Comprehensive Glycaemia Control with

Saxagliptin : Emerging Option for Type 2 DM

Management

Pradana Soewondo
Department of Internal Medicine
Faculty of Medicine University of Indonesia-
Cipto Mangunkusumo National Referral
Hospital
Jakarta, Indonesia
Overview
Epidemiology diabetes in

Indonesia

Results of DiabCare study 2008

Diabetes management

Algorithm Perkeni

Saxagliptin -DDP-4 Inhibitors

Conclusion
 Diagnostic Cut Points for IFG, IGT, and
Diabetes

Fasting Glucose Diabetes

126 mg/dL

100 mg/dL
IFG IFG + IGT

Normal
IGT
Glucose

140 mg/dL 200 mg/dL

2-h Postload Glucose

ADA=American Diabetes Association; IFG=impaired fasting glucose; IGT=impaired glucose tolerance
Adapted from American Diabetes Association. Diabetes Care. 2006; 29(suppl 1): S4S42.
 Prevalence of IGT and DM In Indonesia

N = 24.400
> 15 years

Known DM Undiagnosed Total DM IGT

DM
1,5 % 4,2 % 5,7 % 10,2 %
Indonesian National Health Survey,
2007
 3

2 1
4

Papua Barat (21,8%) Kalimantan Selatan

Sulawesi Barat (17,6%)
(14,7%)
Sulawesi Utara (17,3%)
Jawa Tengah (13,1%)
5

4 2
3 1

Kalimantan Barat (11,1%) Bangka Belitung (8,6%)

Maluku Utara (11,1%)
Riau (10,4%) NAD (8,5%)
 The DiabCare Asia 2008 Study Outcomes on
Control and Complications of Type 2 Diabetic
Patients in Indonesia

Pradana Soewondo, Sidartawan Soegondo, Ketut Suastika,

Agung Pranoto, Djoko Wahono Soeatmadji, Askandar
Tjokroprawiro

Objective
To collect information on diabetes management,
diabetes complications, and awareness of self-
control in diabetic population of the country. This
study also evaluated the physician perspectives,
psychological aspects, and quality of life of
diabetic patients.
 Patient Demographic and Characteristics
Variable Data
Age (Years)* (n=1719) 58.939.57
793 (43.3) / 1010
Gender** (n=1803) Male/ Female
(55.16)
Age at Onset (Years)* (n=1686) 49.686.8
Duration of Diabetes (Years)* (n=1704) 8.615.97
Type of Diabetes**
Type 1 17 (0.9)
Type 2 1785 (97.5)
Others 2 (0.1)
BMI (Kg/m2)14 * (n=1646) 25.23.6
<23 / 23 (%) 28.7 / 71.3
Duration of Treatment (Years)* (n=1817) 8.57.0
Duration of OADs (Years)* (n=1727) 8.46.8
Duration of Insulin (Years)** (n=1176) 2.83.0
Smoking (Yes)** (n=1831) 178 (9.7)
* Data expressed as Mean SD; ** Data expressed as n (%); Percentage are calculated out of total cohort (n=1832) except for BMI.
 Diabetes Management - The DiabCare Indonesia
2008
Diabetes management variable Data, n (%)
Type of Management
Diet -
Insulin monotherapy 317 (17.3)
Insulin and OAD combination 356 (19.4)
OAD monotherapy 1133 (61.9)
Herbal 5 (0.3)
None 20 (1.1)
Type of OAD Therapy
Biguanides 1085(59.3)
Sulphonylureas 1036(56.6)
Meglitinides 8(0.4)
Alpha Glucosidase inhibitors 461(25.2)
Thiazolidinediones 51(2.8)
Other OADs 48 (2.6)
Traditional Herbal medicines 5(0.3)
Double drug fixed dose combination 88 (4.8)
Triple drug fixed dose combination 5 (0.3)
 Use of OADs Decreased at Duration of Diabetes 10
Years
Number of patients (%)
92 -- 89.71
90 --
88 -- 86.67 86.86 86.83
86 -- 84.27
84 --
82 --
80 --
77.71
78 --
76 --
74 --
72 --
70
<1 1 and <3 3
Duration ofand <5 5
diabetes and <7 7 and <10
(years)
10 DiabCare Indonesia
2008
Glycemic Control In The Study Population
250
207.7
Glycaemic control level

