27/05/2013

İncretin Bazlı Tedavilerin Pankreas ve Pankreas Dışı Etkileri

Dr.Hasan İlkova

Cerrahpaşa Tıp Fakültesi

Endokrinoloji Metabolizma ve Diyabet Bilim Dalı

27/05/2013

İnkretin etkisinin fizyolojik bölgeleri

Drucker DJ. Cell Metab. 2006;3:153-65.

Periferik dokularda GLP-1 etkileri

GLP-1, direkt olarak endokrin pankreas, kalp, mide ve beyinde; indirekt olarak karaciğer ve kasta etki

eder

Beyin Kalp

Glukoz üretimi

Potansiyel nöroproteksiyon

İştah

İnsülin duyarlılığı

(indirekt)

Karaciğer

Mide

Gastrik boşalma

Gİ sistem

İnsülin biyosentezi

-hücre proliferasyonu

-hücre apoptozisi

İnsülin salınımı

Glukagon salınımı

Potansiyel

Kardiyoproteksiyon

GLP-1

27/05/2013

GLP-1 ile stimüle insülin salınımında santral nöral yol majör bir rol oynamaktadır

• GLP-1, vagal afferent duyusal nöronlarla etkileşebilir

• Gİ sistemde, hepatoportal bölge ve/veya karaciğer dokusu

• Beyin sapı ve/veya hipotalamusta refleksler oluşturma

• Bu, pankreas ve Gİ sisteme stimüle eden veya inhibitör uyarılar yollayarak vagal motor nöronlarını aktive eder

Adapted from: Holst JJ, Deacon CF. Diabetologia. 2005;48:612-5.

Hipotalamus

Medulla

oblongata

Pankreas

Villus L-hücre

Karaciğer

Mide

27/05/2013

* *

*

*

* *

*

Insülin sekresyonuna İnkretin Etkisi

Mean ± SE; N = 6; *P .05; 01-02 = glucose infusion time. Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

Veno

us P

lasm

a G

luco

se (mmol/L

)

Time (min)

C-pe

ptide (nm

ol/L

)

11

5.5

0

01 60 120 180 01 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min) 02

02

Incretin Effect

Oral Glucose IV Glucose

27/05/2013

Incretin Effect Tip 2 diyabette azalmıştır

0

20

40

60

80

Ins

ulin (mU/L

)

0 30 60 90 120 150 180

Time (min)

* * *

* * * *

0

20

40

60

80

0 30 60 90 120 150 180

Time (min)

* *

*

*P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52.

Patients With Type 2 Diabetes Control Subjects

Intravenous Glucose

Oral Glucose

27/05/2013

Şiddetli Konjestif Kalp Yetersizliği olan

Hastalarda GLP-1’in Kardiyak Etkileri

Ortalama ± SEM. Hastalarda New York Kalp Derneği Klas III ya da IV konjestif kalp yetersizliği mevcuttu. Kontrol Grubu, N=9 (diyabeti

olan 5 hasta); GLP-1 Grup, N=12 (diyabeti olan 8 hasta). LVEF = Sol ventrikül ejeksiyon fraksiyonu.

Sokos GG, et al. J Card Fail. 2006;12:694-699.

Mete

rs

LV

EF

(%

)

6-dakikalık Yürüyüşden sonra

Mesafede Ortalama Değişim

0

50

100

150

200

250

300

Başlangıç 5. hafta

0

5

10

15

20

25

30

Başlangıç 5. hafta

Sol Ventrikül Ejeksiyon

Fraksiyonunda Ortalama Değişim (%)

p<.001 p<.001

GLP-1

Kontrol

AMİ ve Sol Ventriküler Disfonksiyonu olan

Hastalarda GLP-1’in Kardiyak Etkileri

Ortalama ± SEM; Kontrol Grubu, N=10; GLP-1 Grubu, N=11 (Akut miyokard infarktüsü (AMİ) geçirmiş ve başarılı primer anjiyoplastiden

sonra LVEF <%40 olan hastalar). LVEF = sol ventrikül ejeksiyon fraksiyonu. Post IV GLP-1 = 72 saatlik intravenöz GLP-1 infüzyonundan

sonra.

Nikolaidis LA, et al. Circulation. 2004;109:962-965.

