010_lalic

New oral antidiabetic drugs:

DPP-4 inhibitors and

incretin mimetics

Prof dr Nebojsa M. Lalic

School of Medicine, University of Belgrade,

Institute for Endocrinology, Diabetes and Metabolic

Diseases, Clinical Center of Serbia

Serbian Acadademy of Sciences and Arts, Belgrade, Serbia

Athens, July 4, 2009


DPP-4 inhibitors and incretin mimetics

• The use of oral agents in type 2 diabetes treatment: present state

• The incretin effect and the role of GLP-1

• The therapeutic effects of incretin-based treatment: DPP-4 inhibitors and incretin mimetics

• Incretin-based therapeutic agents in the recommendations for type 2 diabetes treatment

Kahn S et al, Nature, 2006; 444:840

Natural History of Type 2 Diabetes

0

50

100

150

200

250

-10 -5 0 5 10 15 20 25 30

Years of Diabetes

Glucose

(mg/dL)

Relative

Function

(%)

Insulin Resistance

Insulin Level-Cell Failure

*IFG=impaired fasting glucose.

50

100

150

200

250

300

350

Fasting

Glucose

Post-meal

Glucose

Obesity IFG* Diabetes Uncontrolled Hyperglycemia

€

€

DeFronzo RA. Ann Intern Med. 1999; 131:281-303.

6

ADA1 ACE2 IDF3

HbA1c <7.0%

(general goal)

≤6.5% <6.5%

Preprandial capillary

plasma glucose

70–130 mg/dL

(3.9–7.2 mmol/L)

<110 mg/dL

(<6.0 mmol/L)

<110 mg/dL

(<6.0 mmol/L)

Peak postprandial

capillary plasma

glucose

<180 mg/dL

(<10.0 mmol/L)

<140 mg/dL

(<7.7 mmol/L)

<145 mg/dL

(<8.0 mmol/L)

ACE=American College of Endocrinology; ADA=American Diabetes Association; HbA1c=hemoglobin A1c; IDF=International Diabetes Federation

Adapted from: 1ADA / EASD consensus statement: Nathan DM, et al. Diabetes Care. 32:193–203;2American Association of Clinical Endocrinologists, American College of Endocrinology. Endocr Pract. 2002; 8 (Suppl 1): 5–11;3International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation; 2005.

Current Treatment Goals for Glycemic Control

From UKPDS 33. Lancet. 1998;352:837-853.

*Decreases were statistically significant.

Optimal Glycemic Control Reduces Complications

• Intensive glucose control in UKPDS 33

results in:0

-50

12%Lower 16%

Lower 21%Lower 24%

Lower 25%Lower

Risk of

Myocardi

al

Infarction

Risk of

Diabetes-

related

Endpoints

*

Risk of

Retinopath

y at 12

Years*

Risk of

Cataract

Extraction

*

Risk of

Microvascular

Endpoints*

Perc

en

tag

e o

f R

isk

Treatment of diabetes

Diet

Physical activity

Self control

Oral agents

Insulin

ADA-EASD Hyperglycemia Algorithm

Nathan et al. Diabetologia (2006) 49:1711–1721

1

2

3

ADA/EASD consensus, October, 2008

Principles in selecting

antihyperglycemic interventions

Choice of specific antihyperglycemic agents is

predicated on:

their effectiveness in lowering glucose,

extraglycemic effects that may reduce long-term

complications,

safety profiles,

tolerability,

ease of use,

expense

Diabetes Care 2009; 32:1–11

Step 1: lifestyle intervention and metformin

The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain the metabolic goals either because of failure to lose weight, weight regain, progressive disease, or a combination of factors.

Therefore, the consensus is that metformin therapy should be initiated concurrently with lifestyle intervention at diagnosis.

Diabetes Care 2009;32:1–11

Step 1: lifestyle intervention and metformin

Metformin is recommended as the initial pharmacological therapy, in the absence of specific contraindications, for its effect on glycemia, absence of weight gain or hypoglycemia, generally low level of side effects, high level of acceptance, and relatively low cost.