200.2
200

143.6
150

100

50

0
FPG (mg/dL) PPG(mg/dLl) RPG(mg/dl)

Fasting Postprandial A1c

143.6 mg% 207.7 mg% 8.1 %

DiabCare Indonesia 2008

 A1c and FPG stratified according to different
guidelines

90
81.01
80
67.85 68.78
70
% of patients

60
50 47.22

40
30
20

10
0
ADA AACE/IDF ADA (>7.22) AACE/IDF
(7%) /APDPG /APDPG
HbA1c (%) (6.5%) FPG (mmol/l) (6.1)

Only 32% patients reach target HbA1c < 7%

DiabCare Indonesia 2008

 A1c Target amongst Asia Countries

Country A1c (%) A1c >7% (%)

Indonesia 8.1 67.7

Bangladesh 8.6 76.9
Singapore 7.8 65.4
Malaysia 8.6 76.5
Taiwan 7.9 69.7
Thailand 8.2 74.3
Philippines 8 31.8

DiabCare Asia - 2008

 Comparison of 2003 and 2008 DiabCare study

Parameter 2003 2008

Age (Yrs) 58.79.3 58.99.5
Duration of diabetes (Yrs) 9.26.6 9.27.2
Sex (M/F) % 42.9/57.1 44/56
Type 2 DM (%) 98.2 97.4
Mean BMI (kg/m2) 24.13.5 25.13.6
Mean A1c (%) 7.92.0 8.11.6
Mean FPG (mmol/l) 8.43.4 7.92.4
Mean PPG (mmol/l) 11.63.9 11.53.6
HDL-cholesterol (mmol/l) 1.30.4 1.30.8
Triglycerides (mmol/l) 2.01.1 1.70.6
 Target of Treatment
Risk CVD (-) Risk CVD (+)
IMT (kg/m2) 18,5 - < 23
Glukosa darah
- Puasa (mg/dL) < 100
- 2 jam PP (mg/dL) < 140
A1C (%) < 7,0 < 7,0
Tekanan Darah < 130/80 < 130/80

Profil Lipid

Total kolesterol (mg/dL)

Trigliserid (mg/dL)
HDL kolesterol (mg/dL)
LDL kolesterol (mg/dL) < 100 < 70

PERKENI Guidelines 2011

 Multiple Factors Contribute to T2DM

Decreased glucose Progressive -cell

uptake dysfunction

Type 2 Diabetes Lack of

Hepatic
glucagon
glucose production
suppression

Impaired Increased Increased

incretin lipolysis renal
signaling glucose transport

1. Bode BW. Postgrad Med. 2009;121:82-93.

2. DeFronzo RA. Ann Intern Med. 1999;131:281-303.
3. DeFronzo RA. Diabetes. 2009;58:773-795.

BMS/AZ CONFIDENTIAL INFORMATION INTERNAL USE ONLY. DO NOT DUPLICATE, DISTRIBUTE OR USE IN CUSTOMER PRESENTATIONS.
17
 Pancreatic Islet Dysfunction Leads to Hyperglycemia
in T2DM

Fewer -Cells
-Cells Hypertrophy

Insufficient Excessive
Insulin Glucagon
+
+

Glucose
Glucose HGO
Uptake

HGO=hepatic glucose output

Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191198.
18
Abnormal Pancreatic Islet Function Determines the Development of
IGT and T2DM in the Setting of Insulin Resistance

Age, lifestyle,
environmental factors

Insulin resistance

Normal islet Abnormal

function islet function

NGT IGT / T2DM

IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus
Adapted from Ahrn B, et al. Diabetes Obes Metab. 2005; 7: 28.
19
Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
Type 2 diabetes mellitus (n=12)*
360 Nondiabetic controls (n=11)
(mg/100 ml)

330
Glucose

Meal
300
270
240
110
80
150 Depressed/delayed insulin response
120
(U/ml)
Insulin