A.S

.E B

ölg

esel

Du

var

Hare

ke

t S

ko

ru

LV

EF

(%

)

Bölgesel Duvar Hareket Skorunda

Ortalama Değişim

0

1

2

3

Başlangıç Post IV GLP-1

0

10

20

30

40

50

Başlangıç Post IV GLP-1

Sol Ventriküler Ejeksiyon

Fraksiyonunda Ortalama Değişim (%)

p<.01

p<.01

GLP-1

Control

GLP-1 İnsüline Dirençli/T2DM Obez Erkeklerde

Natriürezi Artırır ve Hiperfiltrasyonu Azaltır

Kreatinin Klirensi Sodyum Atılımı Klorür Atılımı

0

50

100

150

200 120

80

40

0 0

120

80

40

* * *

mL

/dak

mm

ol/180 d

ak

mm

ol/180 d

ak

Ortalama ± SEM; N=16 obez erkek (insüline dirençli , n=12, tip 2 diyabet, n=4); *p<.05 plasebo ve GLP-1 infüzyonları arasında.

Gutzwiller J-P, et al. J Clin Endrocrinol Metab. 2004;89:3005-3061. Copyright 2004, The Endocrine Society©.

GLP-1

Plasebo

27/05/2013

Liraglutid: bir fare miyokard infarktüsü modelinde yararlı etki

Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009.

Sağkalım Kardiyak debi

PBS, fosfat tamponlu salin

*p<0.002

*

Bir miyokard infarktüsü fare modelinde, 7 günlük liraglutid uygulaması:

• - Bir kardiyoprotektif gen ekspresyonu profilini uyarmıştır

• - İnfarkt boyutu ve kardiyak rüptürü azaltmıştır

• - Plaseboya karşı sağkalımı iyileştirmiştir (sırasıyla %40’a karşı %80; p=0.0001)

Sağkalım

(%

)

Kard

iyak d

ebi

(ml/

dak)

PBS Liraglutid Sham

Sham PBS Liraglutid

Günler

27/05/2013

Farelerde MI’dan 28 gün sonra infarkt boyutu liraglutid tarafından azaltılmıştır

*Plasebo p<0.05

Liraglutid

İnfa

rkt

(%) *

0

10

20

30

Plasebo

İnfarkt

İnfarkt

*Plaseboya karşı p<0.05 Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009.

27/05/2013

Liraglutid kardiyovasküler risk biyobelirteçlerini iyileştirir

Courrèges ve ark. Diab Med 2008: 1Vilsbøll ve ark. Diab Care 2007;30:1608–10.

p<0.05 p<0.01 AD

Pla

seboya k

arş

ı değiş

im %

’si

–%20

–%38

–%25

–40

–30

–20

–10

0 PAI-1 BNP CRP

p=0.01

–%22

Trigliseridler1

Liraglutid 1.90 mg/gün ile 14 haftalık tedavi

Plaseboya karşı p değerleri

27/05/2013

SU kombinasyonu

LEAD 1

Met kombinasyonu

LEAD 2

Met + TZD kombinasyonu

LEAD 4

Met + SU kombinasyonu

LEAD 5

Mono- terapi LEAD 3

***p<0.0001 **p<0.001 *p<0.05 başlangıca karşı.

Colagiuri ve ark. Diabetes 2008;57(Suppl.1):A16.

T2D tedavisinde kullanıldığında, liraglutid SKB’yi azaltmaktadır

SKB d

eğiş

imi (m

mH

g)

1

-5

-6

-7

-4

-3

-2

-1

0

-0.7

-2.8

0.4

-2.6 -2.8

-6.7

-5.6

-4.0

0.5

-0.9

-2.3 -2.1

-3.6

***

**

*

* *

*

-2.5

-2.0

-1.1

Liraglutid 1.8 mg Liraglutid 1.2 mg Glimepirid Rosiglitazon Glarjin Eksenatid Plasebo

Met ve/ veya SU LEAD 6

27/05/2013

Vücut ağırlığı değişimi: liraglutid 1.8 mg

Mono

(LEAD 3)

+Met

(LEAD 2)

+SU

(LEAD 1)

+Met/TZD

(LEAD 4)

+Met/SU

(LEAD 5)

Liraglutid 1.8 mg Glimepirid Plasebo Rosiglitazon Glarjin

+Met/SU

(LEAD 6)

Eksenatid

Weig

ht

change f

rom

baseline (

kg)

