Role of DPP4 inhibition in the management of

Type 2 Diabetes

Current Evidences with Sitagliptin

Fasting State• Blood glucose tends to fall• Insulin Secretion lowered• Increased Glucagon secretion

from Alpha cells• Increased Hepatic Glucose

output• Results Euglycemia

Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254

Postprandial State

• Rising Blood Glucose• Insulin secretion Increases,

Glucagon decreases• Increased Peripheral uptake of

Glucose• Decreased Hepatic Glucose output• Results Euglycemia

Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254

Decreased Insulin, Elevated Glucagon, and Hyperglycemia in Type 2 Diabetes

Adapted with permission in 2006 fromMüller WA et al. N Engl J Med. 1970;283:109–115. Copyright © 1970 Massachusetts Medical Society. All rights reserved.

Glucose, mg %

Insulin, μ/mL

Glucagon, μ/mL

360

330

300

270

240

110

80

Meal

120

90

60

30

0

–60 0 60 120 180 240

140

130

120

110

100

90

Healthy subjects(n=11)

Type 2 diabetes(n=12)

Minutes

Is Insulin Secretion from the beta cells a function of ambient glucose level?

A look at the Intestinal Factors in Insulin Secretion; The Incretins

The Incretin Effect in Subjects Without and With Type 2 Diabetes

IR=Immune Reactive.Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

GLP-1 Modes of Action in Humans

GLP-1 is secretedfrom the L-cellsin the intestine

This in turn…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

Long term effectsdemonstrated in animals…

• Increases beta-cell mass and maintains beta-cell efficiency

• Reduces food intake

Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

Role of Dipeptidyl Peptidase-4

1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372.3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Insulin synthesis and secretion from beta cells

(GLP-1 and GIP)

Glucagon fromalpha cells

(GLP-1)

Release of gut hormones— Incretins1,2

Pancreas2,3

Glucose DependentGlucose DependentGlucose DependentGlucose Dependent

ActiveGLP-1 & GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

Glucose DependentGlucose DependentGlucose DependentGlucose Dependent

↓ ↓ Blood Blood glucoseglucose

GI tractGI tract

↓↓Glucose Glucose production production

by liverby liver

Food ingestionFood ingestion

↑↑Glucose Glucose uptake by uptake by peripheral peripheral

tissuetissue2,42,4

Beta cellsBeta cellsAlpha cellsAlpha cells

*

GLP-1 Levels Are Decreased in Type 2 Diabetes

** *

*

**

Control (n=33)Type 2 diabetes (n=54)

0

5

10

15

20

0 60 120 180 240

GL

P-1

(p

mo

l/L

)

*p<0.05, type 2 diabetes vs control

Adapted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

Meal Started

Meal Finishe

d

(10–15)

Time after start of meal, minutes

BUT, the levels are never ZERO

DPP4 activity increases in Hyperglycemia

0

5

10

15

20

25

30

T2DM T2DM-ND IGT NGT

T2DM

T2DM-ND

IGT

NGT

Mannucci et al, Diabetologia April 2005

Incretin Based Therapies

GLP1 receptor agonists(DPP4 resistant)

Incretin Enhancers(DPP4 Inhibitors)

Substrate-like inhibitors(Vildagliptin, Saxagliptin)

1st Generation Gliptins(Shorter Half Life,

Less DPP4 Specificity)

Non Substrate-like inhibitors

(Sitagliptin, Alogliptin)2nd Generation Gliptins

(Longer Half Life,Very High DPP4 Specificity)

Exendin Based Therapies

(Exenatide)

Human GLP1 Analogue

(Liraglutide)

doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester10.1002/ddr.20138, von Geldern, Trevillyan

Sitagliptin - Overview

• First and ONLY 2nd Generation DPP4 inhibitor available for patient benefits and approved by the FDA on October 17 2006. Also approved by EMeA, March 2007

• Unique >100 fold selectivity for DPP4 (over DPP8 & 9)

• Fully reversible and competitive inhibitor• Most Widely Used Gliptin (currently >19 million patients

worldwide)

N

ONH2

NN

CF3

F

F

F

N

Glucose dependent Insulin from beta cells(GLP-1 and GIP)

