1. Comprehensive Glycaemia Control With Saxagliptin Emerging Option for Type 2 DM Management - Dr. Pradana

7/30/2019 1. Comprehensive Glycaemia Control With Saxagliptin Emerging Option for Type 2 DM Management - Dr. Pradana

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Pradana Soewondo

Department of Internal MedicineFaculty of Medicine University of Indonesia-

Cipto Mangunkusumo National ReferralHospital

Jakarta, Indonesia

Comprehensive Glycaemia Control with

Saxagliptin : Emerging Option for Type 2 DM

Management


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Overview

Epidemiology diabetes in

Indonesia

Results of DiabCare study 2008

Diabetes management

Algorithm Perkeni

Saxagliptin -DDP-4 Inhibitors

Conclusion


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Diabetes

Diagnostic Cut Points for IFG, IGT, and

Diabetes

ADA=American Diabetes Association; IFG=impaired fasting glucose; IGT=impaired glucose tolerance

Adapted from American Diabetes Association. Diabetes Care. 2006; 29(suppl 1): S4S42.

2-h Postload Glucose

Fasting Glucose

100 mg/dL

140 mg/dL

NormalGlucose

200 mg/dL

IGT

126 mg/dL

IFG IFG + IGT


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Prevalence of IGT and DM In Indonesia

Known DM Undiagnosed

DM

Total DM IGT

1,5 % 4,2 % 5,7 % 10,2 %

Indonesian National Health Survey,

2007

N = 24.400

> 15 years


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Papua Barat (21,8%) Sulawesi Barat (17,6%) Sulawesi Utara (17,3%)

Kalimantan Selatan(14,7%)

Jawa Tengah (13,1%)


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Kalimantan Barat (11,1%) Maluku Utara (11,1%) Riau (10,4%)

Bangka Belitung (8,6%)

NAD (8,5%)


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The DiabCare Asia 2008 Study Outcomes onControl 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. Thisstudy also evaluated the physician perspectives,psychological aspects, and quality of life ofdiabetic patients.


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Variable Data

Age (Years)* (n=1719) 58.939.57

Gender** (n=1803) Male/ Female793 (43.3) / 1010

(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

Type 2

Others

17 (0.9)

1785 (97.5)

2 (0.1)

BMI (Kg/m2)14 * (n=1646)


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Diabetes management variable Data, n (%)Type of Management

Diet Insulin monotherapy

Insulin and OAD combination

OAD monotherapy

Herbal

None

-317 (17.3)

356 (19.4)

1133 (61.9)

5 (0.3)

20 (1.1)Type of OAD Therapy

Biguanides

Sulphonylureas

Meglitinides

Alpha Glucosidase inhibitorsThiazolidinediones

Other OADs

Traditional Herbal medicines

Double drug fixed dose combination

Triple drug fixed dose combination

1085(59.3)

1036(56.6)

8(0.4)

461(25.2)51(2.8)

48 (2.6)

5(0.3)

88 (4.8)

5 (0.3)

Diabetes Management - The DiabCare Indonesia

2008


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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


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Glycemic Control In The Study Population

Fasting Postprandial A1c

143.6 mg% 207.7 mg% 8.1 %

143.6

207.7 200.2

0

50

100

150

200

250

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

Glycaemi

ccontrollevel

DiabCare Indonesia 2008


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67.85

81.01

47.22

68.78

0

10

20

30

40

50

60

70

80

90

ADA

(7%)

AACE/IDF

/APDPG(6.5%)

ADA (>7.22) AACE/IDF

/APDPG(6.1)

%o

fpatients

FPG (mmol/l)HbA1c (%)

A1c and FPG stratified according to differentguidelines

DiabCare Indonesia 2008

Only 32% patients reach target HbA1c < 7%


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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


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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

Comparison of 2003 and 2008 DiabCare study


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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


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BMS/AZ CONFIDENTIAL INFORMATION INTERNAL USE ONLY. DO NOT DUPLICATE, DISTRIBUTE OR USE IN CUSTOMER PRESENTATIONS.17

Multiple Factors Contribute to T2DM

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.