Metformin treatment should be titrated to its maximally effective dose over 1–2 months, as tolerated. Rapid addition of other glucose-lowering medications should be considered in the setting of persistent symptomatic hyperglycemia.


Step 2: addition of a second medication

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

The consensus regarding the second medication added to metformin was to choose either insulin or a sulfonylurea.

The A1C level will determine in part which agent is selected next, with consideration given to the more effective glycemia-lowering agent, insulin, for patients with an A1C level of 8.5% or with symptoms secondary to hyperglycemia.


Extrapolation of the time of

deterioration of beta-cell dysfunction

UKPDS 16. Diabetes 1995;44:1249–1258

0

20

40

60

80

100

Years from diagnosis

Beta

-cell

function (

%)

–10 –8 –6 –4 –2 0 2 4 6–12

19

β-cell Function Continues to Decline Regardless of

Intervention in T2DM

T2DM=type 2 diabetes mellitus

*β-cell function measured by homeostasis model assessment (HOMA)

Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.

0

20

40

60

80

100

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Years since Diagnosis

β-c

ell

Fu

nc

tio

n (

%)*

Progressive Loss of β-cell Function

Occurs prior to Diagnosis

Metformin (n=159)

Diet (n=110)

Sulfonylurea (n=511)

20

Traditional Current Oral Therapies Do Not Address

Islet Cell Dysfunction

TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.

Pancreatic Islet Dysfunction

Inadequate

glucagon

suppression

(-cell

dysfunction)

Progressive

decline of β-cell

function

Insufficient

Insulin secretion

(β-cell

dysfunction)

Sulfonylureas

Glinides

TZDsMetformin

Insulin Resistance

(Impaired insulin action)

The Incretin Effect

Ingested glucose results in a more

robust insulin response than glucose

administered intravenously, indicating

the presence of substances within the

gastrointestinal tract that stimulate

insulin release in a glucose-dependent

manner.

Creutzfeldt. Diabetologia. 1985;28:565.

Nauck MA, et al. J Clin Endocrinol Metab. 1986 Aug;63(2):492-498.

Measurement of the Incretin EffectOGTT and Matched IV Infusion

0

50

100

150

200

-30 0 30 60 90 120 150 180 210

Time (min)

0

100

200

300

400

-30 0 30 60 90 120 150 180 210

Time (min)

Oral

IV

Glucose (mg/dL) Insulin (pmol/L)

Definition of Incretins

“Gut-derived factors that increase

glucose-stimulated insulin secretion”

In cre tinIntestine Secretion Insulin

Creutzfeldt. Diabetologia. 1985;28:565.

The Incretins

YA

EG

TF

IS

DY

SI

AM

DK

IH

QQ

DFVNWLLA

QKGKKNDWK

H N QTI

GIP: Gastric Inhibitory PolypeptideGlucose-Dependent Insulinotropic Polypeptide

HA

E GT

FT

SD V

SS

YL

E GQ

AA

KEFIA

WLVKGR

G

GLP-1: Glucagon-Like Peptide 1

Amino acids shown in yellow are homologous with the structure of glucagon.

Drucker. Diabetes Care. 2003;26:2929.

L-cell

(ileum)

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

K-cell

(jejunum)

ProGIP

GIP [1–42]

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

Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.

GLP-1 and GIP are Synthesized and Secreted from the

Gut in Response to Food Intake

26

GLP-1: An Intestinal Hormone

• Secreted from L cells in the intestinal

mucosa after meals

• Effects– Stimulates insulin secretion

– Suppresses glucagon secretion

– Delays gastric emptying

– Enhances satiety

– Enhances -cell mass/replication in animals

• Rapidly degraded by the protease dipeptidyl

peptidase IV (DPP-IV)


Inhibition of DPP-4 Increases Active GLP-1

GLP-1inactive

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½=1–2 min

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1

Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.

Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.28

C CN N

Cytosol

Rasmussen, H.B., et al, (2003) Nat.Struct.Biol., 10, 19-25

Extracellular

Cell membrane

Dimeric Structure of DPP-4 / CD26

Intracellular

Drucker D. Cell Metabolism 3, 153–165, 2006

Contrasting roles of GLP-1 and GIP on glucose homeostasis

Drucker D. Cell Metabolism 3, 153–165, 2006

Incretin Actions on Different Target Tissues

Insulin secretion

Glucagon secretion

Gastric emptying

Appetite

Cardioprotection

Cardiac output

Insulin biosynthesis

cell proliferation

cell apoptosis

Neuroprotection

Glucose production

Insulin sensitivity

Brain

Heart

GI tract

Liver

Muscle

Stomach

GLP-1

Drucker D. J. Cell Metabolism 2006

Nauck. Diabetologia. 1986;29:46.

The Incretin Effect Is Reduced in T2DM Compared With NGT

0

5

10

15

20

25

30

35

40

NGT T2DM0

10

20

30

40

50

60

70

80

NGT T2DM

Incretin

Effect

Insu

lin

(mm

ol/L

/min

)

Glucose:IV (isoglycemic infusion)

Oral (50 g)

30.0

72.8

23.5

34.7

11.3

38.9

-Cell Secretory

Response

NGT=normal glucose tolerance

Co

ntr

ibu

tio

ns o

f In

cre

tin

Facto

rs (

%)

0

5

10

15

20

0 60 120 180 240

NGT

IGT

T2DM

Breakfast

**

*****

*

Time (min)

Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717

Release of GLP-1 Is Impaired in

Patients With T2DMG

LP

-1 (

pm

ol/L

)

*P<0.05 vs T2DM

NGT = normal glucose tolerance

IGT = impaired glucose tolerance

6-Week Subcutaneous

GLP-1 Infusion

Treatment Effects in 20 Patients With T2DM

Saline GLP-1 Rx Effect

(n=9*) (n=10)

Baseline A1C (%) 8.9 9.2

A1C (%) +0.2 -1.3 -1.5%

Weight (kg) -0.7 -1.9 -1.2 kg

Zander. Lancet. 2002;359:824.

*One patient was excluded because noveins were accessible.

Placebo

GLP-1

Nauck NA, et al. Diabetologia. 1993;36:741-744.Minutes

*P <0.05

Insulin

Glucagon

Fasting

Glucose

250

150

5

250

200

100

50

40

30

20

0

mU/L

20

15

10

0 60 120 180 240

15.0

12.5

10.0

7.5

5.0

200

150

100

50Infusion

*

*

* ** * *

* * *

*** *

**

** *

mmol/L mg/dL

pmol/L

pmol/L

n = 10

GLP-1 Actions are Glucose Dependent in Patients with

Type 2 Diabetes

10

β-Cell mass β-Cell proliferation β-Cell apoptosis

Farilla et al. Endocrinology. 2002;143:4397.

0

4

8

12

16

Control GLP-1

treated

0

0.5

1.0

1.5

2.0

2.5

Control0

10

20

30

Control

P<0.001

P<0.05P<0.01

Effect of GLP-1 on β-cell mass in

Zucker diabetic fatty rats

GLP-1

treated

GLP-1

treated

β-C

ell

mass (

mg

)

Pro

life

rati

ng

β-c

ell

s (

%)

Ap

op

toti

c β

-cell

s (

%)

Effect of GLP-1 on -Cell Apoptosis in

Isolated Human Islets

0

5

10

15

20

Ap

op

toti

c N

uc

lei (%

)

Control

P<0.01for days3 and 5

GLP-1

Day 5

Day 3

Day 115.5

18.9

6.1

8.9

Control + GLP-1

Farilla, L. et al. Endocrinology 144: 5149-5158, 2003

1. Endocrinology 2003; 2. J Hypertens 2003; 3. Circulation 2004;

4. Diabetes 2005; 5. Am j Physiol Endo Metab 2004

JPET 317:1106–1113, 2006

Circulation. 2004;109:962-965.

