1

Core Defects of Type 2 Diabetes

Targeting Mechanisms for a Comprehensive Approach

1

2

Objectives

• Discuss challenges in treating type 2 diabetes and rationale for earlier and more aggressive treatment approaches

• Review the physiologic regulation of glucose homeostasis, the role of incretins, and core defects of type 2 diabetes

• Describe the complementary MOAs of agents used in the treatment of type 2 diabetes to address the 3 core defects

• Provide a clinical overview of JANUVIA™ (sitagliptin)

• Provide an overview of the prescribing information for JANUMET™ (sitagliptin/metformin HCl)

3

Reaven GM. Physiol Rev. 1995;75:473-486Clauser, et al. Horm Res. 1992;38:5-12.

MedicationsAging

INSULIN RESISTANCE

Atherosclerosis

Geneticabnormalities

Obesity and inactivity

Raredisorders

PCOS

DyslipidemiaHypertension

Type 2diabetes

Reaven GM. Physiol Rev. 1995;75:473-486Clauser, et al. Horm Res. 1992;38:5-12.

Insulin Resistance: Insulin Resistance: An Underlying Cause of Type 2 DiabetesAn Underlying Cause of Type 2 Diabetes

4

Development and Progression of Type 2 Diabetes (Conceptual Representation)

Metabolic Activity

GlucoseRegulation

Years From Diabetes Diagnosis–10 –5 0 5 10 15 20 25 30

–10 –5 0 5 10 15 20 25 30

NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.

NGT Insulin IGT/ IFG Type 2 Diabetes Resistance

Postprandial glucose

Fasting glucose

Insulin resistance—hepatic and peripheral

Insulin level

Beta-cell function

5

-C

ell

Fu

nct

ion

(%

)*

PostprandialHyperglycemia

IGT† Type 2DiabetesPhase I Type 2

DiabetesPhase II

Type 2 DiabetesPhase III

25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Years From Diagnosis

Patients treated with insulin, metformin, sulfonylureas‡

*Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS.†IGT=impaired glucose testing‡The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model.Lebovitz HE. Diabetes Rev. 1999;7:139-153.

UKPDS: UKPDS: -Cell Loss Over Time-Cell Loss Over Time

6

Med

ian

Hb

A1c

(%

)

ConventionalInsulinChlorpropamideGlibenclamide (glyburide)Metformin

0 306

7

8

9

6 9 10

Time From Randomization (years)

Upper limit of normal range (6.2%)

ADA goal

ADA action

United Kingdom Prospective Diabetes Study (UKPDS)

UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-65.

Intensive Treatments and Increase in Intensive Treatments and Increase in HbAHbA1c1c Over Time Over Time

7

Guideline Recommendations Are Becoming More Aggressive

• 2007 ADA standards1

– “The A1C goal for patients in general is an A1C goalof <7%.”

– “The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” [boldface added]

ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.1. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41. 2. Nathan DM et al. Diabetes Care. 2006;29:1963–1972.

• ADA/EASD consensus statement2

– “If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when A1C goal is not achieved.” [boldface added]

8

7

8

6

9

10

Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment Paradigm

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

OAD=oral antihyperglycemic drug.Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

A1C,%

Mean A1C of patients

Duration of Diabetes

Published Conceptual Approach

9

7

6

9

8

10

Mean A1C of patients

Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

A1C,%

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

Published Conceptual Approach

Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy

10

Challenges in Achieving Glycemic Goalsin Diabetes

• Less aggressive treat-to-target approach by some clinicians1

• Suboptimal use of available therapies1

• Inability of any single agent’s MOA to address all core defects of type 2 diabetes2

• Potential for increased side effects with use of multiple agents3

• Suboptimal adherence to lifestyle measures1

• Underuse of medications as a result of– Cost4

– Complexity of therapy5

1. Blonde L. Clin Cornerstone. 2005;7(suppl 3):S6–S17. 2. Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44–M50.3. McDonald HP et al. JAMA. 2002;288:2868–2879.4. Piette JD et al. Diabetes Care. 2004;27:384–391.5. Donnan PT et al. Diabet Med. 2002;19:279–284.

11

Hepatic glucoseoutput

Insulin resistance

Glucose uptake in muscle and fat

Glucagon(alpha cell)

Insulin(beta cell)

Hyperglycemia

Islet-cell dysfunction

Major Pathophysiologic Defectsin Type 2 Diabetes

Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

PancreasPancreas

LiverLiver Adipose Adipose tissuetissue

LiverLiver

MuscleMuscle

12

Glucose Glucose absorptionabsorption

Hepatic glucoseHepatic glucoseoverproductionoverproduction

Beta-cellBeta-celldysfunctiondysfunction

InsulinInsulinresistanceresistance

Major Targeted Sites of Oral Drug Classes

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.

