GLP-1 DPP4 İnhibitörleri

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
Mide
Gastrik boşalma
Kalp
Potansiyel nöroproteksiyon
Beyin
İştah
GLP-1
Potansiyel
Kardiyoproteksiyon
Gİ sistem
Glukoz üretimi
İnsülin biyosentezi
İnsülin duyarlılığı
-hücre proliferasyonu
(indirekt)
-hücre apoptozisi
İnsülin salınımı
Karaciğer
Glukagon salınımı
Periferik dokularda GLP-1 etkileri
GLP-1, direkt olarak endokrin pankreas, kalp, mide ve beyinde; indirekt olarak karaciğer ve kasta etki
eder
Drucker DJ. Cell Metab. 2006;3:153-65.
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
Hipotalamus
Karaciğer
Mide
Medulla
oblongata
Pankreas
L-hücre
Adapted from: Holst JJ, Deacon CF.Villus
Diabetologia. 2005;48:612-5.
27/05/2013
Insülin sekresyonuna İnkretin Etkisi
Oral Glucose
IV Glucose
2.0
*
C-peptide (nmol/L)
Venous Plasma Glucose (mmol/L)
11
5.5
1.5
*
*
*
*
1.0
Incretin Effect
*
*
0.5
0.0
0
01 0
2
60
120
Time (min)
Mean ± SE; N = 6; *P .05; 01-02 = glucose infusion time.
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
180
01 02
60
120
Time (min)
180
27/05/2013
Incretin Effect
Tip 2 diyabette azalmıştır
Intravenous Glucose
Oral Glucose
Insulin (mU/L)
Control Subjects
Patients With Type 2 Diabetes
80
80
60
60
40
40
20
0
*
0
* * *
* *
*
30
60
90
* *
20
120 150 180
Time (min)
*P ≤.05 compared with respective value after oral load.
Nauck MA, et al. Diabetologia. 1986;29:46-52.
0
0
30
*
60
90
120 150 180
Time (min)
27/05/2013
Şiddetli Konjestif Kalp Yetersizliği olan
Hastalarda GLP-1’in Kardiyak Etkileri
Kontrol
GLP-1
Sol Ventrikül Ejeksiyon
Fraksiyonunda Ortalama Değişim (%)
6-dakikalık Yürüyüşden sonra
Mesafede Ortalama Değişim
p<.001
30
300
25
250
Meters
LVEF (%)
p<.001
20
15
200
150
10
100
5
50
0
0
Başlangıç
5. hafta
Başlangıç
5. hafta
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.
AMİ ve Sol Ventriküler Disfonksiyonu olan
Hastalarda GLP-1’in Kardiyak Etkileri
Control
GLP-1
Sol Ventriküler Ejeksiyon
Fraksiyonunda Ortalama Değişim (%)
Bölgesel Duvar Hareket Skorunda
Ortalama Değişim
p<.01
LVEF (%)
50
40
30
20
10
0
Başlangıç
Post IV GLP-1
A.S.E Bölgesel Duvar
Hareket Skoru
p<.01
3
2
1
0
Başlangıç
Post IV GLP-1
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.
GLP-1 İnsüline Dirençli/T2DM Obez Erkeklerde
Natriürezi Artırır ve Hiperfiltrasyonu Azaltır
Plasebo
GLP-1
*
100
50
0
Kreatinin Klirensi
120
*
80
40
0
mmol/180 dak
150
mmol/180 dak
mL/dak
200
120
*
80
40
0
Sodyum Atılımı
Klorür Atılımı
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©.
27/05/2013
Liraglutid: bir fare miyokard infarktüsü
modelinde yararlı etki
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
Kardiyak debi
*
Kardiyak debi
(ml/dak)
Sağkalım (%)
PBS
Liraglutid
Sham
Sham
Günler
Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009.
PBS, fosfat tamponlu salin
PBS
*p<0.002
Liraglutid
27/05/2013
Farelerde MI’dan 28 gün sonra infarkt
boyutu liraglutid tarafından azaltılmıştır
İnfarkt
İnfarkt
İnfarkt (%)
30
*
20
10
0
Plasebo
*Plasebo p<0.05
*Plaseboya karşı p<0.05
Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009.