Changes in LVEF after 72 hours of rGLP-1 infusion versus control subjects

Pharmacologic Approaches to Enhancing

GLP-1 Action in Diabetes

• GLP-1 receptor agonists

• DPP-IV inhibitors


Dungan. Clin Diabetes. 2005;23:56.

Pharmacologic Approaches to

Enhancing GLP-1 Action in Diabetes

• GLP-1 receptor agonists

– Mimetics

• Possess physiologic characteristics and biologic

activity of native GLP-1 but resist degradation by

DPP-IV

• Exenatide (exendin-4)

– Analogues

• Half-lives increased by modification of rHu GLP-1

to resist DPP-IV degradation

• Liraglutide



Exenatide

GEX060209

SFU

Exenatide Lowered HbA1c at 30 Weeks

MET + SFUMET

Ch

an

ge

in

Hb

A1c

(%)

Placebo BID

Exenatide 5 µg BID

Exenatide 10 µg BID

0.2

-0.6*

*-0.8

ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *P <.005 vs placebo.Mean baseline HbA1c ranged from 8.2% to 8.7% across all trial arms.DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

0.1

-0.5*

*-0.9

-0.4*

-0.8*

-1

-0.5

0

0.5

0.1

Exenatide

GEX060209

Exenatide Reduced Body Weight Over 30 Weeks

MET

Ch

an

ge i

nW

eig

ht

(kg

)

MET + SFU

Time (week)

SFU

0 10 20 30

*

0 10 20 30

*

*

*

** *

Placebo BID

Exenatide 5 µg BID

Exenatide 10 µg BID

0 10 20

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

030

*

*

*

**

**

**

** **-3.5

ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *P <.05 vs placebo; **P <.001 vs placebo.Mean baseline weight ranged from 95 kg to 101 kg across all trial arms.

DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;

Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Time (week) Time (week)

Exenatide

GEX060209

Exenatide once weekly versus twice daily for the

treatment of type 2 diabetes - DURATION-1 Study

Effect on HbA1c

Drucker D et al. Lancet 2008; 372: 1240–50

Exenatide

GEX060209



Effect on body weight


Exenatide

GEX060209



Effect on cardiovascular parameters


* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted. †AMIGO I; ††AMIGO II; †††AMIGO III

HbA

1c(%

)

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

* **

*

*

*

Up to 10 µgtwice daily

Up t

o 2

mg w

eekly

14512

0.7

5 m

g O

D

2.0

mg

OD

1.9

mg

OD

wks

Exenatide BID

Exenatide LAR 1/week

Liraglutide OD

Placebo

Insulin glargine

Glimepiride

Drucker and Nauck, Lancet 2006;368:1696-705

Glycaemic effects of GLP-1 agonists: HbA1c

2.0

mg O

D

wks

3

2

1

-2

-3

-5

*

* * *

*

**

0

-1

-4

30

Duration (weeks)

152615

Change in b

ody w

eig

ht

(kg) 14512

0.7

5 m

g O

D

1.9

mg O

D

*

Weight effects of GLP-1 agonists

Exenatide BID


Liraglutide OD

Placebo

Insulin glargine

Glimepiride


Drucker and Nauck, Lancet 2006;368:1696-705; Kim et al, Diabetes Care 2007; In press

Nausea (

%)

**

*

*

*

*

**

100

80

60

0

40

20

*

512

0.7

5 m

g O

D

2.0

mg

OD

1.9

mg

OD

14 wks

Side effects of GLP-1 agonists: nausea

Exenatide BID


Liraglutide OD

Placebo

Insulin glargine

Glimepiride


Drucker and Nauck, Lancet 2006;368:1696-705; Kim et al, Diabetes Care 2007; In press