Adapted from 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; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

Hyperglycemia

Sitagliptin Improve Glucose Control by Normalizing Incretin Levels in Type 2 Diabetes

Glucagon from alpha cells

(GLP-1)Glucose

dependent

Release of incretins from the

gut

Pancreas

α-cellsβ-cells

Insulinincreases peripheral glucose uptake

Ingestion of food

GI tract

↑insulin and ↓glucagon reduce hepatic glucose output

Inactive incretins

Improved Physiologic

Glucose Control

DPP-4 Enzyme

SITAGLIPTINDPP-4

Inhibitor

X

DPP-4 = dipeptidyl peptidase 4

Pharmacokinetics of 100mg Sitagliptin Supports Once-Daily

Dosing• >80% DPP4 inhibition for 24hrs, >90% for16hrs

>80% inhibition required for full Incretin enhancement

• No effect of food on pharmacokinetics

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

• Low protein binding, app 38%

• Minimal Metabolism in the Liver, primarily renal excretion as parent drug

– ~80% of a dose recovered as intact drug in urine

• No clinically important drug-drug interactions

– No meaningful P450 system inhibition or activation

What is the effect of a Single Tablet of Sitagliptin?

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

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%

p<0.001 for both dose comparisons to placebo for AUC

Is Sitagliptin effective as Monotherapy?

Mea

n C

ha

ng

e in

A1C

, %

‡

A1C

CI=confidence interval. *Compared with placebo. †Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡Difference from placebo. §Combined number of patients on JANUVIA or placebo. ||P<0.001 overall and for treatment-by-subgroup interactions. 1. Raz I et al. Diabetologia. 2006;49:2564–2571.2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.

Mean Baseline: 8.0% P<0.001*

–0.6†

–1.0

–0.8

–0.6

–0.4

–0.2

0.0

–0.8†

Placebo-adjusted results

24-week monotherapy study2

(95% CI: –1.0, –0.6)

18-week monotherapy study1

(95% CI: –0.8, –0.4)

n=193

n=229

Inclusion Criteria: 7%–10%

Overall <8 ≥8–<9 ≥≥99Baseline A1C, %

–1.4

–0.6–0.7

–1.8

–1.6

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0.0

n=411§

n=239§

n=119§

Mea

n C

ha

ng

e in

A1C

, %

Prespecified Pooled Analysis at 18 Weeks||

–0.7

n=769§

Sitagliptin: Significant A1C Reductions as Monotherapy

Is it a PP Drug or a Fasting Drug?

Sitagliptin Monotherapy Impacts both FPG and PPG

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.

How Fast does Sitagliptin Start Working?

Rapid Improvement in Blood Glucose in the First Days of Monotherapy

• Baseline A1c 7.8% (ABG ~ 202)

• After 3 days, Average Blood Glucose -20.4)• After 7 days, Average Blood Glucose -23.5)

• After 24 weeks, the mean changes from baseline for A1C, FPG (FFPG) and PPG were −0.7%, −27 mg/dL, and −61 mg/dL, respectively

• Greater reductions in ABG on Day 7 were observed in patients with higher baseline A1C and FPG

Is Sitagliptin effective when sensitizers fail?

Add-on to patients

failing on pioglitazone2

Mean Baseline A1C: 8.0%, 8.1%

Me

an

Ch

an

ge

in

A1

C F

rom

Ba

se

lin

e,

%SITAGLIPTIN: Significant A1C Reductions From

Baseline When Added to Metformin or Pioglitazone

n=224

Metformin+ Sita

–1.0

–0.8

–0.6

0

–1.0

0

Me

an

Ch

an

ge

in

A1

C F

rom

Ba

se

lin

e,

%–0.7%

Mean Baseline A1C: 8.0%

P<0.001*

P<0.001*

Add-on to patients

uncontrolled on metformin 1

–0.0%

Metformin+ Placebo

Pioglitazone+ Sita

Pioglitazone+ Placebo

*Compared with placebo.1. Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.2. Rosenstock J et al. Clin Ther. 2006;28:1556–1568.

n=453 n=174 n=163

0.7% placebo-subtracted result

0.7% placebo-subtracted result

–0.9%

–0.4

–0.2

–0.8

–0.6

–0.4

–0.2

–0.2%

Is Sitagliptin’s efficacy comparable to that of a Sulfonylurea?

aSpecifically glipizide; bSitagliptin 100 mg/day with metformin (≥1500 mg/day);

Per-protocol population; LS=least squares.

Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.

HbA1c Over Time With Sitagliptin or Glipizide

as Add-on Combination With Metformin: Comparable Efficacy

LS mean change from baseline (for both groups): –0.67%

Achieved primary hypothesis of

noninferiority to sulfonylurea

Sulfonylureaa + metformin (n=411)

Sitagliptinb + metformin (n=382)

Hb

A1

c (

% ±

SE

)

Weeks

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

8.0

8.2

Continuous Up-titration in Glipizide arm

Effects of Sitagliptin and Glipizide on Body Weight and Hypoglycemia

LS Mean Change in Body Weight (kg) Over Time

(APaT population)

Overall Number of Episodes of Hypoglycemia:

Week 0 Through Week 104

805

57

0

200

400

600

800

1000

Week 104 To

tal N

um

ber

of E

pis

od

es, (

n)

Glipizide Sitagliptin 100 mg/d

*(95% CI) LS Means Change in Body Weight (kg) in Between Treatment Groups

Sitagliptin 100 mg/d(n = 253)

Glipizide(n = 261)

LS

Mea

n C

han

ge

Fro

m B

asel

ine

(kg

)

0 12 24 38 52 78 104

–2

–1

0

1

2

Week

∆=−2.3 (−3.0, −1.6)*

CSR

Incidences similar to Placebo+Metformin

Will Sitagliptin work in very late Diabetes?

Pooled Results from all Phase III studies of Sitagliptin 100mg

monotherapyGlycemic endpoints analyzed by duration of type 2 diabetes

Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.

Pla

ceb

o a

dju

sted

LS

mea

n c

han

ge

fr

om

bas

elin

e H

bA

1c

,%,

(95%

CI)

Pla

ceb

o a

dju

sted

LS

mea

n c

han

ge

fro

m

bas

elin

e F

PG

mg

/dl,

(95

% C

I)

Pla

ceb

o a

dju

sted

LS

mea

n c

han

ge

fro

m

bas

elin

e 2-

h P

PG

mg

/d)

(95%

CI)

*Significant reduction of A1c across all duration

Sitagliptin Improved A1C When Added to Glim + MF

*T2DM of long duration

Δ -0.9%; p<0.001*

*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 +Glim + MF (n=116)Placebo + Glim + MF (n=113)

Will Sitagliptin work when Beta cell function is very poor?

Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.

Glycemic endpoints analyzed by baseline HOMA β

Pooled Results from all Phase III studies of Sitagliptin 100mg monotherapy

*Significant efficacy shown even when baseline Beta cell function is poor

Any Indian Data with Sitagliptin?

Placebo Subtracted Change from Baseline in HbA1c Per Country

Country

Placebo Subtracted % A1c change

*Baseline 8.74%

95% Confidence limits

India -1.36 (-1.73, -0.99)

China -0.69 (-0.92, -0.46)

Korea -1.38 (-1.92, -0.83)

DRCP Mohan Yang Son, 2009 Jan;83(1):106-16. Epub 2008 Dec 20

Sitagliptin helps to improve beta-cell function and increases insulin synthesis and release.

Sitagliptin helps to reduce HGO through suppression of glucagon from alpha cells.

Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.

Metformin has insulin- sensitizing properties.

Beta-Cell Dysfunction

Hepatic Glucose Overproduction

(HGO)

Hepatic Glucose Overproduction

(HGO)

Sitagliptin Reduces HyperglycemiaMetformin Reduces HyperglycemiaThe Combination of Sitagliptin and MetforminAddresses the 3 Core Defects of T2DM in a

Complementary Manner

Insulin Resistance

*Please see corresponding speaker note for references.

Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone

* Values represent geometric mean±SE.

