msd trivandrum dr ka

1

Sitagliptin: A Novel Dipeptidyl Peptidase-4 Inhibitor, Improves Glycemic Control in

Patients with Type 2 Diabetes

Dr Karthik AnantharamanMSD Pharmaceuticals Pvt Ltd (India)

Agenda

• Type 2 Diabetes and Islet Cell function

• Incretins, DPP-4 inhibition, and Glucose Homeostasis

• Description of Sitagliptin (Januvia™)

• Phase III Clinical Data for Sitagliptin

• Summary and Future Direction

Old Concept of T2DM

InsulinResistance

InsulinResistance

HyperglycemiaHyperglycemia

InsulinDeficiency

(Beta Cell Dysfunction)

InsulinDeficiency


Patients with T2DM Have Already Lost Substantial

-Cell Function at Diagnosis

*Diet and exercise. N= 376. Adapted from UKPDS 16. Diabetes. 1995;44:1249–1258. Permission required.

Diagnosis

0%

25%

50%

75%

100%

0 1 2 3 4 5 6

Years from diagnosis

Beta

-cell

fu

ncti

on

(%

B)

Conventional therapy*

(%B

)

Beta-Cell Function Is Abnormal in Type 2 Diabetes

• A range of functional abnormalities is present– Abnormal oscillatory

insulin release

– Increased proinsulin levels

– Loss of 1st-phase insulin response

– Abnormal 2nd-phase insulin response

– Progressive loss of beta-cell functional mass

*p<0.05 between groups.

Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46; Polonsky KS et al. N Engl J Med. 1988;318:1231–1239; Quddusi S et al. Diabetes Care. 2003;26:791–798; Porte D Jr, Kahn SE. Diabetes. 2001;50(suppl 1):S160–S163; Figure adapted from Vilsbøll T et al. Diabetes. 2001;50:609–613.

Insu

lin

(pm

ol/L

)

Mixed meal

Normal subjectsType 2 diabetics

Time (min)

**

500

400

300

200

100

00 60 120 180

Reprinted from Ferrannini E et al. J Clin Endocrinol Metab. 2005;90:493–500.

Decrease in Glucose-Stimulated Insulin Secretion in T2DM (Beta Cell glucose

sensitivity)

1000

800

600

400

200

05 10 15 20 25

Insu

lin s

ecre

tio

n r

ate

(pm

oL

·min

-1·m

-2)

Obese NGT tertilesLean NGTIGTT2DM quartiles

Plasma glucose (mmol/L)

Insulin and Glucagon Dynamics in T2DM

-60 0 60 120 180 240

360

330

300

270

240

110

80

140

130

120

110

100

90

120

90

60

30

0

Glucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Meal

Time (min)

Type 2 diabetes

Normal subjects

Delayed/depressedinsulin response

Nonsuppressed glucagon

Normal subjects, n=11; Type 2 diabetes, n=12.Adapted from Müller WA et al. N Engl J Med. 1970;283:109–115.

Hepatic Glucose Output in T2DM

-6

-4

-2

0

2

4

6

-120 0 120 240 360 480

Mixed meal

Fasting Fed

Glucose uptake

Meal-derived glucose

Hepatic glucose production

-8

-6

-4

-2

0

2

4

6

8

10

-120 0 120 240 360 480

Time from start of mixed meal (min)

Hepatic glucose production

Glucose uptake

Meal-derived glucose

Subjects with diabetes (n=7)

Control subjects(n=5)

Glu

cose

flu

x (m

g·k

g-1·m

in-1)

Glu

cose

flu

x (m

g·k

g-1·m

in-1)

Fasting Fed

Adapted from Lebovitz HE et al. Changing the Course of Disease: Gastrointestinal Hormones and Tomorrow's Treatment of Type 2 Diabetes. Available at: http://www.medscape.com from Medscape Diabetes & Endocrinology, Nov 2004 . Accessed August 2005.

Data for controls anddiabetes calculated fromPehling G et al. J Clin Invest. 1984;74:985–991.

Summary – cell in T2DM

• Lack of suppression of glucagon secretion – Reduced insulin– ? Insulin resistance in cell

• Increased secretory capacity

• Increased cell number

• Altered Islet morphology – loss of normal relationship between and cells

Old Concept – Newer Insights

Incretin DefectIncretin Defect

InsulinResistance

InsulinResistance

HyperglycemiaHyperglycemia

InsulinDeficiency


InsulinDeficiency


Increased HGO Non-suppressed

Glucagon(Alpha Cell Dysfunction)

Increased HGO Non-suppressed

Glucagon(Alpha Cell Dysfunction)