Pharmacologic Approaches to

Enhancing GLP-1 Action in Diabetes

• DPP-IV inhibitors

– Advantage of oral administration

– Improve glucose tolerance and increase

insulin release

• Vildagliptin, sitagliptin



Initial Combination Therapy With Sitagliptin Plus Metformin Study: HbA1c Results at 104 Weeks

(Extension Study)

ExtensionStudy

24-weekphase

Continuationphase

LS

M H

bA

1c

Ch

an

ge

Fro

m B

as

eli

ne

, %

Sitagliptin 100 mg qd (n=50)

Metformin 500 mg bid (n=64) Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)

Metformin 1000 mg bid (n=87)

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

–1.1

–1.1

–1.3

–1.4

–1.7

Mean baseline A1C = 8.5%–8.7%

a

a

0 6 12 18 24 30 38 46 54 62 70 78 91 104

6.0

6.5

7.0

7.5

8.0

8.5

9.0

Weeks

APT Population (Extension Study)

APT=all-patients-treated; bid=twice a day; LSM=least-squares mean; qd=daily. aValues represented are rounded. Actual values are 1.15 for sitagliptin 100 mg qd and 1.06 for metformin 500 mg bid.

D. Willams-Herman et al. Substantial Improvement in β-cell Function with Initial Combination Therapy of Sitagliptin and Metformin in Patients with Type

2 Diabetes after 1 Year of Treatment, Poster presented at ADA 2008

HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy

Per-protocol Population

LSM change from baseline

at 52 weeks (for both groups): –0.7%

Achieved primary

hypothesis of

noninferiority to

sulfonylurea

Sulfonylureaa + metformin (n=411)

Sitagliptinb + metformin (n=382)

Hb

A1c,

% ±

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

aSpecifically glipizide ≤20 mg/day;bSitagliptin 100 mg/day with metformin (≥1500 mg/day).

LSM=least squares mean.

SE=standard error.

Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence

of Hypoglycemia

between groups at Week 52 = –2.5 kg

Least squares mean change from baseline

Bo

dy W

eig

ht,

kg

±S

E



−3

−2

−1

0

1

2

3

Weeks

0 12 24 38 52

P<0.001

Hypoglycemia

P<0.001

32%

5%

0

10

20

30

40

50

Week 52

Pa

tie

nts

Wit

h ≥

1 E

pis

od

e

Ove

r 5

2 W

ee

ks

, %



All-patients-as-treated Population

aSpecifically glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); Least squares mean between-group difference at week 52 (95% CI): change in body weight at Week 52 = –2.5 kg [–

3.1, –2.0] (P<.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<.001).

Add-on sitagliptin with metformin vs sulfonylurea with metformin study.

Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

6363

Meal

*

*

*

*

*

** * *

**

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

Vildagliptin Enhances GLP-1 Levels in Patients

with T2DM

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

*P <0.05.

Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.

Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in

combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.

0.0

4.0

8.0

12.0

16.0

17:00 20:00 23:00 02:00 05:00 08:00

Time

Ac

tive

GL

P-1

(p

mo

l/L

)

*

64

Vildagliptin Add-on to Metformin: Significantly Lowers

HbA1c over 52 Weeks

6.8

7.2

7.6

8.0

8.4

−4 0 4 8 12 16 20 24 28 32 36 40 44 48 52

Week

Vilda 50 mg daily + met (extension, ITT n=42)

PBO + met (extension, ITT n=29)

Vilda 50 mg daily + met (core, ITT n=56)

PBO + met (core, ITT n=51)

Hb

A1

c (

%)

P <0.0001

P <0.0001

–1.1 0.2%

n refers to ITT population.

HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin

Adapted from Ahrén B, et al. Diabetes Care. 2004; 27: 2874–2880.