Liraglutid
27/05/2013
Liraglutid kardiyovasküler risk
biyobelirteçlerini iyileştirir
Plaseboya karşı değişim %’si
Liraglutid 1.90 mg/gün ile 14 haftalık tedavi
0
PAI-1
BNP
CRP
Trigliseridler1
–10
–20
–30
–%20
–%25
–40
–%22
–%38
p<0.05
p<0.01
AD
Plaseboya karşı p değerleri
Courrèges ve ark. Diab Med 2008: 1Vilsbøll ve ark. Diab Care 2007;30:1608–10.
p=0.01
27/05/2013
T2D tedavisinde kullanıldığında, liraglutid SKB’yi
azaltmaktadır
1
Monoterapi
LEAD 3
Met
kombinasyonu
LEAD 2
SKB değişimi (mmHg)
0
SU
Met + TZD
Met + SU
Met ve/
kombinasyonu kombinasyonu kombinasyonu veya SU
LEAD 1
LEAD 4
LEAD 5
LEAD 6
0.4
0.5
-0.7
-1
-0.9
-1.1
-2
-2.1
-2.3
-3
-4
-5
-2.8
-3.6
-2.0
-2.6
*
-2.5
-2.8
*
-4.0
*
*
-5.6
-6
-6.7
-7
Liraglutid 1.2 mg
Liraglutid 1.8 mg
Glimepirid
***p<0.0001 **p<0.001 *p<0.05 başlangıca karşı.
Colagiuri ve ark. Diabetes 2008;57(Suppl.1):A16.
***
**
Rosiglitazon
Glarjin
Plasebo
Eksenatid
27/05/2013
Vücut ağırlığı değişimi: liraglutid 1.8 mg
Weight change
(kg)
değişimi(kg)
ağırlıkbaseline
göre from
Başlangıca
Mono
(LEAD 3)
+Met
(LEAD 2)
+SU
(LEAD 1)
+Met/TZD
(LEAD 4)
+Met/SU
(LEAD 5)
+Met/SU
(LEAD 6)
+2.1
+1.6
+1.1
+0.6
+1.0
-0.2†
-2.5†
Başlangıç (kg)
93.3
Liraglutid 1.8 mg
-1.8 *†
-2.0*
-2.8*†
88.6
Glimepirid
-2.9
-3.2
81.6
96.3
Rosiglitazon
* Plaseboya karşı anlamlı; † Aktif karşılaştırmaya karşı anlamlı
85.4
Glarjin
Plasebo
93.1
Eksenatid
27/05/2013
p=0.031
70
60
50
40
30
20
10
0
PBS
Eksenatid
of LV)
size (%(SV
Infarct
%’si)
büyüklüğü
İnfarkt
of AAR)
size (%(AAR
Infarct
%’si)
büyüklüğü
İnfarkt
Domuzlarda 3 gün eksenatid reperfüzyonunun
ardından infarkt büyüklüğü azalmıştır
p=0.047
25
20
15
10
5
0
ARR, risk altındaki alan; LV, sol ventrikül; PBS, fosfat tamponlu salin
Timmers ve ark. J Am Coll Cardiol 2009;53:501–11.
PBS
Eksenatid
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
0
0
-1
-1
-2
-2.4
-3
-4
-5
-6
-5.3
∆Weight (kg)
∆Weight (kg)
Week 30 3.5 y
Week 30
-2
-3
-4
-5.3±0.5 kg
-5
-6
0.0
0.5
1.0
1.5 2.0 2.5
Time (year)
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.
3.0
3.5
Percent Lipid and BP Changes With 3.5 y of
Exenatide
30
+24%
10
0
-10
-4%
-6%
3.5-y completer cohort N = 151; Mean ± SE
Kendall D, et al. Diabetes. 2007:56(Suppl1):A149; data on file, Amylin Pharmaceuticals, Inc.
Diastolic BP
Systolic BP
LDL-C
HDL-C
-12%
TG
-20
-2%
-5%
TC
% Change
20
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.
Sitagliptin ve EPC
n=16 Tip 2 DM olgu
2 KAT
EPCs
p< 0.001
100 mg Sitagliptin
Kontrol Grubu
4 hafta sonrası
%23 DPP-4
İnhibisyonu
%50
SDF-1 alfa
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
Deneysel Fare Modeli: 30 dakika myokardiyal iskemi, 4 saat reperfüzyon
14.Gün
3.Gün
%46.2 %46.4
p< 0.001
%24.3
Doç.Dr.Şevki Çatinkalp’in izniyle
p< 0.001
%23.0
%16.9
Kontrol
Grubu
p< 0.014
Sitagliptin
%19.1
Pioglitazon
%14.7
%12.9
SİTA+ PİO
Yumei Ye et al. Am J Physiol Heart Circ 298: March 2010
Sitagliptin ve Hipertansiyon
Tip 2 DM, n= 17, yaş 67, A1c 6.5, BMI 25
6 aydır antihipertansif tedavi alıyor.
