The Modern Comprehensive Approach for Treating Type 2 Diabetes

Josephine Carlos-Raboca M.D.

2

Table of Contents

–Diabetes Pathophysiology

–Comprehensive Approach is Pathophysiology Based

–Therapy with DPP-4 Inhibitor

3

HYPERGLYCEMIA

Islet cell dysfunction

Pancreatic Beta CellsDecreased

insulin secretion

Pancreatic Alpha CellsExcessive

glucagon secretion

Pancreatic Beta CellsDecreased

insulin secretion

Pancreatic Alpha CellsExcessive

glucagon secretion

Insulinresistance

Adapted with permission from Inzucchi SE. JAMA 2002;287:360–372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247–254.

LiverIncreased

Glucose Production

LiverIncreased

Glucose Production

Peripheral TissuesPeripheral TissuesDecreased

Glucose UptakeIncreased Lipolysis

Combined islet cell dysfunction and insulin resistance

The Pathophysiology of Type 2 Diabetes Involves Multiple Organ Systems

4

Decreased glucagon(alpha cells)

Increased insulin(beta cells)

PancreasPancreas

LiverLiver

MuscleMuscleAdipose Adipose

tissuetissue

Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia

Gut

Peripheral glucose uptake

Glucose production

GIP

GLP-1

Glucose Dependent

Glucose Dependent

Meal

Physiologic Glucose Control

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Drucker DJ. Diabetes Care 2003;26:2929–2940.

5

Summary of Diabetic Pathophysiologies

Islet-cell dysfunction– Dysfunction of both beta cells (insulin production) and alpha cells

(glucagon production) occur

– Dysfunction begins years before diagnosis of type 2 diabetes

– Dysfunction is progressive both before and after diagnosis

– Incretin defects contribute to islet cell dysfunction

Insulin Resistance– Insulin resistance begins years before diagnosis

– After diagnosis of type 2 diabetes there is little worsening of insulin resistance

– Insulin resistance reduces glucose uptake and utilization

Hepatic Glucose Overproduction– Overproduction is a result of islet-cell dysfunction and insulin resistance

6

Management of Type 2 Diabetes

Hormones involved in glucose regulation

• Insulin• Glucagon• Incretins

Insulin Resistance islet cell skeletal muscle adipose tissue liver

7

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

The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes

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

Normal Incretin Effect Diminished Incretin Effect

IR = immunoreactiveAdapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–366.

8

Characteristics of an Ideal Therapy

Characteristics of an ideal oral antidiabetic agent

– Lowers HbA1c to normal levels

– Decreases insulin resistance and hepatic glucose production and increases or preserves beta-cell mass while restoring first-phase insulin response

– Does not cause weight gain

– Does not increase risk of hypoglycemia

– Does not cause edema or congestive heart failure

9

=

–Therapy with DPP-4 Inhibitor

10

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

DPP-4 Inhibitors Improve Glucose Control by Increasing 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

DPP-4 Inhibitor

X

DPP-4 = dipeptidyl peptidase 4

11

DPP-4 Inhibitors

Chemical Class β-phenethylamines1 Cyanopyrrolidines Aminopiperidine8

Generic Name Sitagliptin Vildagliptin4 Saxagliptin6 Alogliptin

Molecular Structure

Selectivity 9.96 ± 1.03 nM2 5.28 ± 1.04 nM2 3.37 ± 0.90 nM2 6.9 ± 1.5 nM9

Half-life ~12.4 h3 ~2–3 h5 ~2–2.8 h7 12.5–21.1 h10

F

F

F O

N

NH2

N NN

CF3

N N

O

H3C

O N

CN

NH2

N

O

HH

NCHO

NH2

HO

NH

O

N

NC

1. Kim D et al. J Med Chem. 2005;48(1):141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1):98–107.3. Data on file, MSD. 4. Villhauer EB et al. J Med Chem. 2003;46(13):2774–2789.5. EMEA approval and SPC for Galvus. http://www.emea.europa.eu/humandocs/Humans/EPAR/galvus/galvus.htm. Accessed on July 8, 2009. 6. Augeri DJ et al. J Med Chem. 2005;48(15):5025–5037. 7. Fura A et al. Drug Metab Dispos. 2009;37(6):1164–1171. 8. Feng J et al. J Med Chem. 2007;50(10):2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589(1–3):306–14. 10.Covington P et al. Clin Ther. 2008;30(3):499–512.