Alpha-Alpha-Glucosidase Glucosidase InhibitorsInhibitors1,21,2

MeglitinidesMeglitinides33 SUsSUs4,54,5TZDsTZDs6,76,7 MetforminMetformin88

DPP-4 DPP-4 InhibitorsInhibitors

Insulin deficiency

Insulin resistance

Excess hepatic glucose output

Maj

or P

atho

phys

iolo

gies

1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

Intestinal glucose absorption

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

April 8, 2023 Confidential

Challenges of not being able to treat patient to goal

Medicines

ClassDosage /

dayMeal

dependenceGI side effects

AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET

SU

TZD

AGI

Exenatide

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU

TZD

AGI

Exenatide

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3

TZD

AGI

Exenatide

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3

TZD 1CHF, Fractures, MI, Class effect

AGI

Exenatide

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3


AGI 3

Exenatide

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3


AGI 3

Exenatide 2 Injectable

Insulin

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3


AGI 3


Insulin 1-3 InjectableIntensive

monitoring

Galvus

Therapy Issues

ClassDosage /

dayMeal


AdminHypo -

glycemiaWeight

GainFluid

retentionOthers

B-cell exhaustion

MET 1-3

SU 2-3


AGI 3


Insulin 1-3 InjectableIntensive

monitoring

Galvus 2Skin lesions, elevated liver

enzymes

Therapy Issues

Incretins, DPP-4 inhibition, and glucose homeostasis

GLP-1 and GIP Are the Two Major Incretins

GLP-1 GIP

• Secreted by L-cells in the distal gut (ileum and colon)

• Stimulates glucose-dependent insulin release

• Secreted by K-cells in the proximal gut (duodenum)

• Stimulates glucose-dependent insulin release

• Suppresses hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent manner

• Enhances beta-cell proliferation and survival in animal models and isolated human islets

• Enhances beta-cell proliferation and survival in islet cell lines

GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptideAdapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.

Active GLP-1 and GIP

Release of incretin gut hormones More stable

glucose controlMore stable

glucose control

GI tract

Ingestionof food

Incretins (GLP-1 and GIP) Regulate Glucose Homeostasis Through Effects on Islet Cell

Function

Pancreas

Beta cellsAlpha cells

Glucoseuptake andstorage inmuscles andadipose tissue

Glucoseuptake andstorage inmuscles andadipose tissue

Glucose dependent Insulin

from beta cells(GLP-1 and GIP)

Glucagon from alpha cells

(GLP-1)Glucose dependent

Glucose release into the bloodstream by liver

Glucose release into the bloodstream by liver

Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653–2659; Zander M et al. Lancet. 2002;359:824–830; Ahrén B. Curr Diab Rep. 2003;3:365–372; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; Holz GG, Chepurny OG. Curr Med Chem. 2003;10:2471–2483; Creutzfeldt WOC et al. Diabetes Care. 1996;19:580–586; Drucker DJ. Diabetes Care. 2003;26:2929–2940.

GLP-1 and GIP metabolites

DPP-4 enzymeDPP-4

enzyme

• In animal models of diabetes both GLP-1 and GIP have been shown to increase β-cell mass• The incretin axis is abnormal in patients with T2DM: Reduced release of GLP-1; reduced response to GIP

*

*

* ** * *

* * *

*** *

**

** *

GLP-1 Actions Are Glucose Dependent in Patients With Type 2 Diabetes

PlaceboGLP-1

Time (min)

*p<.05

Insulin

Glucagon

Fastingglucose

250

150

5

250200

10050

40

30

20

10

0

mU/L

20

15

10

0 60 120 180 240

15.012.510.07.55.0

200

150

100

50Infusion

mmol/L mg/dL

pmol/L

pmol/L Effect declinesas glucose

reaches normal

n=10.Adapted from Nauck NA et al. Diabetologia. 1993;36:741–744.

Summary of Trials: GLP-1 and GIP Levels and Actions in Type 2 Diabetes

*When corrected for gender and BMIAdapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723; Nauck MA et al J Clin Invest 1993;91:301–307.

Patients with type 2 diabetes mellitus

Incretin levels Incretin actions

GLP-1 (p<0.05 vs. NGT) Intact

GIP Intact* (p=0.047 vs. NGT)

Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes

*P<0.05, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

Copyright © 2001, The Endocrine Society.

* * * * ** *

Meal Started

Meal Finished

(10–15)

17

Effects of GLP-1 and GIP on the First- and Second-Phase Insulin Response in Type 2

Diabetes

0.00

0.50

1.00

1.50

2.00

GLP-1 GIP Saline

Type 2 diabetes

Ear

ly-p

has

e in

suli

n A

UC

0-2

0 m

in(2

0 m

in x

nm

ol/

L)

*

*

0

5

10

15

20

25

30

35

40

45

GLP-1 GIP Saline

Type 2 diabetes

Lat

e-p

has

e in

suli

n A

UC

20

-12

0 m

in(1

00 m

in x

nm

ol/

L)

**

GLP-1 and GIP increased first-phase insulin response.

GLP-1 but not GIP increased second-phase insulin response.

n=6

*P<0.05 vs saline.; ** P<0.05 vs saline and GIP.Data are (mean ± SEM) from the cohort of lean patients with type 2 diabetes, who underwent 3 hyperglycemic clamps with continuous infusion of saline, GLP-1 or GIP.Adapted with permission from Vilsbøll T et al. J Clin Endocrinol Metab. 2003:88;4897–4903. Copyright © 2003, The Endocrine Society.