Başlangıç (kg) 93.3 88.6 81.6 96.3 85.4 93.1

* Plaseboya karşı anlamlı; † Aktif karşılaştırmaya karşı anlamlı

-1.8 *†

-2.0*

-2.5†

+1.1

-2.8*†

+1.6

+0.6

-3.2

-2.9

+1.0

-0.2†

+2.1

Başla

ngıc

a g

öre

ağırlık d

eğiş

imi (k

g)

27/05/2013

Domuzlarda 3 gün eksenatid reperfüzyonunun ardından infarkt büyüklüğü azalmıştır

0

10

20

30

40

50

60

70

Infa

rct

siz

e (

% o

f AAR)

PBS Eksenatid

p=0.031

0

5

10

15

20

25

Infa

rct

siz

e (

% o

f LV)

PBS Eksenatid

p=0.047

ARR, risk altındaki alan; LV, sol ventrikül; PBS, fosfat tamponlu salin Timmers ve ark. J Am Coll Cardiol 2009;53:501–11.

İnfa

rkt

büyüklü

ğü (

AAR %

’si)

İnfa

rkt

büyüklü

ğü (

SV %

’si)

Improvements in Cardiovascular Risk Factors

Accompanied Improved Glycemic Control and

Weight Reduction in Patients With Type 2

Diabetes Treated With Exenatide for 3.5 y

David M Kendall1; Lawrence Blonde2; Susanna M Mac1;

Xuesong Guan1; John H Holcombe3; Ted E Okerson1;

Dennis D Kim1; Deepak L Bhole1

1 Amylin Pharmaceuticals, Inc., San Diego, CA; 2 Ochsner Clinic Foundation, New

Orleans, LA; 3 Eli Lilly and Company, Indianapolis, IN

Weight Reductions With 3.5 y of Exenatide

3.5-y completer cohort N = 151; Baseline weight 99.9 kg; Mean ± SE

Kendall D, et al. Diabetes. 2007:56(Suppl1):A149; data on file, Amylin Pharmaceuticals, Inc.

Week 30

Week 30 3.5 y

-6

-5

-4

-3

-2

-1

0

-2.4

-5.3

∆W

eig

ht

(kg

)

Time (year)

-5.3±0.5 kg

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 -6

-5

-4

-3

-2

-1

0

∆W

eig

ht

(kg

)

Percent Lipid and BP Changes With 3.5 y of

Exenatide

3.5-y completer cohort N = 151; Mean ± SE

Kendall D, et al. Diabetes. 2007:56(Suppl1):A149; data on file, Amylin Pharmaceuticals, Inc.

-20

-10

0

10

20

30

TG

TC

HD

L-C

LD

L-C

Systo

lic B

P

Dia

sto

lic B

P

-12%

-5%

+24%

-6%

-2% -4%

% C

han

ge

27/05/2013

Özet ve sonuçlar

•Hayvan modelleri

• MI modellerinde ↑ sağkalım, ↓kardiyak rüptür, ↓iskemi ve ↑kardiyak fonksiyon

• Endotelden bağımsız arter gevşemesini kolaylaştırır

•Klinik çalışmalar

• ↑ sol ventrikül fonksiyonu

• ↑ endotel fonksiyonu (arter çapı)

• ↓ endotel disfonksiyonunun biyobelirteçleri

• ↓ sistolik kan basıncı

• ↓ vücut ağırlığı

27/05/2013

DPP IV inhibitörleri

• Vildagliptin

• Sitagliptin

• Saxagliptin

DPP4 Inhibitörü Sitagliptin tip 2 diyabet

hastalarında Vasküler endotelial progenitör

hücreleri arttırmaktadır.

Doç.Dr.Şevki Çatinkalp’in izniyle

4 hafta sonrası

Sitagliptin ve EPC

n=16 Tip 2 DM olgu

100 mg Sitagliptin

Kontrol Grubu

%23 DPP-4 İnhibisyonu

%50 SDF-1 alfa

2 KAT EPCs

p< 0.001

Gian Paolo Fadini et al .Diabetes Care 33(5), 31 March, 2010

Doç.Dr.Şevki Çatinkalp’in izniyle

Deneysel Fare Modeli: 30 dakika myokardiyal iskemi, 4 saat reperfüzyon

Yumei Ye et al. Am J Physiol Heart Circ 298: March 2010

Kontrol Grubu

%46.2

%24.3

%14.7

%23.0

3.Gün 14.Gün

%46.4

%16.9 %19.1

%12.9

p< 0.001 p< 0.014 p< 0.001

Sitagliptin Pioglitazon SİTA+ PİO

Deneysel Fare Modeli: 30 dakika myokardiyal iskemi, 4 saat reperfüzyon

Doç.Dr.Şevki Çatinkalp’in izniyle

Sitagliptin ve Hipertansiyon

Susumu Ogawa et al. Tohoku J Exp Med 223: 133-135, 2011

Tip 2 DM, n= 17, yaş 67, A1c 6.5, BMI 25 6 aydır antihipertansif tedavi alıyor.

