time (min) Time (min)

OGTT=oral glucose tolerance test; IV=intravenous.

Nauck MA et al. J Clin Endocrinol Metab 1986;63:492–498. Copyright ©1986. The Endocrine Society.
 Reduced effect of incretins in type 2 diabetes

Controls Type 2 Diabetes

80 80
Oral glucose Oral glucose
IV glucose IV glucose
60 60
Insulin (mU/L)

Insulin (mU/L)
40 40

*
20 * * *
* 20
* *

0 0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
Time (min) Time (min)
 Meal size dependent effect of incretins

GLP-1 GIP
50 kcal 260 160 kcal 260
kcal 520 kcal 520
Total GLP-1 (pmol/L)

40

Total GIP (pmol/L)

120

30
80
20

40
10

0 0
-30 0 30 60 90 120 150 180 210 -30 0 30 60 90 120 150 180 210
Time (min) Time (min)
Vilsbøll T et al. J Clin Endocrinol Metab 2003;88:2706–2713. Copyright © 2003. The Endocrine Society.
 Impaired post prandial GLP-1 response in T2D

30

25

Total GLP-1, controls

GLP-1 (pmol/L)

20
Total GLP-1, patients
15
Intact GLP-1, controls
10 Intact GLP-1, patients

0
0 50 100 150
Time (min)

Vilsbøll T et al. J Clin Endocrinol Metab. 2001;50:609–613.

 Exogenes GLP-1 and decreased stomach emptying

GLP-1 [7-36 amide] sc

500 Liquid meal
Gastric volume (mL)

400
** Placebo
300 GLP-1
*
200
*
100
*
0 p <0.0001
-30 0 30 60 90 120 150 180 210 240
Time (min)

Nauck MA et al. Diabetologia 1996;39:1546–1553. Copyright ©1996 Springer. Reprinted with permission.
 Effect of GLP-1 and GIP on insulin
secretion in type 2 diabetic patients

8000
Hyperglycemic Clamp
Saline or GIP or GLP-1
C-peptide (pmol/L)

6000
GLP-1
GIP
Saline
4000

2000

0
-15 -10 0 5 10 15 20 30 45 60 75 90 105 120 150

Time (min)
Adapted from Vilsbøll T et al. Diabetologia 2002;45:1111–1119.
Normal blood glucose levels after GLP-1 infusion in type
2 diabetic patients

16
Diabetic-saline
Diabetic-
14 Diabetic--GLP
Diabetic GLP--1
Nondiabetic
12
(mmol/L)
Glucose

10

2
Breakfast Lunch Snack
0
00:00 04:00 08:00 12:00 16:00
Time of day

Rachman J et al. Diabetologia 1997;40:205–211.

 Glucose dependent response of GLP-1 in
type 2 diabetic patients
mmol/L
15.0 250 mg/dL
12.5
10.0 * 200
Fasting 7.5
* * * 150 Placebo
* * *
glucose 5.0 100 GLP-1
50 *P <0.05
Infusion
pmol/L n = 10
mU/L
250 40
200
30
150
Insulin 100 * * * 20
* * * * *
50 10
0
pmol/L
20
Glucagon 15
10 * * * *
5

0 60 120 180 240

Minutes
Nauck NA et al. Diabetologia 1993;36:741–744.
 Incretine secretion and DPP-4-induced inactivation

Mixed
Meal
Intestinal Decreased gastric emptying, food intake,
GLP-1 and glucagon secretion
Intestinal
Release
GIP
Release
t1/2 = 1 to 2 min
GLP-1 (7-36)
GIP (1-42) Active
Active

DPP-4

Increased insulin secretion

GLP-1 (9-36)
Enhanced beta-cell proliferation Inactive
Reduced beta-cell apoptosis (> 80% of pool)
Reduced glucagon secretion (GLP-1)
DPP-4i
Drucker DJ. Diabetes Care 2003;26:2929–2940.
 Genetic inactivation of DPP-4 increases incretine
response and glucose clearance in vivo

