The Modern Comprehensive Approach for

Treating Type 2 Diabetes

Josephine Carlos-Raboca M.D.

Table of Contents

Diabetes Pathophysiology
Comprehensive Approach is
Pathophysiology Based
Therapy with DPP-4 Inhibitor
2

The Pathophysiology of Type 2 Diabetes Involves

Multiple Organ Systems
Peripheral Tissues
Increased
Decreased
Lipolysis
Glucose Uptake

Liver
Increased
Glucose Production

Pancreatic
Beta Cells
Decreased
insulin secretion

Pancreatic
Alpha Cells
Excessive
glucagon secretion

Insulin
resistance

Islet cell
dysfunction
Combined islet cell dysfunction
and insulin resistance

HYPERGLYCEMIA
Adapted with permission from Inzucchi SE. JAMA 2002;287:360372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247254.

Incretins Modulate Insulin and Glucagon to Decrease

Blood Glucose During Hyperglycemia
Meal

Increased insulin
(beta cells)

GIP

Muscle
Adipose
tissue

Glucose
Dependent

Peripheral
glucose
uptake

Gut

GLP-1

Pancreas

Physiologic
Glucose
Control

Glucose
Dependent
Decreased glucagon
(alpha cells)

Liver

Glucose
production

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

Brubaker PL et al. Endocrinology 2004;145:26532659; Zander M et al. Lancet 2002;359:824930; Ahren B. Curr Diab Rep 2003;3:365372;
Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Drucker DJ. Diabetes Care
2003;26:29292940.

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
5

Management of Type 2 Diabetes

Hormones involved in glucose regulation
Insulin
Glucagon
Incretins
Insulin Resistance
islet cell
skeletal muscle
adipose tissue
liver
6

The Incretin Effect Is Diminished

in Individuals With Type 2 Diabetes
Control Subjects
(n=8)

Patients With Type 2 Diabetes

(n=14)

Normal Incretin Effect

80

0.6

80

Diminished Incretin Effect

0.3

40

0.2
20

0.1
0

0
0

60

120

180

Time, min

60

0.4
0.3

40

nmol/L

0.4

IR Insulin, mU/L

60

0.5

nmol/L

IR Insulin, mU/L

0.5

0.6

0.2
20

0.1
0

0
0

60

120

180

Time, min
Oral glucose load

Intravenous (IV) glucose infusion

IR = immunoreactive
Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag.
Vilsbll T, Holst JJ. Diabetologia 2004;47:357366.

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

Therapy with DPP-4 Inhibitor

DPP-4 Inhibitors Improve Glucose Control by

Increasing Incretin Levels in Type 2 Diabetes
Ingestion
of food

Glucose dependent

Insulin

from beta cells

(GLP-1 and GIP)

GI tract

Release of
incretins from
the gut

DPP-4
Enzyme

DPP-4
Inhibitor
Inactive
incretins

Pancreas
-cells
-cells

Glucagon
from alpha cells
(GLP-1)
Glucose
dependent

Insulin
increases
peripheral
glucose
uptake
Improved
Hyperglycemia
Physiologic
Glucose Control
insulin and
glucagon
reduce hepatic
glucose
output

DPP-4 = dipeptidyl peptidase

4

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:26532659; Zander M et al Lancet 2002;359:824830; Ahrn B
Curr Diab Rep 2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders,
2003:14271483.

10

DPP-4 Inhibitors
Chemical Class

-phenethylamines1

Generic Name

Sitagliptin

Cyanopyrrolidines
Vildagliptin4

Aminopiperidine8
Saxagliptin6

H
Molecular Structure

F
F

F NH2 O
N

N
N N

NC

N
H
HO

Half-life

H NH2
H 3C N

N
NC

HO

CF3
Selectivity

Alogliptin

CN
N
N
NH 2

9.96 1.03 nM2

5.28 1.04 nM2

3.37 0.90 nM 2

6.9 1.5 nM9

~12.4 h3

~23 h5

~22.8 h7

12.521.1 h10

1. Kim D et al. J Med Chem. 2005;48(1):141151.

2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1):98107.
3. Data on file, MSD.
4. Villhauer EB et al. J Med Chem. 2003;46(13):27742789.
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):50255037.
7. Fura A et al. Drug Metab Dispos. 2009;37(6):11641171.
8. Feng J et al. J Med Chem. 2007;50(10):22972300.
9. Lee B et al. Eur J Pharmacol. 2008;589(13):30614.
10.Covington P et al. Clin Ther. 2008;30(3):499512.