DPP9

DPP8

FAP

DPP-4

DPP6

PEP

QPP/DPPII

APP

prolidase

DPP-4 Gene Family

Other Proline Specific Peptidases

Function

unknown

unknown

unknown

unknown

unknown

unknown

unknown

GLP-1 / GIP cleavage

unknown

NH2-Xaa~Pro-COOH

--Xaa-Pro~Yaa--

NH2-Xaa-Pro~Yaa--

NH2-Xaa~Pro-Yaa----

catalytically inactive

NH2-Xaa-Pro~Yaa--

Specificity

DPP-4 Is a Member of a Family of Proline Specific Peptidases

Anatomical Relationship Between GLP-1+ L Cells and DPP-4+ Endothelium

Cleft

Hole

Active site

Probable entrance to active site

Possible exit of cleaved dipeptide

Hole

DPP- 4

Active GLP-1

Inactive GLP-1

Inhibition of DPP-4 Increases Active Incretin Levels, Enhancing Downstream

Incretin Actions

Active GIP

Inactive GIP

Increased insulin secretion Decreased glucagon release

Glucose control improved

DPP-4 inhibitorΧ

Sitagliptin - Overview

• DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006. EU approval March 2007

• Provides potent and highly selective inhibition of the DPP-4 enzyme

• Fully reversible and competitive inhibitor

N

ONH2

NN

CF3

F

F

F

N

Sitagliptin Is Potent and Highly Selective (>2500x)

for the DPP-4 Enzyme

Herman et al. ADA. 2004.

Enzyme IC50 (nM)

DPP-4 18

DPP-8 48,000

DPP-9 >100,000

DPP-2, DPP-7 >100,000

FAP >100,000

PEP >100,000

APP >100,000

Selective DPP-4 Inhibitors Are Not Associated WithPreclinical Toxicities Observed With Non-Selective

Inhibitors

Nonselective inhibitor

(DPP-8/9 and DPP-4)

Selective DPP-8/9 inhibitor

Sitagliptin – highly selective DPP-4 inhibitor

Study of T-Cell Proliferation1

Decreased Proliferation + + –

2-Week Rat Toxicity Study2

Alopecia + + –

Thrombocytopenia + + –

Anemia + + –

Enlarged spleen + + –

Mortality + + –

Acute Dog Toxicity Study2

Bloody diarrhea + + –

1. Leiting B et al. Abstract 6-OR. 64th ADA;2004. 2. Lankas GK et al. Diabetes. 2005;54:2988–2994.

Peter Stein

Monkey toxicity

Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing

• With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80%

– > 80% inhibition provides full enhancement of active incretin levels

• No effect of food on pharmacokinetics

• Well absorbed following oral dosing

• Tmax app 2 hours, t1/2 app 12.4 hours at 100 mg dose

• Low protein binding, app 38%

• Primarily renal excretion as parent drug– Approximately 80% of a dose recovered as intact drug in urine

• No clinically important drug-drug interactions– No meaningful P450 system inhibition or activation

Sitagliptin AUC 0-inf vs. creatinine clearance: AUC increases with decreasing creatinine

clearance

AUC GMR increase < 2-foldwhen CrCl > 50 mL/min

Dos

e-A

djus

ted

(to 5

0 m

g) A

UC

(uM

.hr)

0

4

8

12

16

20

24

28

Creatinine Clearance (mL/min)10 30 50 70 90 110 130 150 170 190 210 230

Dose adjustments< 30 mL/min – ¼ dose30 – 50 mL/min – ½ dose> 50 mL/min – full dose

Single-Dose OGTT Study

One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity

Hours post-dose

~80%

~50%

Trough DPP-4inhibition

Inh

ibit

ion

of

pla

sma

DP

P-4

acti

vity

fro

m b

asel

ine

(%)

0 1 2 4 8 12 16 20 24

–10

0

40

50

60

80

100

90

70

30

20

10

6 10 14 18 22 26

OGTT

Sitagliptin 25 mg (n=56)Sitagliptin 200 mg (n=56)Placebo (n=56)

% Plasma Inhibition of DPP-4 Activity With Sitagliptin 100 mg in Healthy Adults

Sitagliptin 100 mg (N=6)Placebo (N=2)

168

Per

cen

t In

hib

itio

n

Fro

m B

ase

lin

e

Hours postdose

100

90

80

70

60

50

40

30

20

10

0

–10

–200 1 2 4 6 12 24 36 48

Protocol 001.Herman GA et al. Clin Pharmacol Ther. 2005;78:675–688.

OGTT 24 hrs (n=19)

Herman et al. Diabetes. PN005, 2005.