90
60
30
0
140
Glucagon

130
(g/ml)

120 Nonsuppressed glucagon

110
100
90
60 0 60 120 180 240

Time (minutes)
*Insulin measured in five patients
Adapted from Mller WA et al N Engl J Med 1970;283:109115.
21
 Incretins Regulate Glucose Homeostasis
Through Effects on Islet Cell Function
Ingestion of
food Glucose dependent
Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretin gut
hormones Beta cells Blood
Alpha cells glucose control
Active
GLP-1 and GIP
Increased insulin
Glucagon and decreased
glucagon
from alpha cells reduce
(GLP-1) hepatic
Glucose dependent glucose output

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:26532659; Zander M et al Lancet 2002;359:824830; Ahrn B Curr Diab Rep
2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483.
22
GLP-1 and GIP Are Synthesized and Secreted from the
Gut in Response to Food Intake

L-Cell
(ileum)
ProGIP

Proglucagon

GLP-1 [737] GIP [142]

K-Cell
(jejunum)
GLP-1 [736 NH2]
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 29292940.
23
GLP-1 Restores Insulin and Glucagon Responses in a
Glucose-Sensitive Manner in Patients with T2DM

N=10 Glucose (mg/dL) C-Peptide (nmol/L) Glucagon (pmol/L)

300 3.0 30
GLP-1 infusion GLP-1 infusion GLP-1 infusion

250 2.5 25

200 * 20
2.0 *
*
*
*
*
150 1.5 15
*
*
*
*
100 * 1.0 10
*
*
* *
50 0.5 5 * *
*
*

0 0.0 0
30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240 30 0 30 60 90 120 150 180 210 240
Time (Min) Time (Min) Time (Min)
GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
*P <0.05 GLP-1 Placebo
GLP-1(736 amide) infused at 1.2 pmol/kg/min for 240 minutes.

Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741744.

24
 Effects of GLP-1 on Insulin and Glucagon
Shown to Be Glucose Dependent in Type 2 Diabetes
15.0 Placebo
(mmol/L)
GLP-1 infusion
Glucose
12.5
10.0 *
7.5 * *
* *
5.0 * *
Infusion
With hyperglycemia
GLP-1 stimulated insulin
250
(pmol/L)

and suppressed glucagon.

Insulin

200
150
100 * * * *
* * * When glucose levels
50
*
approached normal,
insulin levels declined
Glucagon

20
(pmol/L)

15 and glucagon was no

10 * * * * longer suppressed.
5

0 60 120 180 240

Time (minutes)
N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was
allowed for one day between the experiments with GLP-1 and placebo.
25
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741744.
Decreased Glucose Disposal and Increased HGP
Contribute to Increased FPG in T2DM
2.8
Diagnosis
2.4

Glucose Clearance 2.0

(mL/kg min) 1.6 Impaired
insulin-mediated
1.2 glucose disposal
0.8
50 100 150 200 250 300

4.5
4.0 Excessive
3.5 glucagon-mediated
HGP 3.0
(mg/kg min) glucose output
2.5
2.0
1.5
1.0
50 100 150 200 250 300
FPG (mg/dL)
FPG=fasting plasma glucose; HGP=hepatic glucose production; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Diabetes. 1988; 37: 667687.
26
Treatment Targets: Deteriorating Islet Cell Function in
the Setting of Insulin Resistance

Insulin resistance

Diagnosis Islet cell function

Prediabetes
NGT Diabetes
(IFG/IGT)

IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NGT=normal glucose tolerance

Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.
29
 Pharmacologic Targets of Current Drugs Used in the
Treatment of T2DM
GLP-1 analog (exenatide injectable)
Improves glucose-dependent insulin DPP-4 inhibitors
secretion, suppresses glucagon secretion, Prolong GLP-1 action, stimulate insulin
slows gastric emptying secretion, suppress glucagon release