11

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):141151.
3. Alba M et al. Curr Med Res Opin. 2009;25(10):25072514. eAppendix. doi: 10.1185/03007990902109514.

12

Sitagliptin Lowers Post-meal Glucose

Excursion and Enhances Insulin Secretion
P<0.05 for between group difference

Japanese Monotherapy Study

Baseline
Week 12

280

11.7
mg/dL
-69.2
mg/dL

240

60

Sitagliptin 100 mg qd

Placebo

50
40
30
20
10
0

0 0.5 1.0

2.0

0 0.5 1.0

2.0

Time (hr)

200
160

Placebo

Sitagliptin 100 mg qd

120
0

0.5 1.0

2.0

0.5 1.0

2.0

Time (hr)

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

Insulinogenic Index (U/mg)

Plasma Glucose (mg/dL)

320

Plasma Insulin (U/mL)

Baseline
Week 12

70

Insulinogenic index = I30 / G30

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

13

Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily

Dosing in Monotherapy
18-Week study
Change vs
placebo*
8.4

Japanese study

24-Week study

-0.6%

-0.79%

(P<.001)

-1.05%

(P<.001)

8.4

(P<.001)

8.4

8.0

A1C (%)

8.0

A1C (%)

A1C (%)

8.0

7.6

7.6

7.6

7.2
Placebo (n=74)

7.2

Sitagliptin 100 mg (n=168)

12

Time (wk)

18

Placebo (n=244)

7.2

Sitagliptin 100 mg (n=229)

10

15

20

Time (wk)

25

Placebo (n=75)

6.8

Sitagliptin 100 mg (n=75)

Time (wk)

12

*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
14
Diabetes Association; June 9-13, 2006; Washington, DC.

Sitagliptin Improved Markers of Beta-Cell

Function: 24-Week Monotherapy Study
Proinsulin/insulin ratio
0.48

HOMA-
75

p< 0.001*

0.46

70

0.44

65

0.42

60

0.4

55

0.38

50

0.36

45

0.34

40

0.32

35

0.3

30
Placebo

Placebo

Sitagliptin

from baseline vs= 0.078

pbo
(95% CI -0.114, -0.023)

* P value for change from baseline compared to placebo

p< 0.001*

Hatched = Baseline
Solid = Week 24

Sitagliptin

from baseline vs
= 13.2 +/- 3.3
pbo(95% CI 3.9, 21.9)

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

15

Assessment of Drug Interactions

With 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.

16

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;18:23622367.
3. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):46124619.
4. Alba M et al. Curr Med Res Opin. 2009;25(10):25072514. eAppendix. doi: 10.1185/03007990902109514.

17

Initial Combination Therapy with Sitagliptin and

Metformin: Effective and Durable Glycemic Control
Over 1 Year in Patients With T2DM
Proportion of patients achieving an A1C target
of <7% at Week 24 remaining at <7% at Week 54

Proportion of patients (%)

Proportion of patients (%)

Proportion of patients
achieving an A1C target of <7%

APT

Week 54 Completers

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)

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.