Sitagliptin 50 mg/gün aşırı + Önceki Tedavileri

1

6 ay sonra

2 0 4 3 5 6

100

150

130

119

Aylar

Kan B

asın

cı

mm

Hg

130.4±13.9

119.7±9.4 *

* * * *

*p<0.01

A1c %6.5 %5.8

6 ay sonra

*p<0.001

Kan basıncı ile korele değil r =0.24, p=0.08

Doç.Dr.Şevki Çatinkalp’in izniyle

Doç.Dr.Şevki Çatinkalp’in izniyle

Sitagliptin’in Renal Etkileri

Sachiko Hattori. Endocrine Journal Dec 20, 2010

N= 36 Tip 2 DM, son 6 aydır tedaviye rağmen A1c >6.5, sitagliptin 50 mg/gün

27

Saxagliptin Cardiovascular Safety

A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development

Program for Type 2 Diabetes Mellitus

Overview of FDA Advisory Committee Meeting (CV Assessment Portion) and review article

appearing in Postgraduate Medicine 2010

28

Summary of Phase 2b/3 Clinical Program

• 8 Phase 2b / 3 Clinical Studies

4673 subjects, 3422 saxagliptin treated

Phase 2b, monotherapy dose-ranging study

Six pivotal phase 3 studies

• Two monotherapy

• Three add-on combination

MET

TZD

SU

• One initial combination with metformin

Phase 3 mechanism of action study

29

Time to Onset of First Primary MACE

24 37 50 63 76 89 102 115 128BL

0

1

2

3

4

5

Weeks

Pe

rce

nt

wit

h F

irs

t A

dv

ers

e E

ve

nt

Patients at Risk

Control 1251 935 860 774 545 288 144 123 102 57

All SAXA 3356 2615 2419 2209 1638 994 498 436 373 197

All SAXA

Control

Frederich R, Alexander J, Fiedorek F, et al. Postgraduate Medicine. 2010;122(3):16-27.

30

History of CV Disease

At Least One CV Risk Factor (in addition to

T2DM)

At Least Two CV Risk Factors (in addition to

T2DM)

History of Hypertension

History of Hyper-

cholesterolemia

Male Gender

Age ≥65

n = 569 n = 3759 n = 2286 n = 2438 n = 2041 n = 2279 n = 699

11,4

7,78,08,89,17,0

9,2

0

5

10

15

20

25

30

35

40

45

50

55

60

65

Even

ts p

er

1000 p

ati

en

t-years

9,9

22,5

13,2

22,5

18,4

15,8

46,3

0

5

10

15

20

25

30

35

40

45

50

55

60

65

Incidence Rate for Primary MACE by Subgroups

Error bars represent SEM

SAXA Control

Frederich R, Alexander J, Fiedorek F, et al. Postgraduate Medicine. 2010;122(3):16-27.

31

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251

Total Pt-years 1149 1462 1119 3758 1293

Mean Duration of Follow Up (yrs)

1.23 1.15 1.12 1.12 1.03

Number (%)

FDA-defined

SMQ MACE 28 (3.0) 37 (2.9) 30 (3.0) 100 (3.0) 41 (3.3)

Custom MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 17 (1.4)

Sponsor-defined

Primary MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 18 (1.4)

Acute CV Events 14 (1.5) 10 (0.8) 14 (1.4) 38 (1.1) 23 (1.8)

Frequency of Major CV Endpoints

* Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008)

32

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251

Total Pt-years 1149 1462 1119 3758 1293

Mean Duration of Follow Up (yrs)

1.23 1.15 1.12 1.12 1.03

Number (%)

Patients with Any Cardiac Disorder AE

53 (5.7) 63 (5.0) 48 (4.8) 164 (4.9) 71 (5.7)