Active GLP-1

A Single Dose of Sitagliptin Increased

Active GLP-1 and GIP Over 24 Hours

0

5

10

15

20

25

30

35

40

0 2 4 6 24 26 28

Hours Postdose

GL

P-1

(p

g/m

L)

OGTT 2 hrs (n=55)

Crossover study in patients with T2DM Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

2-fold increase in active GLP-1

p< 0.001 vs placebo

Active GIP

0

10

20

30

40

50

60

70

80

90

0 2 4 6 24 26 28

Hours Postdose

GIP

(p

g/m

L)

OGTT 24 hrs (n=19)

OGTT 2 hrs (n=55)

2-fold increase in active GIP

p< 0.001 vs placebo

A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic Excursion

After a Glucose Load

Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

0

10

20

30

40

0 1 2 3 4

mcI

U/m

L

50

55

60

65

70

75

0 1 2 3 4

Time (hours)

pg

/mL

Glucose load

Drug Dose 22%

~12%

Insulin

Glucagon

Crossover Study in Patients with T2DM

p<0.05 for both dose comparisons to placebo for AUC


Glucose load

Drug Dose

120

160

200

240

280

320

0 1 2 3 4 5 6

Time (hours)

Glucose

~26%


Phase III Clinical Studies of SitagliptinPhase III Clinical Studies of Sitagliptin

● ● MMonotherapy use onotherapy use

(P021, P023, A201, P040)(P021, P023, A201, P040)

●● Combination use with Metformin, a PPAR Combination use with Metformin, a PPAR agent agent

or SU or SU (P019, P020, P035 and P036)(P019, P020, P035 and P036)

●● Active Sulph comparator trial, added to metformin Active Sulph comparator trial, added to metformin

(P024)(P024)

Monotherapy Studies – Patients Studied

• Multinational studies– Mean duration of T2DM of 4.4 years

– Baseline mean A1C - 8.0%

• 54% of patients had A1C < 8%

– 53% prior OHA, mean BMI 31 kg/m2, mean age 54 years, 55% male

• Japanese study– Mean duration of T2DM of ~ 4 years

– Baseline mean A1C 7.6%

• ~ 65% had A1C < 8%

– ~ 45% on prior OHA, mean BMI 25 kg/m2, mean age 55 years, 60% male

38

Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in

Monotherapy

7.2

7.6

8.0

8.4

Placebo (n=244)

Sitagliptin 100 mg (n=229)

24-week Study

Time (weeks)

0 5 10 15 20 25

-0.79%(p<0.001)

*between group difference in LS means

Japanese Study

-1.05%(p<0.001)

Placebo (n=75)


Time (weeks)

0 4 8 12

A1C

(%

)

7.6

8.0

8.4

7.2

6.8

change vs placebo*

18-week Study

Placebo (n=74)


Time (weeks)

0 6 12 18

A1C

(%

)

7.2

7.6

8.0

8.4

-0.6%(p<0.001)

A1C

(%

)

=

Adapted from Raz et al. Diabetologia. 2006;49:2564–2571; Aschner et al. Diabetes Care. 2006;29:2632–2637.; Nonaka K et al; A201. Abstract presented at: ADA 2006

18-week Study

-0.44

-0.61

-1.2

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher

Baseline A1C

Baseline A1c (%)

Mean (%)

Red

ucti

on

in

A1

c (%

)

Inclusion Criteria: 7%–10%

Red

ucti

on

in

A1

c (%

)

<8% 8–9% >9%

7.37 8.40 9.48

24-week Study

-0.57

-0.8

-1.52-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

<8% 8–9% >9%

7.39 8.36 9.58

N=96

N=130N=70

N=62

N=27

N=37

Reductions are placebo-subtractedAdapted from Raz et al. Diabetologia. 2006;49:2564–2571; Aschner et al. Diabetes Care. 2006;29:2632–2637.

Peter Stein

Higher baseline patients - not severe

Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy

Fasting Glucose

Pla

sma G

luco

se m

g/d

L

Time (weeks)

0 5 10 15 20 25144

153

162

171

180

189

Placebo (n=247)Sitagliptin 100 mg (n=234)

FPG* = –17.1 mg/dL (p<0.001)

Post-meal Glucose

Time (minutes)

Pla

sma

Glu

cose

mg

/dL

in 2-hr PPG* = –46.7 mg/dL (p<0.001)

0 60 120 0 60 120

144

180

216

252

288

Placebo (N=204) Sitagliptin (n=201)

Baseline24 weeks

Baseline24 weeks

* LS mean difference from placebo after 24 weeks Adapted from Aschner et al. Diabetes Care. 2006;29:2632–2637.

Sitagliptin Improves the -Cell Response to Glucose

Monotherapy Studies

200

400

600

800

1000

1200

1400

160 180 200 220 240 260

Glucose concentration (mg/dL)

Ins

uli

n s

ec

reti

on

(p

mo

l/m

in)

Pooled monotherapy studies – subset of patients with frequently sampled MTTModel-based assessment of β-cell function

Φs = static component, describes relationship between glucose concentration and insulin secretion

Baseline

End-Treatment

Baseline

End-Treatment

Sitagliptin 100 mg q.d Placebo

Sitagliptin Improved Markers of Beta-Cell Function

24-Week Monotherapy Study

Proinsulin/insulin ratio

Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.