Thiazolidinediones
Increase glucose uptake in
skeletal muscle and
decrease lipolysis in
adipose tissue
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
-glucosidase inhibitors
Delay intestinal carbohydrate
Meglitinides absorption
Increase insulin secretion
from pancreatic -cells
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213226.
30
 Expected HbA1c reduction according to intervention
Intervention Expected in HbA1c (%)
Lifestyle interventions 1 to 2%
Metformin 1 to 2%
Sulfonylureas 1 to 2%
Insulin 1.5 to 3.5%
1
Glinides 1 to 1.5%
Thiazolidinediones 0.5 to 1.4%
-Glucosidase inhibitors 0.5 to 0.8%
GLP-1 agonist 0.5 to 1.0%
Pramlintide 0.5 to 1.0%
DPP-IV inhibitors 0.5 to 0.8%

1. Repaglinide is more effectie than nateglinide 31

Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
 Algoritme Pengelolaan DM tipe-2 Tanpa Dekompensasi

DM Tahap-I Tahap-II Tahap-III

GHS
GHS
+
monoterapi
Catatan: GHS
1. GHS = gaya hidup sehat +
2. Dinayatakan gagal bila
terapi selama 2-3 bulan
Kombinasi 2 OHO
pada tiap tahap tidak
mencapai target terapi GHS
HbA1c <7% Jalur pilihan alternatif, bila:
3. Bila tidak ada -tidak terdapat insulin +
pemeriksaan HbA1c -diabetisi betul-betul menolak Kombinasi 2 OHO
dapat dipergunakan insulin +
pemeriksaan glukosa -kendali glukosa belum
darah optimal Basal insulin
Rata-2 hasil pemeriksaan
beberapa kali gukosa
darah sehari yang
dikonversikan ke HbA1c GSH
menurut kriteria ADA, +
2010 Insulin intensif*
Kombinasi 3 OHO

* Insulin intensif : penggunaan insulin basal bersamaan dengan insulin prandial

 Kadar HbA1c
<7% 7-8% 8-9% >9% 9-10% >10%

GHS GHS
Gaya Hidup +
Sehat
Monoterapi GHS
Penurunan +
berat badan
Met, SU,
Mengatur diit AGI, Glinid, Kombinasi GHS
Latihan TZD,
Jasmani teratur 2 obat +
DPP-IV inh
Met, SU, Kombinasi GHS
AGI, Glinid 3 obat +
Catatan TZD,
1. Dinyatakan gagal bila Met, SU, Kombinasi
DPP-IV inh AGI, Glinid 2 obat
dengan terapi 2-3 bulan
tidak mencapai target TZD, DPP- Met, SU,
HbA1c <7% IV inh
2. Bila tidak ada pemeriksaan
AGI,
HbA1c dapat digunakan Glinid, TZD
pemeriksaan glukosa + GHS
darah. Rata-rata glukosa
darah sehari dikonversikan Basal Insulin +
ke HbA1c menurut kriteria Insulin
ADA 2010 Intensif*
* Insulin intensif : penggunaan insulin basal bersamaan dengan insulin prandial
 -Cell Function Continues to Decline Regardless of
Intervention in T2DM

Progressive loss of -cell function Sulfonylurea (n=511)

100 occurs prior to diagnosis Diet (n=110)
Metformin (n=159)

80
-Cell Function (%)*

60

40

20

0
5 4 3 2 1 0 1 2 3 4 5 6
Years Since Diagnosis
T2DM=type 2 diabetes mellitus
*-cell function measured by homeostasis model assessment (HOMA)
Adapted from UKPDS Group. Diabetes. 1995; 44: 12491258.
34
ADOPT Study: Progression of Hyperglycemia in T2DM

Treatment difference (95% CI)

Rosiglitazone vs metformin, 0.13 (0.22 to 0.05); P=0.002
8.0
Rosiglitazone vs glyburide, 0.42 (0.50 to 0.33); P <0.001

7.6
Glycated Hemoglobin (%)

7.2

6.8

Annualized slope (95% CI)