FDA-defined

Ischemic Heart Disease

14 (1.5) 17 (1.3) 12 (1.2) 43 (1.3) 24 (1.9)

Cardiac Failure 8 (0.9) 7 (0.6) 5 (0.5) 20 (0.6) 7 (0.6)

Cardiac Arrhythmias 32 (3.4) 36 (2.8) 31 (3.1) 99 (2.9) 37 (3.0)

Other 9 (1.0) 8 (0.6) 6 (0.6) 23 (0.7) 7 (0.6)

Sponsor-defined

Secondary MACE 8 (0.9) 7 (0.6) 11 (1.1) 26 (0.8) 20 (1.6)

All Death 3 (0.3) 3 (0.2) 4 (0.4) 10 (0.3) 12 (1.0)

CV Death 1 (0.1) 2 (0.2) 4 (0.4) 7 (0.2) 10 (0.8)

Frequency of Additional CV Endpoints

* Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008)

33

Gönderen Hasan İlkova

Alıcı ilkova@superonline.com

Tarih Çrş 19:02

Posta: 16 / 2381 < > fotograf.JPGAdsız ek

00004.txtKişisel gizliliğinizi korumak

amacıyla postadaki resimler engellendi

Resimleri göster

Hocam bilginiz olsun ………..….. bugün

hasteneye yatmış pankreatit

ataktan....sonuçları bunlar amilazıda 851.

-----Original Message-----

From: Bihter [mailto:bhtrfdn@gmail.com]

Sent: Wednesday, April 17, 2013 6:55 PM

To: hilkova@ttmail.com

Subject: Tahlil

27/05/2013

Acute Pancreatitis in Type 2 Diabetes

Treated With Exenatide or Sitagliptin A retrospective observational pharmacy claims analysis RAJESH GARG, MD 1

WILLIAM CHEN, PHD, MPH 2

MERRI PENDERGRASS, MD, PHD

2,3

OBJECTIVE— Cases of acute pancreatitis have been reported in association with exenatide,

sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether

exenatide or sitagliptin increase the risk of acute pancreatitis.

RESEARCH DESIGN AND METHODS— A retrospective cohort study of a large medical

and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox

proportional hazard models were built to compare the risk of acute pancreatitis between diabetic

and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication

use.

RESULTS— Incidence of acute pancreatitis in the nondiabetic control group, diabetic control

group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient

years, respectively. The risk of acute pancreatitis was significantly higher in the combined

diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI

1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group

(0.9 [0.6 –1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]).

CONCLUSIONS— Our study demonstrated increased incidence of acute pancreatitis in

diabetic versus nondiabetic patients but did not find an association between the use of exenatide

or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis

cannot exclude the possibility of an increased risk.

Diabetes Care 33:2349–2354, 2010

27/05/2013

Kaplan-Meier curve of acute pancreatitis in combined diabetic groups (exenatide,

sitagliptin, diabetes control) and the nondiabeticcontrol group.

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin

A retrospective observational pharmacy claims analysis

RAJESH GARG, WILLIAM CHEN, MERRI PENDERGRASS

Diabetes Care 33:2349–2354, 2010

27/05/2013

Kaplan-Meier curve of acute pancreatitis in exenatide,

sitagliptin, and diabetes control groups.

27/05/2013

Chronic GLP-1 Receptor Activation by Exendin-4 Induces Expansion of Pancreatic

Duct Glands in Rats and Accelerates Formation of Dysplastic Lesions and

Chronic Pancreatitis in the KrasG12D Mouse Model

Belinda Gier,Aleksey V. Matveyenko,David Kirakossian,David Dawson,Sarah M. Dry,

and Peter C. Butler Diabetes 61:1250–1262, 2012

The extent and frequency of PDGs(Pancreatic Duct Glands) surrounding the

main pancreatic duct are increased by exendin-4 treatment in rats.

Sections from the head of the pancreas from an untreated control rat

27/05/2013

after 12 weeks of daily exendin-4 injections

27/05/2013

F–H: In addition, the epithelium often showed pseudostratification

and pseudopapillary features, which are features characteristic for

PanIN-like ( pancreatic intraepitelial neoplasia) lesions.

27/05/2013

27/05/2013

PDG cell replication is increased by exendin-4 treatment in rats.