Blood glucose (mM)

15
‡
+/+
-/ -
†
10

Lower glucose in DPP-

DPP-4-/- mice
0
-30 0 30 60 120 180
Plasma glucose (mM)

20 150 3

GLP-1 (pM)
Plasma insulin (pM)

* *
*

Plasma GLP-
100 2

10
*p <0.05
50 1 †p <0.01
‡p <0.001

0 0 0
+/+ -/- +/+ -/- +/+ -/-

Increased levels of insulin and intact GLP-1 in DPP-4 -/- mice

Marguet D et al. Proc Natl Acad Sci USA 2000;97:6874–6879.
Pharmacological DPP-4 inhibition decreases N-terminal
degradation of GLP-1 in pigs

GLP-1 infusion GLP-1 infusion

500
Glucose Glucose
DPP-4 Inhibition
400
GLP-1(pmol/L)

300

200

100

0
0 20 40 60 80 100 120 140 160 180 200 220

Time (min)
Val-pyr=valine-pyrrolidine.
Deacon CF et al. Diabetes 1998;47:764–769.
 “Pleiotropic effects” of incretins

Neuroprotection
Appetite

Brain

Stomach
Heart
Gastric emptying

Cardioprotection
Cardiac output GLP-1

Liver
GI tract Insulin biosynthesis
Beta-cell proliferation
Beta-cell apoptosis
Insulin sensitivity
Muscle
Insulin secretion
Glucagon secretion
Glucose production

Adapted from Drucker DJ. Cell Metab. 2006;3:153–165.

 GLP-1 receptor agonists vs. DPP-4 inhibitors

GLP-1R Agonists DPP-4 Inhibitors

Administration Injection Orally Available
GLP-1 concentrations Pharmacological Physiological
Mechanisms of action GLP-1 GLP-1 + GIP
Activation of portal glucose
sensor No Yes
Insulin secretion +++ +
Glucagon secretion ++ ++
Gastric emptying Inhibited +/-
Weight loss Yes No
Expansion of beta-cell mass
In preclinical studies Yes Yes
Nausea and vomiting Yes No
Potential immunogenicity Yes No

Adapted from Drucker DJ. Cell Metab 2006;3:153–165.

Combination of metformin und DPP-4 inhibitor increases
GLP-1 levels in rats

250 **,†,#

Plasma active GLP-1 (% of values at 0 h)

200
**,††,#

***,†††,###
150

100

Vehicle
Metformin (300 mg/kg)
50
Val-pyr (30 mg/kg)
Metformin (300 mg/kg) and valine-pyrrolidide (30 mg/kg)

0
0 1 2 3 4 5
Time (h)
*,†,# indicate significant differences vs the vehicle treated group, the metformin treated group, and the valine-pyrrolidide treated group, respectively.
One, two and three symbols indicated p<0.05, p<0.01, and p<0.001 respectively.
Yasuda N et al. Biochem Biophys Res Commun 2002;298:779–784.
 Properties of Saxagliptin

– Highly potent, competitive inhibitor of DPP4

– 2 orders of magnitude or greater selectivity for DPP4 versus HO
other proteases
– Major active mono-hydroxy metabolite (BMS-510849) is 2-fold H2N N
less potent than saxagliptin
O CN
– Pharmacodynamic properties of 5 mg dose consistent with once-
daily dosing BMS-477118

– Rapidly and extensively absorbed after oral dosing; may be taken

without regard to meals OH
– Predictable and dose-proportional pharmacokinetics similar in
healthy and diabetic patients with minimal accumulation with
once-daily dosing HO
– Clearance of saxagliptin and/or its metabolites via metabolism,
renal, and non-renal routes H2N N
O
CN
BMS-510849

32
 Saxagliptin – approved indications

• Indications
– Saxagliptin is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes

• Treatment Settings
– Monotherapy
– Add-on combination to MET, SU, TZD
– Initial Combination with MET

33
 Saxagliptin clinical development program
All Subjects
N = 5346

Clinical Phase 2b
Phase 3
Pharmacology N = 423
N = 4250
N = 673 Study 008

Healthy Subjects Mechanism Initial Comb.