Decreased glucose

uptake

Progressive -celldysfunction

Hepatic

glucose production

Lack of

glucagonsuppression

Impaired

incretinsignaling

Increased

renalglucose transport

Type 2 Diabetes

Increased

lipolysis


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18

Pancreatic Islet Dysfunction Leads to Hyperglycemiain T2DM

Glucose

Fewer-Cells -CellsHypertrophy

Insufficient

Insulin

Excessive

Glucagon+

Glucose

Uptake

HGO

+

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.


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19

Abnormal Pancreatic Islet Function Determines the Development ofIGT and T2DM in the Setting of Insulin Resistance

Age, lifestyle,environmental factors

Insulin resistance

Normal islet

function

NGT IGT / T2DM

Abnormal

islet function

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.


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Insulin and Glucagon Response to a LargeCarbohydrate Meal in Type 2 Diabetes

Insulin

(U/ml)

Glucagon

(g/ml)

Glucose

(mg/100ml)

*Insulin measured in five patientsAdapted from Mller WA et al N Engl J Med1970;283:109115.

Type 2 diabetes mellitus (n=12)*Nondiabetic controls (n=11)

150

0

140

90

360

80

240

60

Time (minutes)

30

60

90

120

110

270

300

330

100

110

120130

Meal

Nonsuppressed glucagon

0 60 120 180 240

Depressed/delayed insulin response


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22

Adapted from Brubaker PL, Drucker DJ Endocrinology2004;145:26532659; Zander M et al Lancet2002;359:824830; Ahrn B Curr Diab Rep2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483.

Incretins Regulate Glucose HomeostasisThrough Effects on Islet Cell Function

Active

GLP-1 and GIP

Release of

incretin guthormones

Pancreas

Blood

glucose control

GI tract

Glucagonfrom alpha cells(GLP-1)

Glucose dependent

Alpha cells

Increased insulin

and decreased

glucagon

reduce

hepatic

glucose output

Glucose dependent

Insulinfrom beta cells

(GLP-1 and GIP)

Beta cells

Insulin

increases

peripheral

glucose

uptake

Ingestion offood


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23

L-Cell

(ileum)

Proglucagon

GLP-1 [737]

GLP-1 [736 NH2]

K-Cell

(jejunum)

ProGIP

GIP [142]

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1

Adapted from Drucker DJ. Diabetes Care. 2003; 26: 29292940.

GLP-1 and GIP Are Synthesized and Secreted from theGut in Response to Food Intake


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24

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

*P


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25

N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule wasallowed for one day between the experiments with GLP-1 and placebo.

*p


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26

FPG=fasting plasma glucose; HGP=hepatic glucose production; T2DM=type 2 diabetes mellitus

Adapted from DeFronzo RA. Diabetes. 1988; 37: 667687.

1.0

1.5

2.02.5

3.0

3.5

4.0

4.5

50 100 150 200 250 300

FPG (mg/dL)

HGP(mg/kg min)

Excessive

glucagon-mediated

glucose output

0.8

1.2

1.6

2.0

2.4

2.8

50 100 150 200 250 300

Glucose Clearance(mL/kg min) Impaired

insulin-mediated

glucose disposal

Diagnosis

Decreased Glucose Disposal and Increased HGPContribute to Increased FPG in T2DM


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29

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.

Prediabetes

(IFG/IGT)NGT Diabetes

Insulin resistance

Islet cell functionDiagnosis

Treatment Targets: Deteriorating Islet Cell Function inthe Setting of Insulin Resistance


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30

Pharmacologic Targets of Current Drugs Used in the

Treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate

absorption

ThiazolidinedionesIncrease glucose uptake inskeletal muscle and

decrease lipolysis in

adipose tissue

SulfonylureasIncrease insulin secretion

from pancreatic -cells

GLP-1 analog (exenatide injectable)

Improves glucose-dependent insulinsecretion, suppresses glucagon secretion,

slows gastric emptying

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.