27/05/2013

Exendin-4 treatment increased chronic pancreatitis and the frequency of mPanIN

lesions in Pdx1-Kras mice. Pancreata from Pdx1-Kras mice treated for 12 weeks with

either vehicle (A) or exendin-4 (B) (203 objective). The pancreas from the exendin-

4–treated animal demonstrates only scant residual intact acini (white arrow) with

more extensive inflammation and fibrosis (stars) and more frequent mPanIN (black

arrows).

27/05/2013

Duct cell replication frequency is increased in the pancreas of exendin-4–

treated Pdx1-Kras mice. Immunohistochemical labeling of Ki-67–positive cells

(brown; counterstained with hematoxylin) in benign ducts in areas of intact acinar

tissue in control mice (A) and exendin-4–treated mice (B).

27/05/2013

GLP-1R expression is present in PDGs in rats and humans.

27/05/2013

GLP-1R expression is present in PDGs in rats and humans.

27/05/2013

Metformin treatment abrogated the effect of exendin-4 in HPDE-Kras cells (P < 0.01)

27/05/2013

There were no cases of pancreatitis, macroscopically or microscopically, in 400 rats.

Neither pancreatitis nor preneoplastic proliferative lesions was found in monkeys

dosed for 87 weeks, with plasma liraglutide exposure 60-fold higher than that

observed in humans at the maximal clinical dose. In conclusion, liraglutide did not

induce pancreatitis in mice, rats, or monkeys when dosed for up to 2 years and

at exposure levels up to 60 times higher than in humans.

Diabetes 61:1243–1249, 2012

27/05/2013

27/05/2013

Pancreatitis cases in completed liraglutide diabetes trials, as per 10 July 2012

Jensen et al. Pancreas 2012:41:1370–1 (Presented at APA/IAP 2012)

Based on all completed clinical trials (phase I–III) in subjects with type 2 diabetes until 10 July 2012 Doses stated are once daily

Pancreatitis (n=13)

Acute (n=9)

Liraglutide (n=8)

Comparator (n=1)

Chronic (n=4)

Liraglutide 1.8 mg (n=6)

Liraglutide 1.2 mg (n=2)

Glimepiride 4 mg (n=1)

Incidence of pancreatitis with liraglutide and active comparator in type 2 diabetes

Liraglutide Active

comparator

Safety analysis set (n) 6628 1877

Total exposure (years) 5051 1356

Events of acute pancreatitis 8 1

Incidence rate of acute pancreatitis* 1.6 0.7

Events of chronic pancreatitis 4 0

Incidence rate of chronic pancreatitis* 0.8 NA

In a diabetes population with a background incidence of 1.5–4.5 events/1000 person-years of exposure, one would expect 7–22 acute

pancreatitis cases in the liraglutide arm and 2–6 in the comparator arm

Based on all completed clinical trials (phase I–III) in subjects with type 2 diabetes until 10 July 2012 *Number of cases/1000 subject-years of exposure Jensen et al. Pancreas 2012:41:1370–1 (Presented at APA/IAP 2012)

Incidence of acute pancreatitis with liraglutide and active comparator

• Reporting rates: low and within predicted range for a T2D population

• 0.5−5.6 cases/1000 PYE2–5

• No significant difference in the incidence of reported acute pancreatitis cases with liraglutide vs. comparators

Liraglutide Active

comparator

Estimated reporting rate ratio (95% CI)

p value

Reported incidence of acute pancreatitis (number of cases/1000 PYE)1

1.6 0.7 2.1

(0.3, 95.3) 0.6948

1. Jensen et al. Pancreas 2012:41:1370–1 (Presented at APA/IAP 2012); 2. Noel et al. Diabetes Care 2009;32:834–8; 3. Girman et al. Diabetes Obes Metab 2010;12:766–71; 4. Garg et al. Diabetes Care 2010;33:2349–54; 5. Gonzalez-Perez et al. Diabetes Care 2010;33:2580–5

CI, confidence interval

Summary of pancreatitis findings

• While more cases of acute pancreatitis were reported with liraglutide vs. comparators, the estimated reporting rate ratio elevation was not statistically significant

• Reporting rates were low and within the predicted range for a population of patients with type 2 diabetes

• Considering patient histories, most reported cases of acute pancreatitis were unlikely to be linked to liraglutide treatment

• Overall, there are too few cases to be able to determine whether or not there is a cause-and-effect relationship between the development of acute pancreatitis and treatment with liraglutide

• Liraglutide has no adverse effects on the pancreas in animal studies

What is to come...

