İncretin Bazlı Tedavilerin Pankreas ve Pankreas Dışı Etkileri

İncretin Bazlı Tedavilerin Pankreas ve Pankreas Dışı Etkileri Dr.Hasan İlkova Cerrahpaşa Tıp Fakültesi Endokrinoloji Metabolizma ve Diyabet Bilim Dalı

İnkretin etkisinin fizyolojik bölgeleri Mide Gastrik boşalma Kalp Beyin Potansiyel nöroproteksiyon İştah Potansiyel Kardiyoproteksiyon Gİ sistem GLP-1 Glukoz üretimi Karaciğer İnsülin duyarlılığı (indirekt) İnsülin salınımı Glukagon salınımı İnsülin biyosentezi -hücre proliferasyonu -hücre apoptozisi 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.

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 Medulla oblongata Mide L-hücre Villus Adapted from: Holst JJ, Deacon CF. Diabetologia. 2005;48:612-5. Pankreas

Venous Plasma Glucose (mmol/l) C-peptide (nmol/l) 27/05/2013 Insülin sekresyonuna İnkretin Etkisi Oral Glucose IV Glucose 11 2.0 * 1.5 * * * 5.5 1.0 * * Incretin Effect 0.5 * 0 0.0 0 1 0 2 60 120 180 0 1 0 2 60 120 180 Time (min) Time (min) Mean ± SE; N = 6; *P.05; 0 1-0 2 = glucose infusion time. Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

Insulin (mu/l) 27/05/2013 Incretin Effect Tip 2 diyabette azalmıştır Intravenous Glucose Oral Glucose 80 Control Subjects 80 Patients With Type 2 Diabetes 60 60 40 40 20 * * * * * * * 20 * * * 0 0 30 60 90 120 150 180 Time (min) 0 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.

LVEF (%) Meters 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 p<.001 30 25 20 15 10 300 250 200 150 100 5 50 0 Başlangıç 5. hafta 0 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.

LVEF (%) A.S.E Bölgesel Duvar Hareket Skoru 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 50 40 p<.01 3 2 p<.01 30 20 1 10 0 Başlangıç Post IV GLP-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.

ml/dak mmol/180 dak mmol/180 dak GLP-1 İnsüline Dirençli/T2DM Obez Erkeklerde Natriürezi Artırır ve Hiperfiltrasyonu Azaltır Plasebo GLP-1 200 150 * 120 * 120 * 100 80 80 50 40 40 0 0 0 Kreatinin Klirensi 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.

Sağkalım (%) Kardiyak debi (ml/dak) 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 PBS Liraglutid Sham * Günler Sham PBS Liraglutid *p<0.002 Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009. PBS, fosfat tamponlu salin

İnfarkt (%) 27/05/2013 Farelerde MI dan 28 gün sonra infarkt boyutu liraglutid tarafından azaltılmıştır İnfarkt İnfarkt 30 * 20 10 0 Plasebo *Plasebo p<0.05 Liraglutid *Plaseboya karşı p<0.05 Noyan-Ashraf ve ark. Diabetes Epub ahead of print: 16 Jan 2009.

Plaseboya karşı değişim % si Liraglutid kardiyovasküler risk biyobelirteçlerini iyileştirir 27/05/2013 Liraglutid 1.90 mg/gün ile 14 haftalık tedavi 0 PAI-1 BNP CRP Trigliseridler 1 10 20 30 %25 %20 %22 40 %38 p<0.05 p<0.01 AD p=0.01 Plaseboya karşı p değerleri Courrèges ve ark. Diab Med 2008: 1 Vilsbøll ve ark. Diab Care 2007;30:1608 10.

SKB değişimi (mmhg) 27/05/2013 T2D tedavisinde kullanıldığında, liraglutid SKB yi azaltmaktadır 1 Monoterapi LEAD 3 Met kombinasyonu LEAD 2 SU kombinasyonu LEAD 1 Met + TZD kombinasyonu LEAD 4 Met + SU kombinasyonu LEAD 5 Met ve/ veya SU LEAD 6 0 0.4 0.5-1 -2-3 -4-5 -2.1-3.6 * -0.7-2.8 * -2.3 * -2.6-2.8-0.9-1.1-4.0 * -2.5-2.0-6 -7 Liraglutid 1.2 mg Liraglutid 1.8 mg Glimepirid Rosiglitazon Glarjin Plasebo Eksenatid ***p<0.0001 **p<0.001 *p<0.05 başlangıca karşı. -6.7 *** -5.6 ** Colagiuri ve ark. Diabetes 2008;57(Suppl.1):A16.