12

Sitagliptin

Sitagliptin is a DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes.1

Sitagliptin is a potent, highly selective, once-daily oral therapy.1

– Sitagliptin is >2,600 times more selective for DPP-4 in vitro than DPP-8, DPP-9, and other related enzymes.2

Sitagliptin 100 mg once daily has shown near maximal and sustained DPP-4 inhibition (97%) over 24 hours.3

DPP-4=dipeptidyl peptidase-4.1. Data on file, MSD.2. Kim D et al. J Med Chem. 2005;48(1):141–151.3. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514.

13

Sitagliptin Lowers Post-meal Glucose Excursion and Enhances Insulin Secretion

Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.

Insulinogenic index = ∆ I30 / ∆ G30

0

0.1

0.2

0.3

0.4

0.5

Week 0 Week 12Between group difference (P<0.001)

Placebo

Sitagliptin 100 mg qd

Insu

lin

og

en

ic I

nd

ex

(µU

/mg

)P<0.001 for difference in change from baseilne in 2-hr PPG

Time (hr)

Pla

sm

a I

nsu

lin

(µ

U/m

L)

0

10

20

30

40

50

60

70

0 0.51.0 0 1.02.0 2.00.5

Sitagliptin 100 mg qd Placebo

P<0.05 for between group difference

Time (hr)

Pla

sm

a G

lucose (

mg

/dL)

120

160

200

240

280

320

0 0.5 1.0 0 1.02.0 2.00.5

-69.2mg/dL

Baseline

Week 12

Placebo Sitagliptin 100 mg qd

Japanese Monotherapy Study

11.7mg/dL

Baseline

Week 12

14

Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy

*Between group difference in LS means. Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: 66 th Scientific Sessions of the American Diabetes Association; June 9-13, 2006; Washington, DC.

Change vs placebo*

Placebo (n=74)

Sitagliptin 100 mg (n=168)

Time (wk)

18-Week study

0 6 12 18

A1

C (

%)

7.2

7.6

8.0

8.4

-0.6%(P<.001)

Placebo (n=244)

Sitagliptin 100 mg (n=229)

24-Week study

Time (wk)0 5 10 15 20 25

-0.79%(P<.001)

A1

C (

%)

7.2

7.6

8.0

8.4

Placebo (n=75)

Sitagliptin 100 mg (n=75)

Time (wk)

Japanese study-1.05%

(P<.001)

A1

C (

%)

7.2

7.6

8.0

8.4

6.8

0 4 8 12

15

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.

= 0.078

(95% CI -0.114, -0.023)* P value for change from baseline compared to placebo

Hatched = BaselineSolid = Week 24

∆ from baseline vs pbo

p< 0.001*

0.3

0.32

0.34

0.36

0.38

0.4

0.42

0.44

0.46

0.48

Placebo Sitagliptin

HOMA-β

∆ from baseline vs pbo

= 13.2 +/- 3.3(95% CI 3.9, 21.9)

p< 0.001*

30

35

40

45

50

55

60

65

70

75

Placebo Sitagliptin

16

Assessment of Drug InteractionsWith Sitagliptin

In vitro unlikely to cause interactions with other drugs– No inhibition of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6– No induction of CYP3A4– Not extensively bound to plasma proteins

In vivo low potential of drug interactions with substrates of CYP3A4, 2C8, and 2C9– No meaningful alteration of the pharmacokinetics of metformin, glyburide, simvastatin,

rosiglitazone, warfarin, or oral contraceptives

Digoxin – No dosage adjustment of digoxin or sitagliptin is recommended

Data on file, MSD.

17

Summary

Sitagliptin is a potent, highly selective once-daily oral therapy.1

Sitagliptin enhances incretin levels through inhibition of DPP-4.1

Sitagliptin is a DPP-4 inhibitor that is not covalently bound.2 It rapidly dissociates and has a prolonged half-life that supports once- daily dosing.1

Sitagliptin 100 mg has shown near maximal and sustained DPP-4 inhibition over 24 hours, resulting in increases in active GLP-1 and GIP.3,4

1. Data on file, MSD. 2. Wallace MB et al. Bioorg Med Chem Lett. 2008;18:2362–2367.3. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):4612–4619.4. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514.