• Preclinical mechanistic safety studies investigating pancreatitis

• Two pharmacoepidemiological trials1

• using i3 Aperio and the Clinical Practice Research Datalink

• LEADER® will study pancreatitis safety in >9000 patients2

• information related to acute or chronic pancreatitis, as well as history of gallbladder disease, will be recorded at screening

• amylase and lipase will be measured at randomisation (visit 3) and again at visits 6, 7, 9, 11, 13 and 15

• additional measurements will be mandated in case of persistent, severe abdominal pain potentially suggestive of pancreatitis

• all suspected events of acute pancreatitis will be evaluated by an independent event adjudication committee

1. Jensen et al. Pancreas 2012:41(8):1370–1 (Presented at APA/IAP 2012); 2. Bergenstal et al. Diabetes 2011;59 (Suppl. 1):2303-PO

27/05/2013

Imbalanced protease expression and activities may contribute to the development of

cancers including neuroblastoma. Neuroblastoma is a fatal childhood cancer of the

sympathetic nervous system that frequently overexpresses mitogenic peptides,

chemokines and their receptors. Dipeptidyl peptidase IV (DPPIV), a cell surface

serine protease, inactivates or degrades some of these bioactive peptides and

chemokines, thereby regulating cell proliferation and survival.

These data support a potential role for DPPIV in

inhibiting neuroblastoma growth and progression.

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C. DPPIV inhibits formation of closed rings arising from HUVEC sprouting (pro-

angiogenic structure) in vitro. HUVECs were co-cultured with control or DPPIV

expressing SK-N-AS cells for 18 h on matrigel basement. (a)Representative

photomicrographs of HUVEC pro-angiogenic structure formation in coculutre

experiments. (b) Tubular length was quantified in five randomly selected fields

(mean ± S.D.; n = 5; *, p < 0.05).

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DPPIV re-expression suppresses the tumorigenic potential of SK-N-AS cells in a

xenotransplantation mouse model. Two different sets of nude mice (BALB/C nu/nu,

n = 5 for each group, SK-N-AS+Vector or SK-N-AS+DPPIV) were injected

subcutaneously with 5X106 cells as a 50% suspension in matrigel. Tumors were

measured every 3 days. A. a.Effects of DPPIV on tumor growth. Results are presented

as average tumor volume +/-SD.b. Photographs of tumors excised from SK-N-

AS+Vector and SK-N-AS+ DPPIV mice.

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B.

a. Representative photomicrographs of TUNEL assay performed on excised tumors showing

increased number of apoptotic cells (green) in tumors developed from SK-N-AS+DPPIV

cells as compared to tumors developed from SK-N-AS+Vector control cells. Magnification

200X. b. Quantification of DPPIV induced apoptosis in tumors. The number of TUNEL

positive cells was counted in a total of 6 high power fields and expressed as mean

percentage of total cells in these fields of the tumor

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C. Immunohistochemical analysis showing CD31 staining as a measure of

vascularity in tumors developed from SK-N-AS +Vector or SK-N-

AS+DPPIV cells. Magnification 200X.

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Belinda Gier, PhD, Peter C. Butler, MD

At present, the GLP-1 class of drugs is heavily promoted (and prescribed) as

having purported advantages that outweigh its risks. Singh and colleagues

provide a timely reminder that, despite large numbers of underpowered

studies claiming the contrary from marketing companies, little is yet

known about long-term adverse effects of the GLP-1 class of drugs on the

exocrine pancreas.

Unfortunate recent history documents unacceptable delays by regulatory

authorities to act on serious adverse effects detected in postmarketing

surveillance of drugs for T2DM, deemed 2 times a farce by Gale.11 We

hope history will not repeat itself with the GLP-1–based drugs, because in

this case, 3 times would not be a charm.

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Morphological stages in the transition from normal

healthy ducts through intermediate premalignant

pancreatic intraepithelial neoplasia (PanIN) lesions and

invasive pancreatic cancer.

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Human expression of glucagonlike peptide 1 (GLP-1) receptor in healthy tissue and

malignant disease. Corresponding immunohistochemical labeling of human tissue for

GLP-1 receptor (brown) in normal pancreatic ducts, premalignant PanIN lesions, and

pancreatic cancer.