Pancreas

↓Glucose level

Muscle and fatLiver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

Alpha-glucosidase inhibitors

Gut

The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.

DPP-4 inhibitorsGLP-1

DPP-4 inhibitors

Biguanides

13

Alpha-Alpha-Glucosidase Glucosidase InhibitorsInhibitors1,21,2

MeglitinidesMeglitinides33 SUsSUs4,54,5 TZDsTZDs6,76,7 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

14

The Role of Incretins in Type 2 Diabetes

15

The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes

Oral glucose load Intravenous (IV) glucose infusion

Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.

Time, min

Control Subjects (n=8)

IR In

sulin

, mU

/L

80

60

40

20

0

18060 1200

Normal Incretin Effect80

60

40

20

0

18060 1200

Subjects With Type 2 Diabetes (n=14)

Diminished Incretin Effect

Time, min

IR In

sulin

, mU

/L

16

GLP-1 Infusion

0

GLP-1 Infusion

GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 Diabetes

Glucose

Glucagon When glucose levels approach normal values, glucagon levels rebound.

When glucose levels approach normal values,insulin levels decrease.

*P <0.05Patients with type 2 diabetes (N=10)

250

200150100

50

mg

/dL

** *

**

* *

40

30

20

10

0

mU

/L

* ** ** * *

*

Time, min

pm

ol/

L 20

15

10

5

0 60 120 180 240

* * * *

Placebo

GLP-1

Insulin

0

Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.

–30

GLP-1 Infusion

17

Incretins Play an Important Role in Glucose Homeostasis

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 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

18

Tips for Diabetes treatment

Reduced HBA1C as low as possible at least below 6.5% without hypoglycemia

Use DM meds that shows benefit beyound glycemic control(Heart , vascular inflamation, microalbuminuria)

Medications that showed sustained effect and preservation of B-cell function

Use meds that have the least side effect.

19

Pills available for DM 2

• No hypoglycemiaNo hypoglycemia:

• TZD(Actos, Avandia)• Metformin/glucophage)• Alpha glucosidase

inhibitor(Precose, Glyset)• Combo(avandamet,

actoplusmet, janumet• DPP IV inhibitor:

– Januvia– Galvus

• Can Cause Can Cause HypoglycemiaHypoglycemia:

• SU(glyburide,Amaryl)

• Prandin/Starlix

• Combo(glucovance, avandaryl, duetact)

20

Non insulin injection for DM2

GLP-1 analog(byetta)

Amylin(Symlin)

21

Metformin

•+insulin sensitizer

Less cardiac event by UKPDS

Weight reduction

Dm prevention data

__ ____ ______

contraindicated in renal failure

GI side effect

had to be stopped 48 hors before and after contrast

22

TZD( actos , Avandia)

•Plus:• Insulin Sensitizer

• Heart and vascular benefit (Proactive ,Chicago)

• Preservation of B- cell( dream , Adopt)

• DM prevention data

• (-): contraindicated in heart failure Stage 3- 4, or liver failure

Edema, weight gain ? Bone density

23

ADOPT: A Diabetes Outcome Progression Trial Avandia Sustained A1C Over Time*

Treatment Difference at 4 Years

RSG vs MET –0.13 (–0.22 to –0.05), P=.002

RSG vs SU –0.42 (–0.50 to –0.33), P<.001

* Mean A1C values per visit are based on a repeated measures mixed model.Kahn SE et al. N Engl J Med. 2006;355:2427-2443.

Number of patients: 4012 3308 2991 2583 2197 822

0 1 2 3 4 5

Time (years)

Hb

A1

C%

0

6.0

8.0

7.0

6.5

7.5

RSG

SU

MET

24

Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM)

Primary Outcome: Rosiglitazone

No. at Risk

Rosiglitazone 2635 2538 2414 1310 217

Placebo 2634 2470 2150 1148 177

The DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

60% risk reduction of development of diabetes or death was seen with rosiglitazone

This reduction was additive to standard counseling on healthy eating and exercise

HR = 0.40 (0.35-0.46); P<0.0001C

umul

ativ

e H

azar

d

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1 2 3 4 5

Placebo

Rosiglitazone

Years

25

Blood Blood glucoseglucose

InactiveGIP

InactiveGLP-1

JANUVIA™ (sitagliptin) Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent

Insulin(GLP-1 and GIP)

Glucagon(GLP-1)

Release of active incretins GLP-1 and GIP

Pancreas

Glucose dependentGlucose dependentGlucose dependentGlucose dependent

DPP-4 enzyme

Glucose dependentGlucose dependentGlucose dependentGlucose dependent

GI tractGI tract

Food ingestionFood ingestion

XJANUVIA

(DPP-4 inhibitor)

• Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal.