Placebo

Metformin 1000 mg Sitagliptin 100 mg

Co-administration of sitagliptin 100 mg + metformin 1000 mg

Mean AUC ratio*Sita + Met: 4.12

Mean AUC ratios*Sita: 1.95 Met: 1.76

–20

10

20

30

40

50

–1 0 1 2 3 4

Act

ive

GLP

-1

Con

cent

ratio

ns, p

M

MealMorning Dose Day 2 Time (hours pre/post meal)

N=16 healthy subjectsAUC=area under the curve

Migoya EM et al. 67th ADA 2007. Oral Presentation OR-0286.Data available on request from Merck & Co., Inc. Please specify 20752937(1)-JMT.

Metformin + Sitagliptin: Effect on Incretin Axis

Mean A1C = 8.8%

Sitagliptin 50 mg + metformin 1,000 mg bid

Metformin 1,000 mg bid

Sitagliptin 100 mg qd

Sitagliptin 50 mg + metformin 500 mg bid

Metformin 500 mg bid

LS

M A

1C C

han

ge

Fro

m B

asel

ine,

%

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

0.5

n=178 n=177 n=183 n=178n=175

–0.8a

–1.0a

–1.3a

–1.6a

–2.1a

Open label

n=117

–2.9b

All patients Treated Populationa LSM placebo adjusted change b LSM change from baseline without adjustment for placebo.bid=twice a day; qd=once a day.

24-Week Placebo-Adjusted Results

A1C Results at 24 Weeks

Mean A1C = 11.2%

Sitagliptin With Metformin Coadministration Initial Therapy Study

Goldstein et al. Diabetes Care 2007; 30: 1979-1987

>77% of patients achieved target A1c in Sita Met1000 arm

Efficacy with Other Sensitizers?

Initial Combination of Sitagliptin with Pioglitazone

2.4%2.4%

1.5%1.5%

3%3%

> 10%

FPG -63

FPG -40

Sita+P30P30

Sita+P30

9.5%

Sita-Pio combination currently undergoing Phase III Trials

For How Long Will Sitagliptin Continue to work?

Long-Term Efficacy with Sitagliptin as Monotherapy or Add-On Therapy to Metformin

ADA 2009 Abstract 540-P

Can Sitagliptin be used with Insulin?

Robust Reduction of A1c when used in patients uncontrolled with Insulin

0.60.6 0.0

Insulin+Sitagliptin Insulin+Placebo

• Average duration of Diabetes ~13 years• Double the reduction achieved with other Gliptins

Baseline 8.7%

Efficacy of Sitagliptin with Glargine

1.69%1.69%

Baseline 8.1%Glar+Sita+Met Glar+Met

1.37%1.37%

Sitagliptin now approved with Insulin by EU

How Safe is Sitagliptin?

Safety and Tolerability Overview

• Completed and ongoing studies more than 8000 patients on sitagliptin (to doses upto 800 mg q.d.)

– 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

– No Significant Drug-Drug Interaction, except increased risk of Hypoglycemia with Sulfonylureas, thus necessitating use of lower dose of SU

Summary Measures of Clinical Adverse Events for Sitagliptin is Similar to Placebo

Pooled 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 0.9Discontinued due to drug-related AE 0.8 0.6 0.0

Discontinued due to SAE 0.6 1.3 0.7Discontinued due to drug-related SAE 0.1 0.1 0.0

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

Cardiovascular Safety 2 years Data

• Only Gliptin with a 2 years Cardio-safety data

• Overall Incidence Rates of Serious Adverse Events, 1.2% vs 1.5% (Sita vs Placebo)

• Ischemia 2% vs 2.3%• Serious Ischemia related events, 1.1% vs 1.5%• Fatal Cardiac events, 0.09% vs 0.23%

Clinically Insignificant Differences in Incidence of AEs: Pooled Phase III Population

Placebo (N = 778)

Sitagliptin 100 mg (N = 1082)

% % Difference vs Placebo

(95% CI)

Upper Respiratory Tract Infection

6.7 6.8 0.1

Headache 3.6 3.6 0

Nasopharyngitis

3.3 4.5 1.2

Diarrhea 2.3 3.0 0.7

Arthralgia 1.8 2.1 0.3

Urinary Tract Infection

1.7 1.7 0

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

Safety in Hepatic Impairment

• Sitagliptin is studied and only Gliptin approved for use in mild to moderate hepatic impairment, but not in fulminant hepatitis as it is not studied in these cases.