N = 583 Add-on
Add-
of Action Monotherapy with MET
21 Studies Combination
N = 36 N = 832 N = 1306
N = 2076
Patients w/ T2DM Study 041 Study 039
N = 40
Study 002 N = 401 Add-on to MET
Add-
+ 66 OL N = 743
Patients w/ Hepatic Study 011 Study 014
Impairment
N = 18
Study 020 Add-on to SU
Add-
N = 365
N = 768
Study 038
Patients w/ Renal Study 040
Impairment
N = 32 Add-on to TZD
Add-
Study 019 N = 565
Study 013
MET = metformin; OL = open-label; SU = sulfonylurea;
T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione 34
 Monotherapy Studies

Change from baseline in A1C at week 24

SAXA (mg)
SAXA (mg) QAM QAM QAM QPM
Dose 2.5 5 10 PBO 2.5 5 2.5 / 5 5 PBO
n= 100 103 95 92 67 69 69 70 68
Bsl Mean (%) 7.91 7.98 7.85 7.88 8.04 7.93 8.02 7.88 7.79
0,6 0,6

0,4 0,4

0,19
0,2 0,2

 A1C (%)
(%) 0,0 0,0
with
95% CI -0,2 -0,2
-0,26
-0,4 -0,4
-0,43 -0,46
-0,6 -0,54 -0,6
* -0,63 -0,61
-0,8 * -0,8 -0,71 -0,66
* **
* **
-1,0 * p < .0001 vs. PBO -1,0 *
* p < .01 vs. PBO ** p < .02 vs. PBO
35
 Combination Studies: MET, TZD, SU

Change from baseline in A1C at week 24

SAXA + MET PBO + SAXA + TZD PBO SAXA + GLY PBO
Dose 2.5 5 10 MET + +
2.5 5 TZD 2.5 5 GLY
n= 186 186 180 175
192 183 180 246 250 264
Bsl Mean (%) 8.08 8.07 7.98 8.06
8.25 8.35 8.19 8.36 8.48 8.44

0,4 0,4 0,4

0,08
0,2 0,13 0,2 0,2
(%) with 95% CI

0,0 0,0 0,0

-0,2 -0,2 -0,2

-0,3
 A1C (%)

-0,4 -0,4 -0,4

-0,6 -0,6 -0,6

-0,59 -0,58
-0,66 -0,54 -0,64
* -0,69 *
-0,8 * -0,8 -0,8
*
* **
-1,0 -1,0 -0,94 -1,0

-1,2 -1,2
* -1,2
* p < .0001 vs. PBO + MET *p < .0001 vs. PBO + TZD * p < .0001 vs. PBO + GLY
** p = .0007 vs. PBO + TZD
36
Initial Combination Study with MET

Change from baseline in A1C at week 24

SAXA (mg) + MET SAXA (mg)
Dose 5 10 10 MET
n= 306 315 317 313
Baseline Mean (%) 9.41 9.53 9.61 9.43
0,0

-0,5

-1,0
 A1C (%)
(%)
with
-1,5
95% CI
-1,69
-2,0
-1,99

-2,5
-2,53 -2,49
* *
-3,0
* p < .0001 vs. MET
37
 Difference from placebo in adjusted mean change from
baseline in A1C

Phase 2b/3 Monotherapy Studies Phase 3 Add-

Add-on Combination Studies
Post--hoc Pooled Analysis (Wk 12)
Post ST Period (Wk 24)
Pooled Pooled SAXA + MET SAXA + TZD SAXA + SU
SAXA SAXA (014) (013) (040)
2.5 mg 5 mg 2.5 mg 5 mg 2.5 mg 5 mg 2.5 mg 5 mg
0,0 0,0