• JANUVIA blocks DPP-4 to enhance the level of active incretins for 24 hours.

Beta cellsBeta cellsAlpha cellsAlpha cells

Glucose Glucose productionproduction

by liver by liver

Glucose Glucose uptake byuptake by

peripheral tissueperipheral tissue

X

26

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.

PPARγ=peroxisome proliferator-activated receptor gamma.

27

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 ≥9Baseline 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§

JANUVIA™ (sitagliptin): Significant A1C Reductions as Monotherapy

28

*Compared with placebo.†Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value.‡Difference from placebo.CI=confidence interval; FPG=fasting plasma glucose; PPG=postprandial plasma glucose (meal challenge test).Aschner P et al. Diabetes Care. 2006;29:2632–2637.

FPG 2-Hour PPG

24-week placebo-adjusted results

Mean Baseline: 170 mg/dL P<0.001*

Me

an

Ch

an

ge

in

FP

G,

mg

/dL

‡

(95% CI: –24, –10)

–17†n = 234

Me

an

Ch

an

ge

in

2-H

ou

r P

PG

, m

g/d

L‡

Mean Baseline: 257 mg/dLP<0.001*

(95% CI: –59, –34)

–47†

n = 201

–60

–40

–30

–20

–10

0

–50

–60

–40

–30

–20

–10

0

–50

JANUVIA™ (sitagliptin) Monotherapy Significantly Lowers FPG and PPG Levels

29

Add-on to pioglitazone study2

Mean Baseline A1C: 8.0%, 8.1%

Me

an

Ch

an

ge

in

A1

C F

rom

Ba

se

lin

e,

%JANUVIA™ (sitagliptin): Significant A1C Reductions

From Baseline When Added to Metformin or Pioglitazone

24-week change from baseline

n=224

Metformin+ JANUVIA

–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 metformin study1

–0.0%

Metformin+ Placebo

Pioglitazone+ JANUVIA

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%

30

• Monotherapy studies

– No increase in body weight from baseline with JANUVIA compared with a small reduction in the placebo group

• Add-on to metformin

– A similar decrease in body weight for both treatment groups

• Add-on to pioglitazone

– No significant difference in body weight change between treatment groups

JANUVIA™ (sitagliptin): Effect on Body Weight

31

JANUVIA™ (sitagliptin):Adverse Reactions

Overall:

• Adverse reactions and discontinuation rates were similar to placebo (both as monotherapy and as combination therapy)

• Incidence of hypoglycemia with JANUVIA was similar to placebo (1.2% vs 0.9%)

• The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy or in combination with pioglitazone and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.

• Incidence of selected GI adverse reactions in patients treated with JANUVIA vs placebo was as follows:– Abdominal pain (2.3%, 2.1%)

– Nausea (1.4%, 0.6%)

– Diarrhea (3.0%, 2.3%)

32

Usual Dosing for JANUVIA*

Patients With Renal Insufficiency*,†

A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

50 mg once daily 25 mg once daily

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

Men: >1.7–≤3.0; Women: >1.5–≤2.5)

Severe and ESRD‡

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

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with

metformin or a PPAR agonist.

Assessment of renal function is recommended prior to JANUVIAinitiation and periodically thereafter.

JANUVIA™ (sitagliptin): Once-Daily Dosing—Proven 24-Hour Glycemic Control

*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.

33

• Contraindications– None

• Warnings and Precautions

– Use in patients with renal insufficiency:A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

– Use with medications known to cause hypoglycemia:As monotherapy and as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia were similar to rates in patients taking placebo.

The use of JANUVIA in combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not been adequately studied.

JANUVIA™ (sitagliptin): Contraindications/Warnings and Precautions

34

Summary of JANUVIA™ (sitagliptin)

• JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme• Indication:

– Indicated as monotherapy and in combination with metformin or TZDs

– Usual recommended dose is 100 mg once daily• In clinical studies:

– JANUVIA significantly improved A1C, FPG, and PPG – Mean A1C response with JANUVIA appears to be related to

baseline A1C level• Overall:

– Incidence of adverse reactions was similar to that with placebo Overall incidence of hypoglycemia similar to that with placebo A neutral effect on weight relative to that with placebo

• Before prescribing JANUVIA, please read the full Prescribing Information, available at this presentation.