Duration: 52 weeks

Vilda add-on to met

65

Vildagliptin: as Effective as Glimepiride when Added to

Metformin at 52 Weeks

Time (Weeks)

Me

an

Hb

A1

c(%

)

CI=confidence interval; glim=glimepiride; HbA1c=hemoglobin A1c; met=metformin; NI=not inferior; vilda=vildagliptin

Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393).

Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print.

NI: 97.5%

CI (0.02, 0.16)

Add-on Treatment to Metformin (~1.9 g Mean Daily)

−0.4%

−0.5%

Vildagliptin 50 mg twice daily + metformin

Glimepiride up to 6 mg once daily + metformin

Duration: 52 weeks

Add-on to met:

vilda vs glim

66

Vildagliptin: No Weight Gain

Time (Weeks)

−1.8 kg

difference

Vildagliptin 50 mg twice daily + metformin

Glimepiride up to 6 mg once daily + metformin

Duration: 52 weeks

Add-on to met:

vilda vs glim

Add-on Treatment to Metformin (~1.9 g Mean Daily)

Bo

dy W

eig

ht

(kg

)

Glim=glimepiride; met=metformin; vilda=vildagliptin

Per protocol population. Vildagliptin (n=1396); glimepiride (n=1393).

Ferrannini E, et al. Diabetes Obes Metab. 2008; Epub ahead of print.

Data on file, Novartis Pharmaceuticals, LAF237A2308.

Vildagliptin Improves Postprandial Lipid and Lipoprotein

Metabolism

Vilda=vildagliptin

Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057.

Before vilda, Week 0 (n=13)

Vilda 50 mg twice daily,

Week 4 (n=15)

0.8

0.6

0.4

0.2

0.0−1 0 1 2 3 4 5 6 7 8

0.08

0.06

0.04

0.02

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

0.50

0.40

0.30

0.20

0.10

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

4.0

3.5

3.0

2.5

2.0

1.5

1.0−1 0 1 2 3 4 5 6 7 8

Plasma TG Chylomicron TG

Chylomicron apo B-48 Chylomicron cholesterol

mm

ol/

L

mm

ol/

Lm

mo

l/L

mg

/L

67

68

Vildagliptin: Mean Change in Blood Pressure in T2DM

Patients with SBP >140 mmHg and DBP >90 mmHg

-7.5

-9.1

-4.2

-5.3

-10.0

-5.0

0.0

DBP SBP

BL=baseline; DBP=diastolic blood pressure; SBP=systolic blood pressure; T2DM=type 2 diabetes mellitus

*P <0.05 vs metformin.

Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.

Ch

an

ge

fro

m B

L (

mm

Hg

)

n = 89 53 150 84

BL= 94 94 149 150

*

*Metformin 1000 mg twice daily

Vildagliptin 50 mg twice daily

Duration: 52 weeks

Vildagliptin vs metformin

69

Overall Incidence of Serious Cardiovascular Events by

Treatment

0.01 0.1 1 10 100

Vildagliptin better Vildagliptin worse

Vilda 50 mg qd* 08/1469 (0.54) 0.79

Vilda 50 mg bid* 25/4594 (0.54) 0.79

Placebo 09/1304 (0.69)

Vilda 50 mg qd** 08/1469 (0.54) 0.70

Vilda 50 mg bid** 25/4594 (0.54) 0.70

All comparators 34/4357 (0.78)

n/N (%)Serious CV

events

Odds Ratio

Vildagliptin 50 mg once daily

Vildagliptin 50 mg twice daily

*Comparison vs placebo; **Comparison vs all comparators.

bid=twice daily; comparators=all non-vildagliptin treatment groups; CV=cardiovascular; qd=once daily; vilda=vildagliptin

Kothny W, et al. Poster 915. Presented at: 44th Annual Meeting of the European Association for the Study of Diabetes;

September 7-11, 2008; Rome, Italy.