-0,2 -0,2
(%) with 95% CI

-0,4 -0,4 -0,36

-0,51
-0,6 -0,6
 A1C (%)

-0,61 -0,63 -0,62

-0,8 -0,8 -0,73 -0,72
-0,83
-1,0 -1,0

-1,2 -1,2

38
Add--on Combination Study with MET
Add
Difference from Control in Change from Baseline in A1C at Week 24
(LOCF) for Saxagliptin 5 mg by Subgroup
SAXA PBO
Subset n n
Gender Male 100 95
Female 86 80
Race White 154 146
Non-White 32 29
Age (yrs) < 65 156 149
 65 30 26
Baseline A1C (%) <8 88 84
8–<9 68 60
9 30 31
Duration of disease (yrs)  1.5 13 20
3 46 49
3–<5 39 36
5 101 90
 10 36 47

Creatinine Clearance  80 31 24
(ml/min)  80 155 151

39
 General Safety Profile

– Well-tolerated at all doses studied in Phase 3

– Low risk for hypoglycemia
– No adverse effects in lipid parameters, blood pressure or heart rate
– Associated with no or minimal differences in weight change
compared with control
– No identified hepatic, pancreatic, skeletal myopathy, or renal safety
signals
– No evidence for clinically meaningful effects on hematology or
chemistry parameters

40
 Controlled Phase 2b/3 Pooled Population

Cardiovascular Risk Factors (in addition to T2DM)

Number (%) of Patients

SAXA SAXA SAXA
2.5 mg 5 mg 10 mg All SAXA3 Control
N = 937 N = 1269 N = 1000 N = 3356 N = 1251
Patients with at least one
CV Risk Factor 777 (83) 1015 (80) 803 (80) 2724 (81) 1035 (83)
in addition to T2DM
Hypertension 519 (55) 655 (52) 510 (51) 1750 (52) 688 (55)
Hypercholesterolemia1 471 (50) 565 (45) 353 (35) 1475 (44) 566 (45)
Smoking History 383 (41) 449 (35) 393 (39) 1301 (39) 471 (38)
First degree family
member with
190 (20) 248 (20) 186 (19) 677 (20) 265 (21)
Premature Coronary
Heart Disease
Patients with
118 (13) 150 (12) 118 (12) 404 (12) 165 (13)
Prior CV Disease2
1 Includes mixed dyslipidemia
2 Prior CV Disease defined as previous myocardial infarction, congestive heart failure, hospitalization for
unstable angina, stable angina, percutaneous coronary intervention, coronary artery bypass graft, coronary
artery disease, cerebrovascular disease, peripheral vascular disease
3 Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008). 41
 Controlled Phase 2b/3 Pooled Population

Time to Onset of First Primary MACE

5
Percent with First Adverse Event

3
Control
2
All SAXA

0
BL 24 37 50 63 76 89 102 115 128
Weeks
Patients at Risk
Control 1251 935 860 774 545 288 144 123 102 57
All SAXA 3356 2615 2419 2209 1638 994 498 436 373 197

42
 Controlled Phase 2b/3 Pooled Population

Incidence Rate Ratio of Primary MACE by Therapy

0,45
Pooled Phase 2b/3 0,24 0,83

Phase 2 Dose-Ranging (-008) 0,01 0,30 11,55

Monotherapy (-011) 0,47 4,09

0,07

Monotherapy (-038) 0,003 0,11 1,36

MOA (-041) 0,02 0,80 31,02

+ MET (-014) 0,37

0,12 1,30

+ SU (-040) 0,28
0,07 0,95

+ TZD (-013) 1,25

0,25 9,90

Initial Combination with MET (-039) 0,50

0,18 1,52

0,001 0,01 0,1 1 10 100

Ratio of Saxagliptin to Control

Saxagliptin Better Control Better

Data represent point estimate and 95% CI.
Size of point estimate is relative to number of events. 43
 Controlled Phase 2b/3 Pooled Population