35

Complementary Mechanisms of Action

Combining Sitagliptin and Metformin

36

Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity

MetforminMetformin Blood glucoseBlood glucose

↑Glucose uptake in

muscle and fat by

increasing insulin

sensitivity5

1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026.3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626.5. Bailey CJ et al. N Engl J Med. 1996;334:574–579.

MuscleMuscleAdipose Adipose

tissuetissue

LiverLiver

↓ Gluconeogenesis↓ Glycogenolysis↑ Glycogen synthesis

↓Glucose production

reduced by1–4:LiverLiver

37

Sitagliptin improves beta-cell function and increases insulin synthesis and release.

Sitagliptin reduces 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 Metformin

Addresses the 3 Core Defects of Type 2 Diabetesin a Complementary Manner

Insulin Resistance

*Please see corresponding speaker note for references.

38

JANUMET™ (sitagliptin/metformin HCl): Indications and Usage

• Indication

– JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin.

• Important limitations of use

– JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

39

• The labeling for JANUMET contains a boxed warning for lactic acidosis, a rare,* but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET.

• The risk of lactic acidosis increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure.

• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

• Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

• If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately.

See the full Prescribing Information for the complete Boxed Warning.

JANUMET™ (sitagliptin/metformin HCl):Boxed Warning: Lactic Acidosis

*The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50% of cases.

40

JANUMET™ (sitagliptin/metformin HCl): Pharmacokinetics

• Bioequivalence: A clinical bioequivalence study has demonstrated that JANUMET is bioequivalent to corresponding doses of sitagliptin plus metformin as individual tablets

• Bioavailability:

– Sitagliptin ~87%

– Metformin ~50–60%

• Metabolism: both sitagliptin and metformin are predominantly excreted unchanged in the urine

• Pharmacokinetics: no meaningful changes in either sitagliptin or metformin with co-administration

41

FPGMean Baseline: 170 mg/dL

P <0.001*

–60

–50

–40

–30

–20

–10

0

Me

an

Ch

an

ge

in F

PG

, mg

/dL

§

A1CMean Baseline A1C: 8.0%

P <0.001*

–1.00

–0.75

–0.50

–0.25

0.00

Me

an

Ch

an

ge

in A

1C

, %

§

*Compared with placebo plus metformin.†In patients inadequately controlled on metformin monotherapy.‡Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value.§Difference from placebo.

n=453 n=454

24-week placebo-adjusted results†

–0.7%‡

–25‡

2-Hour PPGMean Baseline: 275 mg/dL

P <0.001*

–60

–50

–40

–30

–20

–10

0

Me

an

Ch

an

ge

in P

PG

, mg

/dL

§

n=387

–51‡

(95% CI: –0.8, –0.5) (95% CI: –31, –20) (95% CI: –61, –41)

JANUMET™ (sitagliptin/metformin HCl) Label Data:Sitagliptin Plus Metformin Provided Significant Improvements

in Glycemic Control Beyond Metformin Alone*

42

JANUMET™ (sitagliptin/metformin HCl) Label Data:Percentage of Patients Achieving A1C <7.0% With the

Combination of Sitagliptin and Metformin

A total of 41 (of 224) patients on placebo plus metformin and 213 (of 453) patients on sitagliptin plus metformin achieved A1C <7.0%.Intent-to-treat population using last observation on study before pioglitzone rescue therapy.

0

10

20

30

40

50

Placebo JANUVIA

0

10

20

30

40

50

Placebo JANUVIA

47%

18%

n=224

n=453

Per

cen

tag

e o

f p

atie

nts

Placebo + metformin

Sitagliptin +metformin

P<0.001

24-Week Study

43

2.1%1.3%

0

2

4

6

8

10

Patients with at least 1 episode ofhypoglycemia over 24 weeks

Pa

tie

nts

, %

Placebo + metformin (n=169)

Sitagliptin + metformin (n=399)

–1.3 –1.5

–3

–2

–1

0

1

2

Me

an

Ch

an

ge

in B

od

y W

eig

ht

Fro

m B

as

elin

e, l

b

Placebo + metformin (n=169)

Sitagliptin + metformin (n=399)

JANUMET™ (sitagliptin/metformin HCl) Label Data:Weight Change and Hypoglycemia Incidence in Patients

Treated With the Combination of Sitagliptin and Metformin

24-Week Add-On Therapy to Metformin Study

HypoglycemiaWeight Change

44

JANUMET™ (sitagliptin/metformin HCl) Label Data:Overall Incidence of Selected Adverse Reactions in Patients Treated With the Combination of Sitagliptin and Metformin

Overall:

• The incidence of side effects and discontinuation rates with sitagliptin and metformin were similar to those with placebo and metformin.