Safety population up to 24 weeks

Placebo

Vildagliptin

Sitagliptin

Metformin

Rosiglitazone

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

* * *

*

*

*

* *

50 mg

100 mg

Up to200 mg

Up to100 mg

25mg

100mg

HbA

1c(%

)Glycaemic effects of DPP-4 inhibitors: HbA1c


* Significant differences vs. placebo or respective comparator; if no comparator shown, results placebo-subtracted

Duration (weeks)

Change in b

ody w

eig

ht

(kg)

3

2

1

-2

-3

-5

0

-1

-4

*

2412 52 12 52 18

*

24

Weight effects of DPP-4 inhibitors

Placebo

Vildagliptin

Sitagliptin

Metformin

Rosiglitazone

Insulin glargine



Nausea (

%)

100

80

60

0

40

20

Side effects of DPP-4 inhibitors: nausea

Placebo

Vildagliptin

Sitagliptin

Metformin

Insulin glargine



Incretin mimetics and DPP-4 inhibitors:

major differences

Properties/effect Incretin mimetics DPP-4 inhibitors

Mechanism of stimulation of insulin

secretion exclusively through GLP-1 effect

Yes Unknown

Restitution of insulin secretion (2 phases) Yes (exenatide) Yes

Hypoglycaemia No No

Maintained counter-regulation by

glucagon in hypoglycaemia

Yes Not tested

Inhibition of gastric emptying Yes Marginal

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

Gallwitz. Eur Endocr Dis. 2006

Road Maps to Achieve Glycemic Control

In Type 2 Diabetes Mellitus

ACE/AACE Diabetes Road Map Task Force

Chairpersons

Paul S. Jellinger, MD, MACE, Co-Chair

Jaime A. Davidson, MD, FACE, Co-Chair

Task Force Members

Lawrence Blonde, MD, FACP, FACE

Daniel Einhorn, MD, FACP, FACE

George Grunberger, MD, FACP, FACE

Yehuda Handelsman, MD, FACP, FACE

Richard Hellman, MD, FACP, FACE

Harold Lebovitz, MD, FACE

Philip Levy, MD, FACE

Victor L. Roberts, MD, MBA, FACP, FACE

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced

or distributed in any form without the express permission of AACE.

Revision March 2008

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)

Initial

A1C%

Achieve ACE

Glycemic Goals†

( FPG, PPG, and A1C ) Intervention

Continuous

Titration of Rx

( 2 - 3 months )

If ≤ 6.5% A1C Goal

Not Achieved

Assess FPG

and PPG

Initial Therapy

Monitor / adjust Rx

to maximal effective

dose to meet ACE

Glycemic Goals

Intensify Lifestyle

Modification

Intensify or combine Rx

including incretin mimetic*1

Target: PPG

and FPG

Monitor / adjust Rx


dose to meet ACE

Glycemic Goals

Combine Therapies 6,7

Intensify Lifestyle

Modification

Intensify or combine Rx, including incretin mimetic

with SU, TZD, and/or metformin

6 - 7

7 - 8

Life

sty

le

Mo

dific

atio

n

Life

sty

le

Mo

dific

atio

n


Not Achieved

Alternatives

• Glinides

• SU (low dose)

• Prandial insulin5,8

Preferred:

• Metformin4

• TZD10,11,12

• AGI

• DPP-4 Inhibitor

Alternatives


• Premixed insulin

preparations8

• Basal insulin

analog9

• Metformin• Glinides• AGI• TZD12

• SU• DPP-4 Inhibitor + met• Colesevelam + met, SU or insulin

Revision March 2008

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,

reproduced or distributed in any form without the express permission of AACE.












Endocr Pract. 2007;13:260-268

†ACE Glycemic Goals

≤ 6.5% A1C

< 110 mg/dL FPG

< 110 mg/dL Preprandial

< 140 mg/dL 2-hr PPG

Access Roadmap at:

www.aace.com/pub

* Available as exenatide1 Indicated for patients not at goal despite SU and/or metformin

or TZD therapy; incretin mimetic is not indicated forinsulin-using patients

4 Preferred first agent in most patients5 Rapid-acting insulin analog (available as lispro, aspart and

glulisine), inhaled insulin, or regular insulin6 Appropriate for most patients7 2 or more agents may be required8 Analog preparations preferred9 Available as glargine and detemir

10 A recent meta-analysis suggests a possible link ofrosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated “In their entirety, the availabledata on the risk of myocardial infarction are inconclusive.”