Incidence Rate for Primary MACE by Subgroups

65
65

60
60 Saxa Control
55
55 Error bars represent SEM
50
50
Events per 1000 patient-years

46,3
45
45

40
40

35
35

30
30

25
25 22,5 22,5
20
20 18,4
15,8
15
15 13,2
11,4
9,2 9,1 9,9
10
10 8,8 8,0 7,7
7,0
55

00
At Least One At Least Two
History of
History of CV Risk Factor CV Risk Factors History of Male
Hyper- Age ≥65
CV Disease (in addition to (in addition to Hypertension Gender
cholesterolemia
T2DM) T2DM)
n = 569 n = 3759 n = 2286 n = 2438 n = 2041 n = 2279 n = 699
44
 Controlled Phase 2b/3 Pooled Population

Frequency of Major CV Endpoints by Definition

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251

Total Pt-years 1149 1462 1119 3758 1293

Mean Duration of
1.23 1.15 1.12 1.12 1.03
Follow Up (yrs)

Number (%)

FDA-defined

SMQ MACE 28 (3.0) 37 (2.9) 30 (3.0) 100 (3.0) 41 (3.3)

Custom MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 17 (1.4)

Investigator-defined

Primary MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 18 (1.4)

Acute CV Events 14 (1.5) 10 (0.8) 14 (1.4) 38 (1.1) 23 (1.8)

* Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008). 45

 Controlled Phase 2b/3 Pooled Population

Frequency of Additional CV Endpoints by Definition

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251
Total Pt-years 1149 1462 1119 3758 1293
Mean Duration of
1.23 1.15 1.12 1.12 1.03
Follow Up (yrs)
Number (%)
Patients with Any
53 (5.7) 63 (5.0) 48 (4.8) 164 (4.9) 71 (5.7)
Cardiac Disorder AE
FDA-defined
Ischemic Heart Disease 14 (1.5) 17 (1.3) 12 (1.2) 43 (1.3) 24 (1.9)
Cardiac Failure 8 (0.9) 7 (0.6) 5 (0.5) 20 (0.6) 7 (0.6)
Cardiac Arrhythmias 32 (3.4) 36 (2.8) 31 (3.1) 99 (2.9) 37 (3.0)
Other 9 (1.0) 8 (0.6) 6 (0.6) 23 (0.7) 7 (0.6)
Investigator-defined
Secondary MACE 8 (0.9) 7 (0.6) 11 (1.1) 26 (0.8) 20 (1.6)
All Death 3 (0.3) 3 (0.2) 4 (0.4) 10 (0.3) 12 (1.0)
CV Death 1 (0.1) 2 (0.2) 4 (0.4) 7 (0.2) 10 (0.8)

* Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008). 46

 Saxagliptin – Demonstrated Benefits

• Clinically meaningful reductions in A1C, FPG, and PPG

– Demonstrated in wide-range of treatment contexts (monotherapy,
add-on and initial combination)
– Consistent effect across subgroups
– Complementary mechanism of action to currently existing
therapies

47
 Saxagliptin – Favorable Safety Profile

– Studied in extensive clinical program at exposures

up to 80x proposed usual clinical dose
– Well-tolerated at all doses studied in Phase 3
– Low risk for hypoglycemia
– No or minimal differences in body weight change compared with control
– No identified hepatic, pancreatic, renal safety signals
– No human clinical correlate to monkey skin-findings
– Small decrease in mean, absolute lymphocyte count
• Not associated with effect on infectious-related AEs
• Changes stable, non-progressive over long-term dosing

– No identified CV safety signal

48
 Conclusion

• Saxagliptin provides meaningful benefits in

glycemic control
• Saxagliptin provides a favorable safety and
tolerability profile
• Saxagliptin offers a new treatment option with a
favorable benefit / risk profile for patients with
type 2 diabetes

49