0.3

0.35

0.4

0.45

0.5

0.55

p< 0.001*

*P value for change from baseilne compared to placebo

Hatched = BaselineSolid = Week 24

∆ from baseline vs pbo = 0.078(95% CI -0.114, -0.023)

Placebo Sitagliptin 100 mg

Rati

o (

pm

ol/L

/ p

mol/L)

HOMA-β

30

35

40

45

50

55

60

65

70

75

80

p< 0.001*

∆ from baseline vs pbo = 13.2 (95% CI 3.9, 21.9)

Placebo Sitagliptin 100 mg

ihc

Peter,Peter,You requested that we not change any other data on the slides, however we believe that the CIs listed below each bar graph are incorrect.They should be:(95% CI -0.111, 0.046)and (95% CI 6.7, 19.7)

Study 040.

Indian Clinical Trial

Study 040.

PN040, Comparable Baseline Characteristics

Sitagliptin 100 mgn = 352

Placebo n = 178

Mean age, y 50.9 50.9

Female, n (%) 152 (43.2) 72 (40.4)

Race/Ethnicity, n (%)

Chinese 163 (46.3) 82 (46.1)

Korean 62 (17.6) 33 (18.5)

Indian 127 (36.1) 63 (35.4)

Mean weight, kg 66.8 66.6

Mean BMI, kg/m2

Mean A1c, %Duration of Diabetes

25.18.742.1

24.98.751.9

BMI = body mass index.

Study 040.

Placebo Subtracted Change from Baseline in HbA1c

Per Country

Placebo Subtracted

% A1c change

95% Confidence

limits

India -1.36 (-1.73, -0.99)

China -0.69 (-0.92, -0.46)

Korea -1.38 (-1.92, -0.83)

Study 040.

Sitagliptin Reduces FPG Levels Significantly From Baseline (APT Population)

Values represent mean ± SE.

0 6 12 18

–30

–20

–10

0

10

Sitagliptin 100 mg Placebo

Week

LS

M C

ha

ng

e F

rom

Bas

elin

e, m

g/d

L

31.0p<0.00

1

Study 040.

Four-Point Meal Tolerance Test at Baseline and Week 18 (APT Population)

120

170

220

270

0 30 60 120 0 30 60 120

Sitagliptin 100 mg Placebo

Minutes After Initiation of Meal Challenge

Mea

n P

lasm

a G

luco

se, m

g/d

L

Baseline Week 18

Study 040.

Incidence of Adverse Events

Event, n (%)Sitagliptin 100 mg

n = 352Placebon = 178

One or more AE 82 (23.3) 27 (15.2)

Drug-related AE 10 (2.8) 3 (1.7)

Serious AE 6 (1.7) 2 (1.1)

Serious drug-related AE 1 (0.3) 1 (0.6)

Discontinued due to AE 5 (1.4) 2 (1.1)

Discontinued due to drug-related AE

2 (0.6) 1 (0.6)

AE = adverse event.

Study 040.

Incidence of Laboratory Adverse Events

Tolerability, n (%)Sitagliptin 100 mg

n = 352Placebo n = 178

One or more LAE 22 (6.5) 12 (7.0)

Drug-related LAE 9 (2.6) 3 (1.8)

Serious LAE 0 0

Serious drug-related LAE 0 0

Discontinued due to LAE 1 (0.3) 1 (0.6)

Discontinued due to drug-related LAE

0 0

LAE = laboratory adverse event.

Study 040.

Summary

• Compared with placebo, treatment with Sitagliptin for 18 weeks resulted in– Significantly lower HbA1C,

– Significant improvements in FPG and 2-hour PPG levels

– Slight weight gain (0.6 kg)

• Sitagliptin was well tolerated and showed no clinically meaningful difference with placebo in incidence of AEs.

• No events of hypoglycemiaPPG = postprandial plasma glucose.

Phase III Clinical Studies of SitagliptinPhase III Clinical Studies of Sitagliptin

● ● MMonotherapy use onotherapy use

(P021, P023, A201, P040)(P021, P023, A201, P040)

●● Combination use with Metformin, a PPAR Combination use with Metformin, a PPAR agent agent

or SU or SU (P019, P020, P035 and P036)(P019, P020, P035 and P036)

●● Active Sulph comparator trial, added to metformin Active Sulph comparator trial, added to metformin

(P024)(P024)

Sitagliptin Once Daily Significantly Lowers A1C When Added On to Metformin or Pioglitazone

Add-On to Metformin Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Time (weeks)

A1

C (

%)

Add-On to Pioglitazone Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24

Time (weeks)

A1

C (

%)

in A1C vs Pbo* = –0.65% (p<0.001)



in A1C vs Pbo* = –0.70% (p<0.001)

*Placebo Subtracted Difference in LS Means.Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568.

Sitagliptin Added to Ongoing Metformin or Pioglitazone Therapy in Patients With T2DM:

Change in Body Weight Over Time

LS M

ean C

hange f

rom

Base

line in

Body W

eig

ht

(kg)

Placebo + Met (n=169)Sita 100 mg qd + Met (n=399)

0.0

-0.4

-0.6

-0.8

-0.2

0 12 24

Study Week

-1.0

0.0

0.5

1.0

1.5

2.0

-0.5

-1.0

0 6 12 18 24

Weeks

Placebo + pioglitazone (n=174)

Sita 100 mg qd + pioglitazone (n=163)

Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568.