MeglitinidesIncrease insulin secretion

from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action, stimulate insulin

secretion, suppress glucagon release


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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%

Glinides 1 to 1.5%1

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 nateglinideAdapted from Nathan DM, et al. Diabetes Care2009;32:193-203.

Al it P l l DM ti 2 T D k i


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Algoritme Pengelolaan DM tipe-2 Tanpa Dekompensasi

DM Tahap-I Tahap-II Tahap-III

GHSGHS

+

monoterapi

GHS

+Kombinasi 2 OHO

GSH

+

Kombinasi 3 OHO

GHS

+

Kombinasi 2 OHO

+

Basal insulin

Insulin intensif*

Jalur pilihan alternatif, bila:-tidak terdapat insulin

-diabetisi betul-betul menolak

insulin

-kendali glukosa belum

optimal

Catatan:1. GHS = gaya hidup sehat

2. Dinayatakan gagal bi laterapi selama 2-3 bulan

pada tiap tahap tidak

mencapai target terapi

HbA1c


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9% 9-10% >10%

Kadar HbA1c

GHS

Gaya HidupSehat

Penurunan

berat badan

Mengatur diit

Latihan

Jasmani teratur

GHS

+

Monoterapi

Met, SU,

AGI, Glinid,

TZD,

DPP-IV inh

GHS

+

Kombinasi

2 obat

Met, SU,AGI, Glinid

TZD,

DPP-IV inh

GHS

+

Kombinasi3 obat

Met, SU,

AGI, Glinid

TZD, DPP-

IV inh

GHS

+

Kombinasi

2 obat

Met, SU,

AGI,Glinid, TZD

+

Basal Insulin

GHS

+

Insulin

Intensif*

Catatan

1. Dinyatakan gagal bila

dengan terapi 2-3 bulan

tidak mencapai target

HbA1c


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34

-Cell Function Continues to Decline Regardless ofIntervention in T2DM

T2DM=type 2 diabetes mellitus

*-cell function measured by homeostasis model assessment (HOMA)

Adapted from UKPDS Group. Diabetes. 1995; 44: 12491258.

0

20

40

60

80

100

5 4 3 2 1 0 1 2 3 4 5 6

Years Since Diagnosis

-CellFunction(

%)*

Progressive loss of-cell functionoccurs prior to diagnosis

Metformin (n=159)

Diet (n=110)

Sulfonylurea (n=511)


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35

ADOPT Study: Progression of Hyperglycemia in T2DM

*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment

Kahn SE, et al. N Engl J Med. 2006; 355: 24272443.

Years

6.0

7.6

8.0

6.8

0 1 2 3 4 5

GlycatedHemoglobin(%)

7.2

0

Rosiglitazone, 0.07 (0.06 to 0.09)

Metformin, 0.14 (0.13 to 0.16)*

Glyburide, 0.24 (0.23 to 0.26)*

6.4

No. of Patients 4012 3308 2991 2583 2197 822

Treatment difference (95% CI)

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


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36

Traditional Current OralTherapies Do Not AddressIslet Cell Dysfunction

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24S40.

Pancreatic Islet Dysfunction

Inadequate

glucagon

suppression

(-cell

dysfunction)

Progressive

decline of-cell

function

Insufficient

Insulin secretion

(-cell

dysfunction)

Sulfonylureas

Glinides

TZDsMetformin

Insulin Resistance

(Impaired insulin action)

C t i di ti d P ti f C t T2DM


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37

Contraindicated in renal dysfunction, avoid in liver disease, monitor

renal function

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

for hypoglycemia

TZDs

-Glucosidase

inhibitors

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.