18

Initial Combination Therapy with Sitagliptin and Metformin: Effective and Durable Glycemic Control

Over 1 Year in Patients With T2DM

23

41

25

35

44

57

48

6367

77

0

10

20

30

40

50

60

70

80

90

Week 54 CompletersAPT

Pro

port

ion

of

pati

en

ts (

%)

Proportion of patients achieving an A1C target of <7%

Sitagliptin 100 mg qd (n=106/58)Metformin 500 mg bid (n=117/77)Metformin 1000 mg bid (n=134/101)Sitagliptin 50 mg + metformin 500 mg bid (n=147/106)Sitagliptin 50 mg + metformin 1000 mg bid (n=153/124)

Proportion of patients achieving an A1C targetof <7% at Week 24 remaining at <7% at Week 54

Pro

port

ion

of

pati

en

ts (

%)

70

59

79 8085

0

10

20

30

40

50

60

70

80

90

Sitagliptin 100 mg qd (n=33)

Metformin 500 mg bid (n=34)Metformin 1000 mg bid (n=63)

Sitagliptin 50 mg + metformin 500 mg bid (n=65)Sitagliptin 50 mg + metformin 1000 mg bid (n=96)

Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.

19

Sitagliptin Add-on to Metformin Improved 24-Hour Glucose Profile in Patients With Type 2 Diabetes

Post Prandial

Fasting/Pre-Prandial

20

Sitagliptin Added to Ongoing Metformin Therapy: Sustained Glycemic Control Over

54-weeks With Weight Loss

6.5

6.7

6.9

7.1

7.3

7.5

7.7

7.9

0 6 12 18 24 30 38 46 54

Phase A Interim Phase B

Weeks

Mean

A1

C (

%)

Phase A Interim Phase B

0 12 24 38 54-2.0

-1.0

0.0

1.0

2.0

WeeksLS

mean

ch

an

ce f

rom

baselin

ein

bod

y w

eig

ht

(kg

)

Karasik A et al. Poster presented at 2007 ADA Annual Meeting.

A1C (%) Weight (kg)

LS mean change from baselineat week 54

-0.7% (95% CI: -0.8, -0.6)

LS mean change from baseline at week 54

-0.6 kg (95% CI: -1.5, -0.2)

21

Initial Combination Therapy with Sitagliptin and Metformin: Change From Baseline in A1C at Week 54 by Baseline A1C Subgroups*

10%(mean 10.4%)

9% and <10%(mean 9.4%)

8% and <9% (mean 8.4%)

<8%(mean 7.6%)

Hb

A1

C C

han

ge f

rom

baselin

e

at

Week 5

4 (

%)

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Sitagliptin 100 mg (28/43/19/16)

Metformin 500 mg bid (32/39/30/16)

Metformin 1000 mg bid (40/53/33/8)

Sitagliptin 50 mg + metformin 500 mg bid (39/49/38/21)

Sitagliptin 50 mg + metformin 1000 mg bid (33/60/43/17)

*Mean change SE: APT Population.Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.

22

-0.8-1

-1.6

-0.8

-1.3

-2.1

Effect of FDC Sitagliptin/Metformin on A1C Reduction Is Higher Than Monotherapy

Sitagliptin100 mg qd

A1C

red

ucti

on

fro

m b

aselin

e (

%)

Placebo-Subtracted Data in 24-Week Study

FDC=fixed-dose combination.

Williams-Herman D et al. Presented at: 19th World Diabetes Congress (IDF) in South Africa, 2006.

Sitagliptin100 mg qd

Metformin500 mg bid

CombinationSita 50 mg/

Met 500 mg bidMetformin

1000 mg bid

CombinationSita 50 mg/

Met 1000 mg bid

Additive to 89%1.6/(0.8 + 1.0)89%

Additive to 100%2.1/(0.8 + 1.3)=100%

P<.001

P<.001-2.5

-2.0

-1.5

-1.0

-0.5

-0

23

Complementary Effect of Sitagliptin + Metformin on Active GLP-1

8.41

*14.81

*16.37

*34.68

0

5

10

15

20

25

30

35

40

Placebo MetforminSitagliptinSitagliptin + metformin

Acti

ve G

LP

-1 (

pM

)

*P<.001 vs placebo.

Migoya EM et al. Presented at 2007 ADA Annual Meeting. Abstract # 286-OR.

24

Incidence of Hypoglycemia With Sitagliptin With Metformin Was Similar to Placebo With Metformin

24-Week Add-on Therapy to Metformin Study

All-patients-as-treated populationaSitagliptin 100 mg/day; bMetformin ≥1500 mg/day

Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.

Patients with at least one episode of hypoglycemia over 24 weeks

Pat

ien

ts (

%)

Placebo + metforminb (n=237)

Sitagliptina + metforminb (n=464)

2.1%

1.3%

0.0

1.0

2.0

3.0

4.0

5.0

25

Sitagliptin With Metformin Provided Weight Loss Similar to Placebo With Metformin at Week 24

24-Week Add-on Therapy to Metformin Study

aExcluding data after initiation of glycemic rescue therapy; bleast squares means; cSitagliptin 100 mg/day; dMetformin ≥1500 mg/day

Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.