18

Sitagliptin Add-on to Metformin Improved 24-Hour Glucose

Profile in Patients With Type 2 Diabetes

Post Prandial

Fasting/Pre-Prandial

19

Sitagliptin Added to Ongoing Metformin Therapy: Sustained

Glycemic Control Over
54-weeks With Weight Loss
A1C (%)
Phase A

Weight (kg)
Interim Phase B

Phase A
2.0

Mean A1C (%)

7.7

LS mean change from baseline

at week 54
-0.7% (95% CI: -0.8, -0.6)

7.5
7.3
7.1
6.9
6.7
0

12

18

24

30

38

46

LS mean chance from baseline

in body weight (kg)

7.9

6.5

Interim Phase B

0.0

-1.0

-2.0
54

Weeks

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

LS mean change from

baseline at week 54
-0.6 kg (95% CI: -1.5, -0.2)

1.0

12

24

38

54

Weeks

20

HbA1C Change from baseline

at Week 54 (%)

Initial Combination Therapy with Sitagliptin and Metformin: Change

From Baseline in A1C at Week 54 by Baseline A1C Subgroups*

0.0

<8%
(mean 7.6%)

8% and <9%
(mean 8.4%)

9% and <10%
(mean 9.4%)

10%
(mean 10.4%)

0.0

-0.5

-0.5

-1.0

-1.0

-1.5

-1.5

-2.0
-2.5
-3.0
-3.5

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.

-2.0
-2.5
-3.0
-3.5

21

Effect of FDC Sitagliptin/Metformin on A1C Reduction Is

Higher Than Monotherapy

A1C reduction from baseline (%)

Placebo-Subtracted Data in 24-Week Study

-0

Sitagliptin
100 mg qd

Combination
Metformin
Sita 50 mg/
500 mg bid Met 500 mg bid

Combination
Sitagliptin Metformin
Sita 50 mg/
100 mg qd 1000 mg bid Met 1000 mg bid

-0.5
-1.0
-1.5
-2.0
P<.001

-2.5

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

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

P<.001
Additive to 100%
2.1/(0.8 + 1.3)=100%

22

Active GLP-1 (pM)

Complementary Effect of Sitagliptin

+ Metformin on Active GLP-1

Placebo

Metformin Sitagliptin Sitagliptin +

metformin

*P<.001 vs placebo.
Migoya EM et al. Presented at 2007 ADA Annual Meeting. Abstract # 286-OR.

23

24-Week Add-on Therapy to Metformin Study

Incidence of Hypoglycemia With Sitagliptin With

Metformin Was Similar to Placebo With Metformin

Placebo + metforminb (n=237)

5.0

Sitagliptina + metforminb (n=464)

Patients (%)

4.0
3.0

2.1%
2.0

1.3%
1.0
0.0
Patients with at least one episode of hypoglycemia over 24 weeks

All-patients-as-treated population
a
Sitagliptin 100 mg/day; bMetformin 1500 mg/day
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:26382643.

24

24-Week Add-on Therapy to Metformin Study

Sitagliptin With Metformin Provided Weight Loss

Similar to Placebo With Metformin at Week 24

Change in Body Weighta

from baseline (kg)b

0
-0.1
-0.2
-0.3

Placebo + metformind (n=169)

-0.4

Sitagliptinc + metformind (n=399)

-0.5
-0.6
-0.7
-0.8

0.6
P=0.017
vs baseline

0.7
P<0.001
vs baseline

Excluding data after initiation of glycemic rescue therapy; bleast squares means;
Sitagliptin 100 mg/day; dMetformin 1500 mg/day

a
c

Adapted from Charbonnel B et al. Diabetes Care. 2006;29:26382643.

25

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.

26

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 PPAR agonist (TZD)
Combination therapy with metformin, sulfonylurea, or PPAR, 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 PPAR agonist, when dual therapy with these agents with diet and
exercise does not provide adequate glycemic control

Combination 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

27

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

Mild=CrCl 50 mL/min.
Moderate=CrCl 30 to <50 mL/min.
c
Severe=CrCl <30 mL/min.
d
Requiring hemodialysis or peritoneal dialysis. JANUVIA may be administered without regard to the timing of hemodialysis.
a

28

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 PPAR 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 PPAR
agonist (ie, thiazolidinediones)
In combination with insulin as an adjunct to diet and exercise

29

JANUMET (sitagliptin/metformin, MSD) Contraindications: Based on

the Worldwide Product Circular

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

30

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 59,
2009.

31

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

32