6.4
Rosiglitazone, 0.07 (0.06 to 0.09)
Metformin, 0.14 (0.13 to 0.16)*
Glyburide, 0.24 (0.23 to 0.26)*
6.0

0
0 1 2 3 4 5
Years

No. of Patients 4012 3308 2991 2583 2197 822

*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment

Kahn SE, et al. N Engl J Med. 2006; 355: 24272443.
35
Traditional Current Oral Therapies Do Not Address
Islet Cell Dysfunction

Insulin Resistance Pancreatic Islet Dysfunction

(Impaired insulin action)
Inadequate Insufficient Progressive
glucagon Insulin secretion decline of -cell
suppression (-cell function
(-cell dysfunction)
dysfunction)

Metformin TZDs Sulfonylureas

Glinides

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24S40.
36
 Contraindications and Precautions for Current T2DM
Treatments Limit Use

Contraindicated in renal dysfunction, avoid in liver disease, monitor

Metformin
renal function

Use with caution in elderly, and in renal and hepatic impairment, watch
SUs
for hypoglycemia

Meglitinides Use with caution in elderly, and in renal and hepatic impairment

TZDs
Contraindicated in severe liver disease, congestive heart failure,
monitor liver enzymes

-Glucosidase Not recommended in severe renal impairment,

inhibitors check serum liver enzymes
Exenatide
injectable Use caution in severe renal or severe GI disease

GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione

From Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004; Starlix [package insert]. East Andover, NJ: Novartis
Pharmaceuticals Corporation; 2004; Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2006; Byetta [package insert].
San Diego, CA: Amylin Pharmaceuticals, Inc; 2006.
37
Major Adverse Events of Current Treatments for T2DM Limit
Efficacy

Metformin1 GI effects (nausea, diarrhea), lactic acidosis (rare)

SUs1
Hypoglycemia, weight gain, hyperinsulinemia a
Meglitinides1
Weight gain, edema, CHF, bone fractures (pioglitazone,
TZDs1-3 rosiglitazone)
Myocardial ischemic events (rosiglitazone)

-glucosidase GI effects (flatulence, diarrhea)

inhibitors1

Incretin GI effects (nausea, vomiting, diarrhea), pancreatitis,

mimetics4-8 hypoglycemia (in add-on to SU)
CHF=congestive heart failure; GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedione
aRole uncertain
1Inzucchi SE. JAMA 2002; 287: 360-372; 2Avandia US Prescribing Information; 3Dormandy JA, et al. Lancet 2005; 366: 1279-1289; 4Buse JB, et al.

Diabetes Care 2004; 27: 2628-2635; 5DeFronzo RA, et al. Diabetes Care 2005; 28: 1092-1100; 6Kendall DM, et al. Diabetes Care 2005; 28: 1083-1091;
7Kolterman OG, et al. Am J Health-Syst Pharm 2005; 62: 173-181; 8Byetta US Prescribing Information.

38
Weight Gain is a Common Side Effect of Diabetes
Treatments

OAD Agents Weight Change (kg)

-3.80.5
Metformin13
-0.41.7
SUs14
0.94.6
TZDs46
0.33.0
Meglitinides4,7,8
-0.31.9
Metformin + SU13
0.82.1
Metformin + TZD5,6,9

-5 -4 -3 -2 -1 0 1 2 3 4 5
OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione
1. Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2004. 2. Glucovance [package insert]. Princeton, NJ: Bristol-Meyers
Squibb Company; 2004. 3. Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2002. 4. Malone M. Ann Pharmacother. 2005; 39:
20462055. 5. Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004. 6. Avandia [package insert]. Research Triangle Park, NC:
GlaxoSmithKline; 2005. 7. Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8. Prandin [package insert].
Princeton, NJ: Novo Nordisk, Inc; 2004. 9. Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
39
Hypoglycemia is Common with SUs

25
Incidence of Hypoglycemia (%)

21.3%

20

15.3%
15 14%

11%
10

5%
5 2.9%*

0
Glyburide1 Chlorpropamide2 Glibenclamide3 Glimepiride3 Gliclazide4 Glipizide5

Sulfonylureas

*Hypoglycemia: fingerstick blood glucose measurement 50 mg/dL (2.75 mmol/L)