Contraindicated in severe liver disease, congestive heart failure,

monitor liver enzymes

Not recommended in severe renal impairment,

check serum liver enzymes

Metformin

SUs

Meglitinides

Contraindications and Precautions for Current T2DM

Treatments Limit Use

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

Exenatide

injectable Use caution in severe renal or severe GI disease


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38

Metformin1

TZDs1-3

-glucosidase

inhibitors1

CHF=congestive heart failure; GI=gastrointestinal; SU=sulfonylurea; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedioneaRole uncertain1Inzucchi SE. JAMA 2002; 287: 360-372; 2Avandia US Prescribing Information; 3Dormandy JA, et al. Lancet2005; 366: 1279-1289; 4Buse JB, et al.Diabetes Care2004; 27: 2628-2635; 5DeFronzo RA, et al. Diabetes Care2005; 28: 1092-1100; 6Kendall DM, et al. Diabetes Care2005; 28: 1083-1091;

7Kolterman OG, et al. Am J Health-Syst Pharm2005; 62: 173-181; 8Byetta US Prescribing Information.

Incretin

mimetics4-8

Weight gain, edema, CHF, bone fractures (pioglitazone,rosiglitazone)

Myocardial ischemic events (rosiglitazone)

GI effects (flatulence, diarrhea)

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

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

hypoglycemia (in add-on to SU)

SUs1

Meglitinides1

Hypoglycemia, weight gain, hyperinsulinemiaa

Major Adverse Events of Current Treatments for T2DM LimitEfficacy

W i ht G i i C Sid Eff t f Di b t


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39

TZDs46

Metformin + TZD5,6,9

Metformin + SU13

Meglitinides4,7,8

SUs14

Metformin13

Weight Change (kg)OAD Agents

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.

Weight Gain is a Common Side Effect of DiabetesTreatments

-5 -4 -3 -2 -1 0 1 2 3 4 5

-3.80.5

-0.41.7

0.94.6

0.33.0

-0.31.9

0.82.1


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41

Hypoglycemia is Common with SUs

*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. Lancet1998; 352: 837853. 3. Draeger KE, et al. Horm Metab Res. 1996; 28: 419425. 4.McGavin JK, et al. Drugs2002;

62; 13571364. 5.Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002

Sulfonylureas

Glipizide5Gliclazide4Chlorpropamide2Glyburide1

0

5

10

15

20

25

IncidenceofHypoglycemia(%) 21.3%

15.3%

5%

2.9%*

14%

11%

Glibenclamide3 Glimepiride3

Bl ki g DPP 4 C I I ti A ti it d


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44

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.

Insulin

Glucagon

Improved

glycemic control

Incretinactivity

prolonged

Improved islet

function

DPP-4 inhibitor

Insulin

Glucagon

HyperglycemiaIncretin

response

diminished

Further impaired

islet function

T2DM

Blocking DPP-4 Can Improve Incretin Activity andCorrect the Insulin:Glucagon Ratio in T2DM


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45


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46Source: IMS ITMA June 2010 June 2011

Trend of OAD usage in Indonesia 2010 -2011

Oral Anti Diabetic Agents

Data Juni 2010 Juni 2011

Unit

(000)

Share

(%)

Growth

(%)

TOTAL 695,858 100.00 9.01

SULPHONYLUREA 412,510 59.28 7.56

BIGUANIDE 243,620 35.01 12.67

GLITAZONE 4,471 0.64 2.14

A-GLUCOSIDASE INH 27,959 4.02 -2.64

GLINIDE 632 0.09 -50.10

OTHER DRUGS 67 0.01 -19.42

DPP-IV INHIBITOR 6,599 0.95 57.61

JANUVIA 2,457 37.24 51.74GALVUS 2,691 40.78 23.77

GALVUSMET 1,434 21.73 264.88

ONGLYZA 16 0.25 999.00

More patients get OADtreatment vs Last Year

SU and metformin stillpopular in Indonesia

DPP-IV Inhibitor as newcomer is well acceptedby doctors and patients

S li ti P id Si ifi t R d ti i A1C FPG


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

-8.7

6.1

-80

-70

-60

-50

-40

-30

-20

-10

010

20

30

-43.3

-6.0

1.Rosenstock J et al. Curr Med Res Opin. 2009;2401-241.2.AstraZeneca. Data on file, Study CV181011.

