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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 [email protected]
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:[email protected]]
Sent: Wednesday, April 17, 2013 6:55 PM
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
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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.