1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2. UKPDS Group. Lancet
1998; 352: 837853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419425. 4. McGavin JK, et al. Drugs 2002;
62; 13571364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002
41
Blocking DPP-4 Can Improve Incretin Activity and
Correct the Insulin:Glucagon Ratio in T2DM

Insulin
T2DM
Incretin
Further impaired
response Hyperglycemia
islet function
diminished

Glucagon

DPP-4 inhibitor
Insulin

Incretin
Improved islet Improved
activity
function glycemic control
prolonged

Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.
44
45
Trend of OAD usage in Indonesia 2010 -2011

Data Juni 2010 Juni 2011

Oral Anti Diabetic Agents
Unit Share Growth
(000) (%) (%)
TOTAL 695,858 100.00 9.01 More patients get OAD
SULPHONYLUREA 412,510 59.28 7.56 treatment vs Last Year
BIGUANIDE 243,620 35.01 12.67
GLITAZONE 4,471 0.64 2.14 SU and metformin still
A-GLUCOSIDASE INH 27,959 4.02 -2.64 popular in Indonesia
GLINIDE 632 0.09 -50.10
OTHER DRUGS 67 0.01 -19.42
DPP-IV Inhibitor as new
comer is well accepted
DPP-IV INHIBITOR 6,599 0.95 57.61
by doctors and patients
JANUVIA 2,457 37.24 51.74
GALVUS 2,691 40.78 23.77
GALVUSMET 1,434 21.73 264.88
ONGLYZA 16 0.25 999.00

Source: IMS ITMA June 2010 June 2011 46

 Saxagliptin Provides Significant Reductions in A1C, FPG,
and PPG in Drug-Nave Patients at Week 24 (Monotherapy)

SAXA 5 mg Placebo
A1C, %* FPG, mg/dL PPG, mg/dL
n= 103 92 105 92 84 71
Baseline Mean 8.0 7.9 171 172 278 283
0.6 3030
0.19 2020 6.1
0.4
6.1

AM From Baseline, mg/dL

1010
0.2
AM From Baseline, %

00
0.0
-10-10 -6.0
-8.7
-0.2 -20-20 -8.7
-0.4 -30-30 -6.0

-0.6
-40
-40
-50 -43.3
-0.8 -0.46 -50
-60
-1.0 -60 -43.3
-70
-1.2 -70-80

*P<.0001 vs placebo; P=.007;P=.0009.

BMS/AZ CONFIDENTIAL INFORMATION INTERNAL USE 1.Rosenstock
ONLY. DO NOT DUPLICATE,
J et al. Curr MedDISTRIBUTE OR USE IN CUSTOMER PRESENTATIONS.
Res Opin. 2009;2401-241.
47
2.AstraZeneca. Data on file, Study CV181011.
Saxagliptin + Metformin Provides Significant
Reductions in A1C, FPG, and PPG at Week 24
SAXA 5 mg + MET Placebo + MET
A1C, %* FPG, mg/dL* PPG, mg/dL*
n= 186 175 187 176 155 135
Baseline Mean 8.1 8.1 180 174 296 295

0.4 10 1.2
0.13
0.2 0

AM From Baseline, mg/dL

AM From Baseline, %

0 -10
-0.2 -20
-0.4 -30 -22.0
-18.0
-0.6 -40
-0.8 -50
-0.69
-1 -60
-1.2 -70
-58.2
-80
*P<.0001 vs placebo + MET.
1. DeFronzo R et al. Diabetes Care. 2009;32:1649-1655.
2. AstraZeneca. Data on file, Study CV181014.