• Reason of safety, primarily excreted unchanged in urine, unlike most other drugs which are metabolized in the liver

• 2 years pooled safety analysis showed no risk of increased liver enzymes post treatment, and was safe and effective in patients with pretreatment elevated liver enzymes 3xULN

Patients With Renal Insufficiency

Renal Insufficiency

Mild ModerateSevere and

ESRD*

Increase in Plasma AUC of Sitagliptin†

~1.1 to 1.6-fold increase‡

~2-fold increase

~4-fold increase

Recommended Dose

100 mg no dose

adjustment required

50 mg 25 mg

• To achieve plasma concentrations similar to patients with normal renal function, lower doses of Sitagliptin

are recommended in moderate and severe renal insufficiency.

ESRD=end-stage renal disease; AUC=area under the curve.*Includes patients on hemodialysis or peritoneal dialysis.†Compared with normal healthy control subjects.‡Not clinically relevant.

Studied in post-Renal Transplant cases; Effective and SafeNo change in tacrolimus/sirolimus (Immunosuppressive drugs) levels

Safety related to Pancreatitis

0.00%

0.10%

0.20%

0.30%

0.40%

0.50%

Exentd Sita Ctrl

Incidences ofPancreatitis

• 540 Days• 13 million patients

•No Increased Risk of Pancreatitis with Sitagliptin in any Randomized trial

•88 cases reported by FDA based upon Voluntary submissions, out of over 10 million patients, No claim of establishing cause effect relationship by FDA

Hypoglycemia; How Safe is Sitagliptin

Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading

to Weight Gain

Placebo Sitagliptin 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

ADA-EASD Consensus Statement; Sitagliptin Does Not cause Hypoglycemia when used as monotherapy

Hypoglycemia

Weight Changes

JANUVIA™ (sitagliptin)

Indications and Usage

• Monotherapy– JANUVIA is indicated as an adjunct to diet and exercise to

improve glycemic control in patients with type 2 diabetes mellitus.

• Combination therapy

– JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPAR agonist (eg, thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control.

• Important limitations of use

– JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

Please ADD ON, Do Not REPLACE

PPARγ=peroxisome proliferator-activated receptor gamma.

Use in Specific Populations• Pregnancy (Category B)

– No adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed.

• Nursing Mothers

– Not known whether sitagliptin is excreted in human milk. Caution should be exercised when administered to a nursing woman.

• Pediatric Use

– Safety and effectiveness in pediatric patients are not established.

• Geriatric Use

– No overall differences in safety and efficacy observed between subjects upto 95 years and younger subjects.

– No dosage adjustment is required based solely on age.

• Because the elderly are more likely to have decreased renal function, it may be useful to assess renal function before initiating dosage and periodically thereafter.

50 mg once daily 25 mg once daily

Moderate Severe and ESRD‡

CrCl 30 to <50 mL/min(~Serum Cr levels [mg/dL]

Men: >1.7–≤3.0; Women: >1.5–≤2.5)

CrCl <30 mL/min(~Serum Cr levels [mg/dL]Men: >3.0; Women: >2.5)

Dosage and Administration• Usual Dosing for JANUVIA™ (sitagliptin phosphate)*

The recommended dose of JANUVIA is 100 mg once daily

as monotherapy or as combination therapy with metformin or a PPAR agonist.

• Patients With Renal Insufficiency*,†

*JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily.‡ESRD = end-stage renal disease requiring hemodialysis or peritoneal dialysis.

Positioning of Sitagliptin + Metformin (Janumet) FDC

• This FDC is for drug naïve, newly detected T2DM patient uncontrolled on LSM alone

• Positioning is as first line therapy• It is dosed twice daily

(Sitagliptin50mg, Metformin500mg)

(Sitagliptin50mg, Metformin1000mg)

Janumet OD with Extended Release Metformin currently being developed

DPP4 Inhibitors, position in Guidelines

Thank You!