0

10

20

30

40

50

0

10

20

30

40

50

Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Mono- or Combination

Therapy

0

10

20

30

40

50

SitagliptinPlacebo

Monotherapy Study Add-On to Metformin Study

Add-On to TZD Study

Perc

en

tage

Perc

en

tage

Perc

en

tage

P<0.001

P<0.001P<0.00

1

17%

41%

18%

47%

23%

45%

Goal A1C < 7%

Aschner et al. Diabetes Care. 2006;29:2632–2637. Charbonnel et al. Diabetes Care. 2006;29:2638–2643 ; Rosenstock et al. Clin Ther. 2006;28:1556–1568.

Placebo

Placebo Controlled Add-on to Glimperide or Glimepiride/Metformin Study – Design and Patients

035

Phase B

Sitagliptin 100 mg qd

ScreeningPeriod

Single-blindPlacebo

Stratum 1 Glim (≥ 4 mg/day) alone (~50%, n=212)

Stratum 2 Glim + MF ≥1500 mg/d) (~50%, n=229)

Week 24

RANDOMIZATION

Week 80Week 0

T2DM, Baseline A1c = 8.34 Age 18-78 yrs

Continue/startregimen of glimepiride± metformin

Week -2 eligible if

A1c 7.5-10.5%

Double-blind


Pio 30 mg qd

Sitagliptin Improved A1C When Added to Glim

*Difference in LS Mean change from baseline

Hermansen et al, Diabetes Obesity Metabolism 2007

Weeks

0 6 12 18 24

A1

C (

%)

7.2

7.6

8.0

8.4

8.8

Sitagliptin + GlimPlacebo + GLIM

Δ -0.6 %;p<0.001*

Sitagliptin Improved A1C When Added to Glim + MF 035

Weeks

0 6 12 18 24

A1

C (

%)

7.2

7.6

8.0

8.4

8.8

Sitagliptin +Glim + MFPlacebo + Glim + MFSitagliptin + GlimPlacebo + Glim

Δ -0.9%; p<0.001*

*Difference in LS Mean change from baseline

Hermansen et al, Diabetes Obesity Metabolism 2007

Sitagliptin Increased Rates of Hypoglycemia in Combination with Sitagliptin ± Metformin 035

Treatment Group N

222

219

Overalln (%)

27 (12.2)

4 (1.8)

4 (1.8)

0

Requiring Non-Medical

Assistance and NotExhibiting Marked

Severity‡

0

0

Requiring MedicalAssistance or Exhibiting

Marked Severity‡

Patients With at Least One Episode† n (%)

Total Number of Episodes†

Sitagliptin + Glim ± MF

Overalln

55

20

9

0

0

0

Placebo + Glim ± MF

Placebo +Glim ± MF

Sitagliptin + Glim ± MF

Sitagliptin + Metformin Factorial Study Design

N = 1091 Randomized

Mean baseline A1C = 8.8%

ScreeningPeriod

Single-blindPlacebo Double-blind Treatment Period

Diet/exercise Run-in Period

Eligible if A1C 7.5 to 11%

If on an OHA, D/C’ed

Week- 2 Day 1

Sitagliptin 50/Met 1000 BID

Placebo


Metformin 500 BID

Metformin 1000 BID

Sitagliptin 50/Met 500 BID

Week 24

Duration up to 12 weeks based on prior therapy

Open Label Cohort Sitagliptin 50/Met 1000 BID

RANDOMIZATION

Goldstein et al, Diabetes Care: 30; 1979 – 1987, 2007

Initial Combination of Sitagliptin and Metformin Produced a Marked Improvement in A1C

-2.5

-2.0

-1.5

-1.0

-0.5

A1

C (

%)*

-0.8-1.0

-1.3

-1.6

-2.1

Mean baseline A1C = 8.8%

Placebo change from Baseline = 0.17 %

*Placebo-subtracted LS mean change from baseline at Week 24

Open LabelSita 50 mg + MF 1000 mg b.i.d.

Sita 50 mg + MF 1000 mg b.i.d.


MF 1000 mg b.i.d.

MF 500 mg b.i.d.

Sita 100 mg q.d.


0 6 12 18 247

8

9

10

11

12

Rapid Improvement in FPG in High Baseline PatientsTreated with Initial Combination Therapy

* Mean Change from Baseline p<0.001

Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d.

0 3 6 12 18 248

10

12

14

16

18

20

∆ FPG = -7.32 mmol/l*

∆ A1C = -2.94%*

A

1C (

%)

FP

G (

mm

ol/l)

Weeks Weeks


24-Week (Phase A) Continuation Phase (Phase B)

6.00

6.50

7.00

7.50

8.00

8.50

9.00

0 6 12 18 24 30 38 46 54

Week

Mean A1C Levels Through 54 Weeks(Completers)

Sit 50 mg BID + met 1000 mg BID (n = 153)

Met 1000 mg BID (n = 134)

Sit 100 mg QD (n = 106)

Sit 50 mg BID + met 500 mg BID (n = 147)

Met 500 mg BID (n = 117)

A1C

, %

APT = all patients treated; sit = sitagliptin; met = metformin; Values represent mean ± SE.