Sitagliptin
50 mg/gün aşırı
+
Önceki Tedavileri
6 ay sonra
Kan Basıncı mmHg
150
6 ay sonra
A1c %6.5
%5.8 *p<0.001
130
130.4±13.9
*
* *
119
100
0
*
*
119.7±9.4
*p<0.01
1
2
3
4
5
6
Aylar
Kan basıncı ile korele değil r =0.24, p=0.08
Doç.Dr.Şevki Çatinkalp’in izniyle
Susumu Ogawa et al. Tohoku J Exp Med 223: 133-135, 2011
Doç.Dr.Şevki Çatinkalp’in izniyle
Sitagliptin’in Renal Etkileri
N= 36 Tip 2 DM, son 6 aydır tedaviye rağmen A1c >6.5, sitagliptin 50 mg/gün
Doç.Dr.Şevki Çatinkalp’in izniyle
Sachiko Hattori. Endocrine Journal Dec 20, 2010
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
27
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
28
Time to Onset of First Primary MACE
Percent with First Adverse Event
5
4
3
2
1
Control
0
BL
24
37
50
63
76
Weeks
89
102
115
All SAXA
128
Patients at Risk
Control
All SAXA
1251
3356
935
2615
860
2419
774
2209
545
1638
288
994
144
498
123
436
102
373
57
197
Frederich R, Alexander J, Fiedorek F, et al. Postgraduate Medicine. 2010;122(3):16-27.
29
Incidence Rate for Primary MACE by Subgroups
65
60
55
SAXA
50
46,3
Control
Error bars represent SEM
45
Events per 1000 patient-years
40
35
30
25
22,5
22,5
18,4
20
15,8
13,2
15
10
9,2
9,1
7,0
8,8
8,0
11,4
7,7
9,9
5
0
History of
CV Disease
n = 569
At Least One
At Least Two
History of
CV Risk Factor CV Risk Factors History of
Hyper(in addition to (in addition to Hypertension
cholesterolemia
T2DM)
T2DM)
n = 3759
n = 2286
n = 2438
n = 2041
Male
Gender
Age ≥65
n = 2279
n = 699
Frederich R, Alexander J, Fiedorek F, et al. Postgraduate Medicine. 2010;122(3):16-27.
30
Frequency of Major CV Endpoints
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)
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)
Sponsor-defined
* Includes contribution from 20–100 mg saxagliptin in Phase 2b Study (-008)
31
Frequency of Additional CV Endpoints
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)
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)
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)
7 (0.2)
10 (0.8)
FDA-defined
Sponsor-defined
CV Death
1 (0.1) in Phase
2 2b
(0.2)
* Includes
contribution from 20–100 mg saxagliptin
Study (-008) 4
(0.4)
32
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
To: [email protected]
Subject: Tahlil
33
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
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
Kaplan-Meier curve of acute pancreatitis in combined diabetic groups (exenatide,
sitagliptin, diabetes control) and the nondiabeticcontrol group.
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 exendin4–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
Pancreatitis
(n=13)
Acute
Chronic
(n=9)
Liraglutide
(n=8)
Liraglutide 1.8 mg
(n=6)
(n=4)
Comparator
(n=1)
Liraglutide 1.2 mg
(n=2)
Glimepiride 4 mg
(n=1)
Based on all completed clinical trials (phase I–III) in subjects with type 2 diabetes until 10 July 2012
Doses stated are once daily
Jensen et al. Pancreas 2012:41:1370–1 (Presented at APA/IAP 2012)
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
8
1
1.6
0.7
4
0
0.8
NA
Events of acute pancreatitis
Incidence rate of acute pancreatitis*
Events of chronic pancreatitis
Incidence rate of chronic pancreatitis*
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
Reported
incidence of
acute
pancreatitis
(number of
cases/1000
PYE)1
•
Active
comparator
1.6
0.7
2.1
(0.3, 95.3)
p value
0.6948
Reporting rates: low and within predicted range for a T2D population
•
•
Liraglutide
Estimated
reporting
rate ratio
(95% CI)
0.5−5.6 cases/1000 PYE2–5
No significant difference in the incidence of reported acute pancreatitis
cases with liraglutide vs. comparators
CI, confidence interval
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
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.
27/05/2013
27/05/2013
27/05/2013
C. DPPIV inhibits formation of closed rings arising from HUVEC sprouting (proangiogenic 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).
27/05/2013
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-NAS+Vector and SK-N-AS+ DPPIV mice.
27/05/2013
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
27/05/2013
C. Immunohistochemical analysis showing CD31 staining as a measure of
vascularity in tumors developed from SK-N-AS +Vector or SK-NAS+DPPIV cells. Magnification 200X.
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
27/05/2013
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.
27/05/2013
Morphological stages in the transition from normal
healthy ducts through intermediate premalignant
pancreatic intraepithelial neoplasia (PanIN) lesions and
invasive pancreatic cancer.
27/05/2013
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.