• The incidence of hypoglycemia in patients treated with sitagliptin and metformin was similar to that in patients treated with placebo and metformin (1.3% vs 2.1%).

• The incidence of gastrointestinal disturbances in patients treated with sitagliptin and metformin was similar to that in patients treated with placebo and metformin (11.6% vs 9.7%).

• The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.

• The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

45

JANUMET™ (sitagliptin/metformin HCl) Label Data:Incidence of Selected Gastrointestinal Adverse Reactions in

Patients Treated With Sitagliptin and Metformin

Other AEsSitagliptin and Metformin,

%Placebo and Metformin,

%

Nausea 1.3 0.8

Vomiting 1.1 0.8

Abdominal Pain 2.2 3.8

Diarrhea 2.4 2.5

Incidence in Patients With Sitagliptin or Placebo Added to a Twice-Daily Metformin Regimen

46

JANUMET™ (sitagliptin/metformin HCl): Contraindications

• JANUMET is contraindicated in patients with:

– Renal disease or renal dysfunction, eg, as suggested by serum creatinine levels ≥1.5 mg/dL (males),≥1.4 mg/dL (females) or abnormal creatinine clearance

– Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

• JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration ofrenal function.

47

JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions

• Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should notreceive JANUMET.

• Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.

• Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution.

48

JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions

• Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET therapy, the drug should be promptly discontinued.

• Use of JANUMET should be temporarily suspended for periods of stress, trauma, infection, or any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

• Patients should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET.

• JANUMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

• Hematologic parameters should be measured annually.

49

JANUMET™ (sitagliptin/metformin HCl): Drug Interactions

• Drug Interactions

– Pharmacokinetic drug interaction studies with JANUMET have not been performed; however, such studies have been conducted with the individual components of JANUMET (sitagliptin and metformin hydrochloride).

– Use cationic drugs with caution.

– There are no known clinically meaningful drug interactions for sitagliptin.

• Use of Metformin With Other Drugs

– When drugs that tend to produce hyperglycemia are administered to a patient receiving JANUMET, thepatient should be closely monitored to maintain adequate glycemic control.

50

JANUMET™ (sitagliptin/metformin HCl): Recommended Dosing

• In general: twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal side effects due to metformin

• Starting dose based on patient’s current regimen• Available dosage forms:

– 50 mg sitagliptin/500 mg metformin– 50 mg sitagliptin/1,000 mg metformin

• Patients inadequately controlled on metformin: – Starting dose equal to 100 mg sitagliptin daily plus current

metformin dose• Patients inadequately controlled on sitagliptin:

– Starting dose 50 mg sitagliptin/500 mg metformin twice daily – Titrated up to 50 mg sitagliptin/1,000 mg metformin twice daily

• Patients switching from sitagliptin coadministered with metformin: – Initiate at current doses of sitagliptin and metformin

Tablets not shown at actual size.

51

7.0%

7.2%

7.4%

7.6%

7.8%

8.0%

8.2%

8.4%

8.6%

8.8%

9.0%

2005 2006 2007

A1C

, % Treatment:Metformin initiated

Patient History:45-year-old woman,

bus driverBMI = 31 kg/m2

Borderline hypertensionType 2 diabetes diagnosed

Lab Results:A1C = 7.6%

FPG = 150 mg/dLSerum creatinine = 0.9 mg/dL

(CrCl = 104 mL/min)

Treatment:Diet and exercise

recommended

Lab Results:A1C = 8.0%

FPG = 170 mg/dLSerum creatinine = 1.0 mg/dL

(CrCl = 100 mL/min)

Treatment:Metformin up-titrated to

2,000 mg/day

Case Study: Caroline D.

Considerations for next treatment decision: • Mechanism of action• Efficacy• Tolerability

Current Lab Results: A1C = 7.7%

FPG = 150 mg/dL

52

Overall Summary

• A majority of patients with type 2 diabetes may fail to attain A1C goal with the conventional treatment paradigm

• The components of JANUMET™ (sitagliptin/metformin HCl) have complementary MOAs and comprehensively address3 core pathophysiologic defects of type 2 diabetes.

• Coadministration of sitagliptin and metformin results in:

– Significant reductions in A1C, FPG, and PPG compared with metformin alone

– Weight loss comparable to metformin alone

– Low incidence of hypoglycemia comparable to metformin alone

– Similar overall incidence of side effects to metformin alone