Summary of Clinical Adverse Experiences (AEs) Through 54 Weeks (Phase A and B Combined, cont.)

Number (%) of patients:

Sita 100 mg q.d.

N = 179

Metformin 500 mg b.i.d

N = 182

Metformin 1000 mg b.i.d.

N = 182


N = 190

Sita 50 mg +MF 1000 mg b.i.d.

N = 182

Special AEs of Clinical Interest

Hypoglycemia 2 (1) 2 (1) 2 (1) 4 (2) 5 (3)

All Gastrointestinal AEs

18 (10) 26 (14) 56 (31) 36 (19) 48 (26)

Gastrointestinal AEs Through 54 Weeks

3.2

10.8

5.67.5

1.2

3.82.4

4.7

9.6

5.9

0.8

2.7

21.2

2.2

5.9

25.8

0

5

10

15

20

25

30

Overall Abd pain Diarrhea Nausea Vomiting GERD Dyspepsia Constipation

Sitagliptin/Metformin Combination

Metformin Monotherapy

%

27.7

Change in Body Weight From Baseline at Week 54 (LS mean change ± SE)

Bo

dy

Ch

ang

e F

rom

Bas

elin

eA

t W

eek

54 (

kg)

–2.0

–1.5

–1.0

–0.5

0.0

0.5

1.0

Sit 50 mg BID + met 1000 mg BIDSit 50 mg BID + met 500 mg BID

Met 1000 mg BIDMet 500 mg BIDSit 100 mg QD

n=100

n=116 n=132 n=143 n=153

*Change from baseline P < 0.05.

**

*

*

23%

41%

25%

35%

44%

57%

48%

63%67%

77%

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

APT Completers

Sita 50 mg BID + Met 1000 mg BIDSita 50 mg BID + Met 500 mg BID

Met 1000 mg BIDMet 500 mg BIDSita 100 mg QD

58 77 101 106 124106 117 134 147 153n =

Proportion of Patients with A1C Goal <7% at Endpoint (Week 54 Analysis)

Per

cen

t o

f p

atie

nts

Active-Comparator (Glipizide) Controlled Add-on to Metformin Study (024) – Design and

PatientsDesign

• Patients with T2DM (on monotherapy or combination OHA) ➜ started/continued on metformin monotherapy (at least 1500 mg/d) during run-in period, randomized if A1C 6.5–10% after run-in period

Patient population• 1172 randomized patients, mean age 57 years, ~60% male

• Mean duration of T2DM 6 years, baseline mean A1C = 7.5%

ScreeningPeriod

Single-blindplacebo

Double-blind Treatment Period:

Glipizide or Sitagliptin 100 mg q.d.

Metformin monotherapy Run-In Period

Week -2:eligible if A1C

6.5 to 10%

Continue/startregimen of met

monotherapy

Day 1Randomization

monotherapy with metformin (stable dose > 1500 mg/d)

Week 52

Glipizide: 5 mg qd increased to 10 mg bid (held if FS < 110 mg/dL or hypoglycemia)

Sitagliptin Once Daily Shows Similar Glycemic Efficacy to Glipizide When Added to Metformin (52 Weeks)

Sitagliptin 100 mg qd + Metformin (n=382)

Glipizide + Metformin (n=411)

Mean

Ch

an

ge in

Hb

A1c Mean change from baseline (for both groups)*: -

0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52

Time (weeks)

*per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis

Nauck et al, Diabetes Obesity Metabolism 9: 194 – 205, 2007

Progressively Greater Reductions in A1C as Baseline A1C Rises

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

<7% 7-<8% 8<9% > 9%

Baseline A1C CategoryStudy

inclusion criteria 6.5-

10%

Change from

baseline in A1C

(%)

Sitagliptin 100 mg q.d.

Glipizide

N=112

N=167

N=82

N=21

N=117

N=179

N=82

N=33

Per Protocol Population

Peter Stein

add % to goal...

Sitagliptin Once Daily Shows Better Safety and Tolerability Profile Compared to Glipizide (52 Weeks)

Glipizide (n=584)


p<0.001

Change in Body Weight

86

88

90

92

94

0 12 24 38 52

Time (weeks)

Bo

dy

we

igh

t (k

g)

Sitagliptin 100 mg qd (n=382)

Glipizide (n=411)

Nauck et al, Diabetes Obesity Metabolism 9: 194 – 205, 2007

between groups = –2.5 kg (p<0.001)

Hypoglycemia

32%

4.9%

0

10

20

30

40

50

Week 52

Inci

den

ce

(%)

Safety and Tolerability Overview

• Well tolerated in Phase I through III trials – in completed and ongoing studies more than 7000 patients on sitagliptin (to doses of 200 mg q.d. in Phase III studies)