–0.6P=0.017

vs baseline –0.7P<0.001

vs baseline

Placebo + metformind (n=169)

Sitagliptinc + metformind (n=399)

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Ch

ang

e in

Bo

dy

Wei

gh

ta fr

om

bas

elin

e (k

g)b

26

Combination Therapy Offers Advantages Over Monotherapy

Combination therapy may provide more glycemic control than the individual monotherapies

Combination therapy may provide more comprehensive coverage of the key pathophysiologies of type 2 diabetes than monotherapy

An appropriately chosen combination therapy may help more patients achieve their HbA1c goal without increasing side effects1

Adapted from Del Prato Int J Clin Pract 2005;59:1345-1355.

27

JANUVIA™ (sitagliptin) Indications and Contraindications: Based on the Worldwide Product Circular

Indications– JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2

diabetes mellitus as:• Monotherapy • Initial combination therapy with metformin• Initial combination therapy with a PPARγ agonist (TZD)• Combination therapy with metformin, sulfonylurea, or PPARγ, when the single agent alone with diet and exercise

does not provide adequate glycemic control• Combination therapy with metformin and a sulfonylurea, when dual therapy with these agents with diet and exercise

does not provide adequate glycemic control• Combination therapy with metformin and a PPARγ agonist, when dual therapy with these agents with diet and

exercise does not provide adequate glycemic controlCombination with Insulin• JANUVIA is indicated in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve

glycemic control in combination with insulin (with or without metformin).Contraindications

– JANUVIA is contraindicated in patients who are hypersensitive to any components of this product

28

JANUVIA™ (sitagliptin) Recommended Dosing: Based on the Worldwide Product Circular

Dosage– Recommended dosage of JANUVIA is 100 mg once daily taken with or without

food– When JANUVIA is used in combination with a sulfonylurea or with insulin, a lower

dose of the sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia

– For patients with renal insufficiency• Milda — no dosage adjustment is required• Moderateb — JANUVIA 50 mg once daily• Severec or end-stage renal diseased — JANUVIA 25 mg once daily

– Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter

aMild=CrCl ≥50 mL/min. bModerate=CrCl ≥30 to <50 mL/min. cSevere=CrCl <30 mL/min. dRequiring hemodialysis or peritoneal dialysis. JANUVIA may be administered without regard to the timing of hemodialysis.

29

JANUMET™ (sitagliptin/metformin, MSD) Indications: Based on the Worldwide Product Circular

Indications – JANUMET is indicated in patients with type 2 diabetes mellitus to improve

glycemic control • As initial therapy when diet and exercise do not provide adequate

glycemic control• As an adjunct to diet and exercise in patients who have inadequate

glycemic control on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin

• In combination with a sulfonylurea (ie, triple combination therapy) as an adjunct to diet and exercise in patients who have inadequate glycemic control with any 2 of the 3 agents: metformin, sitagliptin, or a sulfonylurea

• In combination with a PPARγ agonist (ie, triple combination therapy) as an adjunct to diet and exercise in patients who have inadequate glycemic control with any 2 of the 3 agents: metformin, sitagliptin, or a PPARγ agonist (ie, thiazolidinediones)

• In combination with insulin as an adjunct to diet and exercise

30

Contraindications– JANUMET is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance, which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.

• Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride or any other component of JANUMET

• 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 the use of such products may result in acute alteration of renal function

JANUMET™ (sitagliptin/metformin, MSD) Contraindications: Based on the Worldwide Product Circular

31

Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: Conclusions

Compared with metformin alone, in patients with type 2 diabetes and moderate to severe hyperglycemia on diet and exercise initial combination therapy with sitagliptin/metformin FDC (JANUMET) provided1,2

• Superior glycemic improvements resulting in more patients achieving HbA1c goal

• A similar incidence of hypoglycemia, and lower incidences of abdominal pain and diarrhea compared with metformin alone.

FDC=fixed-dose combination.1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.2. Data on file, MSD.

32

Conclusions

Treatment to achieve glycemic control early is important to help reduce complications of type 2 diabetes1

Many patients on current monotherapies do not achieve glycemic control2

Combination therapy with a DPP-4 inhibitor and metformin offers opportunity for improved glycemic efficacy, complementary mechanisms of action, and a low risk of hypoglycemia without weight gain

Sitagliptin/metformin provides a more comprehensive approach for addressing the key pathophysiologies of type 2 diabetes