BMS/AZ CONFIDENTIAL INFORMATION INTERNAL USE ONLY. DO NOT DUPLICATE, DISTRIBUTE OR USE IN CUSTOMER PRESENTATIONS.
48
 Saxagliptin + Metformin helps more patients achieve target
HbA1c compared to placebo plus metformin1

Percentage of patients reaching HbA1c <7.0% as add-on

to metformin alone compared to placebo1

50
P<0.0001
Patients reaching HbA1c <7% at week 24 (%)

44%
40

30

20
17%

10

0
Metformin + Metformin +
Placebo Onglyza 5 mg
1. DeFronzo RA, et al. Diabetes Care. 2009;32(9):1649-55.

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49
 Saxagliptin + Thiazolidinedione Provides Significant
Reductions in A1C, FPG, and PPG at Week 24
SAXA 5 mg + TZD Placebo + TZD
A1C, %* FPG, mg/dL PPG, mg/dL*
n= 183 180 185 181 134 127
Baseline Mean 8.4 8.2 160 162 303 291

0 10
0

AM From Baseline, mg/dL

AM From Baseline, %

-0.2
-10 -2.8

-0.4 -20
-17.3
-0.3 -30 -14.6
-0.6
-40

-0.8 -50
-60
-1
-0.9
-70

-1.2 -80 -64.6

*P<.0001 vs placebo + TZD.
P=.0005 vs placebo + TZD.
1. Hollander P et al. J Clin Endocrinol Metab. 2009;94:4810-4819.
2. AstraZeneca. Data on file, Study CV181013.

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50
 Saxagliptin + TZD results in significant increases in the
percentage of patients reaching HbA1c <7.0%1

Percentage of patients reaching HbA1c <7.0% as add-on

to a glitazone alone1

50
Patients reaching HbA1c <7% at week 24 (%)

P<0.0013 41.8%
40

30
25.6%
20

10

0
Glitazone + Glitazone +
Placebo Onglyza 5 mg

1. Hollander P, et al. J Clin Endocrinol Metab. 2009;94(12):4810-9.

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51
 Saxagliptin + Sulfonylurea Provides Significant
Reductions in A1C, FPG, and PPG at Week 24
SAXA 5 mg + SU Placebo + SU
A1C, %* FPG, mg/dL PPG, mg/dL*
n= 250 264 252 265 202 206
Baseline Mean 8.5 8.4 175 174 315 323
20 7.6
0.7 8.0
0.4 10
0.08 0.7

AM From Baseline, mg/dL

0.2 0
AM From Baseline, %

0 -10
-9.7
-20 -9.7
-0.2
-30
-0.4
-40 -34.0
-0.6 -34.2
-50
-0.8 -60
-0.64
-1 -70
-1.2 -80

*P<.0001 vs placebo + SU.

P=.0020 vs placebo + SU.
1. Chacra AR et al. Int J Clin Pract. 2009;63:1395-1406.
2. AstraZeneca. Data on file, Study CV181040.

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52
 Saxagliptin + sulfonylurea results in significant increases in
the percentage of patients reaching HbA1c <7.0%1

Percentage of patients reaching HbA1c <7.0% as add-on

to sulphonylurea alone compared to placebo1

50
Patients reaching HbA1c <7% at week 24 (%)

40

30
P<0.0001
22.8%
20

10 9.1%

0
Up-titrated glibenclamide + Glibenclamide +
Placebo Onglyza 5 mg

1. Chacra AR, et al. Int J Clin Pract. 2009;63(9):1395-406.

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53
 Low Incidence of Hypoglycemia
With Saxagliptin 5 mg

Add-on to MET1 Add-on to TZD2 Add-on to SU3

SAXA + PBO + SAXA + PBO + SAXA + PBO +

MET MET TZD TZD SU SU
(n=191) (n=179) (n=186) (n=184) (n=253) (n=267)
% of Patients
Reported
5.2 5.0 2.7 3.8 14.6 10.1
hypoglycemia

Confirmed
0.5 0.6 0 0 0.8 0.7
hypoglycemia

1. DeFronzo R et al. Diabetes Care. 2009;32:1649-1655.

2. Hollander P et al. J Clin Endocrinol Metab. 2009;94:4810-4819.
3. Chacra AR et al. Int J Clin Pract. 2009;63:1395-1406.