• Pre-specified Pooled Phase III analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo

– Summary measures of adverse experiences (AEs) were similar to placebo

• Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures

– Small differences in incidence of specific AEs

• Between group difference (sitagliptin 100 mg – placebo group) in incidence > 1% for only 1 specific AE (nasopharyngitis 1.2% difference)

Summary Measures of Clinical Adverse Events for

Sitagliptin is Similar to PlaceboPooled Phase III Population Placebo

(N=778)

Sitagliptin 100 mg

(N=1082)

Sitagliptin 200 mg

(N=456)

% of Patients with % % %

One or more AEs 55.5 55.0 54.2

Drug-related AEs 10.0 9.5 9.4

Serious AEs 3.2 3.2 3.3

Drug-related SAEs 0.1 0.3 0.0

Deaths 0.0 0.0 0.0

Discontinued due to AE 1.9 2.6 0.9

Discontinued due to drug-related AE 0.8 0.6 0.0

Discontinued due to SAE 0.6 1.3 0.7

Discontinued due to drug-related SAE 0.1 0.1 0.0

Recommended dose in proposed label: 100 mg q.d.

Only Small Differences in Incidence of AEs: Pooled Phase III Population

Placebo (N = 778)

Sitagliptin 100 mg (N = 1082)

% % Difference vs Pbo

(95% CI)

Upper Respiratory Tract Infection

6.7 6.8 0.1 (-2.3, 2.4)

Headache 3.6 3.6 0

Nasopharyngitis

3.3 4.5 1.2 (-0.7, 3.0)

Diarrhea 2.3 3.0 0.7 (-0.9, 2.2)

Arthralgia 1.8 2.1 0.3 (-1.1, 1.6)

Urinary Tract Infection

1.7 1.7 0

AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group

Recommended dose in proposed label: 100 mg q.d.

Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to

Weight Gain

PlaceboSitagliptin 100 mg

q.d.Sitaglitpin 200 mg

q.d.

Patients with hypoglycemia (%) 0.9% 1.2% 0.9%

• Neutral effect on body weight– In monotherapy studies, small decreases from baseline (~ 0.1 to 0.7

kg) with sitagliptin; slightly greater reductions with placebo (~ 0.7 to 1.1 kg)

– In combination studies, weight changes with sitagliptin similar to placebo-treated patients

Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs placebo

Hypoglycemia

Weight Changes

Summary on Sitagliptin

• Sitagliptin is a potent and selective DPP-4 inhibitor administered once-daily for the treatment of T2DM

Once-daily regimen of sitagliptin provides

• A once-daily regimen of sitaglitpin provides substantial glycemic efficacy

– Significant reductions in A1C across a range of starting A1C levels in monotherapy and combination use

– Sustained A1C reduction to 1 year

– Improvements in multiple measures of beta-cell function

• Compared to a sulfonylurea agent, sitagliptin provides– Similar efficacy

– Superior improvements in beta-cell function, less hypoglycemia, and weight loss (vs weight gain)

• Sitagliptin was well tolerated with summary measures of AEs similar to placebo

ihc

Peter and Louise...Phil suggests we add 100 mg once daily in 2nd bulletWe also added "GI AEs" into 3rd sub-bullet of bullet #2

Advantages of DPP-IV Inhibition

• Oral, Once daily

• Meal independent administration

• Low risk of hypoglycemia

• No clinically meaningful drug-drug interactions

• Significant improvements in Glucose sensitivity of beta cells, pro-insulin/insulin ratio & HOMA-beta

• Oral therapy, providing dosing convenience to the patient

• Endogenous GLP-1 & GIP levels are increased in response to meal and are transient

• Avoid tolerability/immunogenicity issues with exogenous GLP-1

• Multiple mechanisms of GLP-1 in T2DM– Insulin release is glucose dependent

– Reduced hepatic glucose production

– Improved peripheral glucose utilization

– -cell preservation / neogenesis and restoration in animal modelsSource: Drucker DJ. Diabetes Care 2003;26:2929-2940.

1.1%

Effect of Des-F-Sitagliptin onBeta-Cell Mass

NondiabeticControl

H&E insulin (I) glucagon (G) I/G

Diabetic Control

Diabetic Mice Treated with

Des-F-sitagliptin

0.1%

0.4%

Figure 3. HFD/STZ diabetic mice were treated with vehicle or des-fluoro-sitagliptin at indicated dosages for 11 weeks. Whole pancreas from each group was cryopreserved and consecutive sections were stained with H&E, anti-insulin antibody (green), or anti-glucagon antibody (red). Shown are representative islets from each group with single staining and the overlay of the insulin and glucagon staining (I/G).

GLP-1 Preserved Morphology of Human Islet Cells In Vitro

Day 1

GLP-1–treated cellsControl

Day 3

Day 5

Islets treated with

GLP-1 in culture were

able to maintain their

integrity for a longer

period of time.

Adapted from Farilla L et al. Endocrinology. 2003;144:5149–5158.

Thank You

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