-0.46

0.19

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

*P


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Saxagliptin + Metformin Provides SignificantReductions in A1C, FPG, and PPG at Week 24

-22.0

-58.2

1.2

-18.0

-80

-70

-60

-50

-40

-30

-20

-10

0

10

SAXA 5 mg + MET Placebo + MET

*P


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Saxagliptin + Metformin helps more patients achieve targetHbA1c compared to placebo plus metformin

1

Percentage of patients reaching HbA1c


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Saxagliptin + Thiazolidinedione Provides SignificantReductions in A1C, FPG, and PPG at Week 24

-0.9

-0.3

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

*P


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Saxagliptin + TZD results in significant increases in thepercentage of patients reaching HbA1c


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Saxagliptin + Sulfonylurea Provides SignificantReductions in A1C, FPG, and PPG at Week 24

-9.7

0.7

-80

-70

-60

-50

-40

-30

-20

-10

0

10

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

AM

FromBaseline

,%

AM

FromBaseline,m

g/dL

*P


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Saxagliptin + sulfonylurea results in significant increases inthe percentage of patients reaching HbA1c


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Low Incidence of HypoglycemiaWith Saxagliptin 5 mg

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.

% of Patients

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

SAXA +MET

(n=191)

PBO +MET

(n=179)

SAXA +TZD

(n=186)

PBO +TZD

(n=184)

SAXA +SU

(n=253)

PBO +SU

(n=267)

Reportedhypoglycemia

5.2 5.0 2.7 3.8 14.6 10.1

Confirmedhypoglycemia

0.5 0.6 0 0 0.8 0.7

Combination Therapy With Saxagliptin 5 mg


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Combination Therapy With Saxagliptin 5 mgWas Weight Neutral

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

SAXA +MET

(n=191)

PBO +MET

(n=177)

SAXA +TZD

(n=185)

PBO +TZD

(n=182)

SAXA +SU

(n=253)

PBO +SU

(n=265)

Baseline mean(SE), kg

87.27(1.23) 87.45(1.32) 80.5(1.42) 80.9(1.60) 76.2(1.11) 75.6(1.07)

Mean (SE)change frombaseline

0.87(0.23)

0.92(0.22)

1.4(0.23)

0.9(0.20)

0.8(0.13)

0.3(0.14)

SE, standard error.

1. AstraZeneca. Data on file, Study CV181014.



Adverse Reactions Occurring in 5% of


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% 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

Adverse Reactions Occurring in 5% ofPatients: Pooled Data From Clinical Trials

* 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.

Saxagliptin + Metformin vs Glipizide +


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Saxagliptin + Metformin vs Glipizide +Metformin: 52-Week Noninferiority Trial

*Per-protocol analysis set (primary analysis); Full analysis set, LOCF;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.

-0.74

-0.80

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

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

AM

FromBaselin

e,%

AM

FromBaseline,mg/dL

-9.5

-49.2

-15.6

-28.5

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

Saxagliptin + Metformin vs Sulfonylurea +


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g p yMetformin: Difference in Hypoglycemia

SAXA + MET(N=428)

GLIP + MET(N=430)

Number (%) of patients with ahypoglycemic event

13 (3.0) 156 (36.3)

Difference in proportions vs GLIP + MET

Difference 33.2%

95% 2-sided CI for difference 38.1,28.5

Pvalue


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g p yMetformin: Difference in Weight Gain

SAXA + MET(N=424)

GLIP + MET(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

Pvalue


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Conclusions

There is a need for a large proportion ofpatients to be adjusted to more intensivepharmacotherapy

Traditional oral treatments of T2DM do not

address the key driver of T2DM: the sensitivitythe -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.


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Documents

1. Comprehensive Glycaemia Control With Saxagliptin Emerging Option for Type 2 DM Management - Dr. Pradana