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54
 Combination Therapy With Saxagliptin 5 mg
Was Weight Neutral
Add-on to MET1 Add-on to TZD2 Add-on to SU3

SAXA + PBO + SAXA + PBO + SAXA + PBO +

MET MET TZD TZD SU SU
(n=191) (n=177) (n=185) (n=182) (n=253) (n=265)

Baseline mean 87.27 87.45 80.5 80.9 76.2 75.6

(SE), kg (1.23) (1.32) (1.42) (1.60) (1.11) (1.07)
Mean (SE)
0.87 0.92 1.4 0.9 0.8 0.3
change from
(0.23) (0.22) (0.23) (0.20) (0.13) (0.14)
baseline
SE, standard error.

1. AstraZeneca. Data on file, Study CV181014.

2. AstraZeneca. Data on file, Study CV181013.
3. AstraZeneca. Data on file, Study CV181040.

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55
 Adverse Reactions Occurring in 5% of
Patients: Pooled Data From Clinical Trials
% of Patients
SAXA 5 mg Placebo
Add-on therapy and monotherapy* N=882 N=799
Upper respiratory tract infection 7.7 7.6
Urinary tract infection 6.8 6.1
Headache 6.5 5.9
Metformin in drug-nave N=320 N=328
Headache 7.5 5.2
Nasopharyngitis 6.9 4.0
* Data pooled from 5 placebo-controlled trials: 2 monotherapy trials and 1 add-on combination therapy trial with each of the following: metformin,
thiazolidinedione, or glyburide; table shows 24-week data regardless of glycemic rescue.; data from a 24-week, active-controlled trial of
saxagliptin plus metformin verus placebo plus metformin in treatment-nave patients.

OnglyzaTM [package insert]. Princeton, NJ: Bristol-Myers Squibb Company & Wilmington, DE: AstraZeneca Pharmaceuticals LP; July 2009.

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58
 Saxagliptin + Metformin vs Glipizide +
Metformin: 52-Week Noninferiority Trial
SAXA 5 mg + MET SU + MET
A1C, %* FPG, mg/dL PPG, mg/dL
n= 293 293 424 426 18 17
Baseline Mean 7.5 7.5 162 161 285 280

0.0 20
10

AM From Baseline, mg/dL

AM From Baseline, %

-0.2 0
-10
-0.4 -20 -9.5
-15.6
-30
-0.6 -40
-50
-60
-0.8
-0.74 -70 -28.5
-0.80
-80
-1.0
*Per-protocol analysis set (primary analysis); Full analysis set, LOCF; -90 -49.2
Full analysis set, LOCF, oral glucose tolerance test subset.

Gke B, et al. Presented at: 70th Annual Meeting of the American Diabetes Association; June 25-29, 2010. Orlando, FL. Abstract 578-P.
AstraZeneca. Data on file, Study D1680C00001.

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59
 Saxagliptin + Metformin vs Sulfonylurea +
Metformin: Difference in Hypoglycemia

SAXA + MET GLIP + MET

(N=428) (N=430)
Number (%) of patients with a
13 (3.0) 156 (36.3)
hypoglycemic event
Difference in proportions vs GLIP + MET
Difference 33.2%
95% 2-sided CI for difference 38.1, 28.5
P value <.0001*
*Between-group comparison significant after controlling overall alpha of the study

AstraZeneca. Data on file, Study D1680C00001.

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 Saxagliptin + Metformin vs Sulfonylurea +
Metformin: Difference in Weight Gain

SAXA + MET GLIP + MET

(N=424) (N=428)
Baseline mean, kg (SE) 88.7 (0.91) 88.6 (0.95)
Adjusted mean change from baseline 1.1 (0.17) 1.1 (0.17)
Difference vs glipizide + metformin
Mean (SE) 2.2 (0.24)
95% 2-sided CI 2.7, 1.7
P value <.0001*
*Between-group comparison significant after controlling overall alpha of the study

AstraZeneca. Data on file, Study D1680C00001.

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61
 Conclusions
There is a need for a large proportion of
patients to be adjusted to more intensive
pharmacotherapy
Traditional oral treatments of T2DM do not
address the key driver of T2DM: the sensitivity
the -cell and -cell to glucose
Saxagliptin - DDP-4 inhibitor as monotherapy
or add on, provided statistically and clinically
important reductions in glyceamia parameters
(HbA1c, FPG, PPG) with lower incidence of
Hypoglycemia.