11 Cannot be used in NYHA CHF Class 3 or 4 12 According to the FDA, rosiglitazone not recommended with insulin

http://www.aace.com/pub/

8 - 9

Initial

A1C%

Achieve ACE

Glycemic Goals†

( FPG, PPG, and A1C ) Intervention

Continuous

Titration of Rx

( 2 - 3 months )


Not Achieved

Target: FPG

and PPG

Monitor / adjust Rx


dose to meet ACE

Glycemic Goals

Intensify Lifestyle Modification

Intensify or combine Rx including

prandial insulin5,8, incretin

mimetic1, or amylin analog**

(with prandial insulin5,8)

Target: FPG

and PPG

Monitor / adjust Rx


dose to meet ACE

Glycemic Goals

Combine Therapies

to Address FPG and PPG7

Combine Therapies

to Address FPG and PPG7

9 - 10


• Premixed insulin preparations8

• NPH• Other approved

combinations

• Metformin• TZD10,11,12

• SU• Glinides• DPP-4 Inhibitor• Basal insulin analog9


• Premixed insulin preparations8

• NPH• Other approved

combinations

• Metformin

• TZD12

• SU

• Glinides

• Basal insulin analog9


Not Achieved

Life

sty

le

Mo

dific

atio

n

Life

sty

le

Mo

dific

atio

n

Intensify Lifestyle Modification

Initiate or intensify insulin therapy or add incretin mimetic1

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)












†ACE Glycemic Goals

≤ 6.5% A1C

< 110 mg/dL FPG

< 110 mg/dL Preprandial

< 140 mg/dL 2-hr PPG

Endocr Pract. 2007;13:260-268

Access Roadmap at:

www.aace.com/pub

** Available as pramlintide

1 Indicated for patients not at goal despite SU and/or metformin

or TZD therapy; incretin mimetic is not indicated for

insulin-using patients

5 Rapid-acting insulin analog (available as lispro, aspart and

glulisine), inhaled insulin, or regular insulin

7 2 or more agents may be required

8 Analog preparations preferred

9 Available as glargine and detemir

10 A recent meta-analysis suggests a possible link of rosiglitazone to

cardiovascular events; other studies do not confirm or exclude this risk.

The FDA has stated “In their entirety, the available data on the risk of

myocardial infarction are inconclusive.”

11 Cannot be used in NYHA CHF Class 3 or 4

12 According to the FDA, rosiglitazone not recommended with insulin Revision March 2008

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,

reproduced or distributed in any form without the express permission of AACE.

http://www.aace.com/pub/

How to treat hyperglycemia, Finland

Diabetes: Käypä hoito -suositus, Duodecim 2007

+ metformin

NICE clinical guideline 87, May 2009

82

Pharmacologic Targets of Current Drugs Used in

the Treatment of T2DM

-glucosidase inhibitors

Delay intestinal carbohydrate

absorption

Thiazolidinediones

Decrease lipolysis in

adipose tissue, increase

glucose uptake in skeletal

muscle and decrease

glucose production in liverSulfonylureas

Increase insulin secretion

from pancreatic -cells

GLP-1 analogues

Improve pancreatic islet glucose sensing,

slow gastric emptying, improve satiety

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.

Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.

Glinides

Increase insulin secretion

from pancreatic -cells

DPP-4 inhibitors

Prolong GLP-1 action leading to improved

pancreatic islet glucose sensing, increase

glucose uptake

010_lalic

Documents

incretin mimetics incretin

incretin effect

use of oral agents

therapeutic agents

metformin treatment

metformin metformin

based treatment

metformin therapy