Başlangıca Weight change göre from ağırlık baseline değişimi (kg) (kg) 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) +Met/SU (LEAD 6) +2.1 +1.1 +1.0 +0.6 +1.6-0.2-2.5-2.8* -2.0* -1.8 * -3.2-2.9 Başlangıç (kg) 93.3 88.6 81.6 96.3 85.4 93.1 Liraglutid 1.8 mg Glimepirid Rosiglitazon Glarjin Plasebo Eksenatid * Plaseboya karşı anlamlı; Aktif karşılaştırmaya karşı anlamlı

İnfarkt Infarct büyüklüğü size (% (AAR of AAR) % si) İnfarkt Infarct büyüklüğü size (% (SV of LV) % si) 27/05/2013 Domuzlarda 3 gün eksenatid reperfüzyonunun ardından infarkt büyüklüğü azalmıştır 70 p=0.031 25 p=0.047 60 50 40 20 15 30 10 20 10 5 0 PBS Eksenatid 0 PBS Eksenatid ARR, risk altındaki alan; LV, sol ventrikül; PBS, fosfat tamponlu salin Timmers ve ark. J Am Coll Cardiol 2009;53:501 11.

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 Kendall 1 ; Lawrence Blonde 2 ; Susanna M Mac 1 ; Xuesong Guan 1 ; John H Holcombe 3 ; Ted E Okerson 1 ; Dennis D Kim 1 ; Deepak L Bhole 1 1 Amylin Pharmaceuticals, Inc., San Diego, CA; 2 Ochsner Clinic Foundation, New Orleans, LA; 3 Eli Lilly and Company, Indianapolis, IN

Weight (kg) Weight (kg) Weight Reductions With 3.5 y of Exenatide 0 Week 30 3.5 y 0-1 -1 Week 30-2 -3-4 -5-6 -2.4-5.3-2 -3-4 -5-6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time (year) -5.3±0.5 kg 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.

TG TC HDL-C LDL-C Systolic BP Diastolic BP % Change Percent Lipid and BP Changes With 3.5 y of Exenatide 30 +24% 20 10 0-10 -5% -6% -2% -4% -20-12% 3.5-y completer cohort N = 151; Mean ± SE Kendall D, et al. Diabetes. 2007:56(Suppl1):A149; data on file, Amylin Pharmaceuticals, Inc.

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

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 100 mg Sitagliptin 2 KAT EPCs p< 0.001 Kontrol Grubu 4 hafta sonrası %23 DPP-4 İnhibisyonu %50 SDF-1 alfa Doç.Dr.Şevki Çatinkalp in izniyle Gian Paolo Fadini et al.diabetes Care 33(5), 31 March, 2010

Deneysel Fare Modeli: 30 dakika myokardiyal iskemi, 4 saat reperfüzyon Deneysel Fare Modeli: 30 dakika myokardiyal iskemi, 4 saat reperfüzyon 3.Gün 14.Gün %46.2 %46.4 p< 0.001 p< 0.014 p< 0.001 %24.3 %16.9 %23.0 %19.1 %14.7 %12.9 Kontrol Grubu Sitagliptin Pioglitazon SİTA+ PİO Doç.Dr.Şevki Çatinkalp in izniyle Yumei Ye et al. Am J Physiol Heart Circ 298: March 2010

Kan Basıncı mmhg 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 A1c %6.5 %5.8 6 ay sonra *p<0.001 150 130 119 130.4±13.9 * * * * * 100 0 1 2 3 4 5 6 Aylar 119.7±9.4 *p<0.01 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

Percent with First Adverse Event Time to Onset of First Primary MACE 5 4 3 2 1 0 BL 24 37 50 63 76 89 102 115 128 Weeks Control All SAXA 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 Frederich R, Alexander J, Fiedorek F, et al. Postgraduate Medicine. 2010;122(3):16-27. 29

Events per 1000 patient-years Incidence Rate for Primary MACE by Subgroups 65 60 55 50 45 40 46,3 SAXA Control Error bars represent SEM 35 30 25 20 15 10 5 9,2 7,0 15,8 9,1 18,4 8,8 22,5 8,0 13,2 7,7 22,5 11,4 9,9 0 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 Hypercholesterolemia Male Gender Age 65 n = 569 n = 3759 n = 2286 n = 2438 n = 2041 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) 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) * 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) Patients with Any Cardiac Disorder AE FDA-defined Ischemic Heart Disease 1.23 1.15 1.12 1.12 1.03 Number (%) 53 (5.7) 63 (5.0) 48 (4.8) 164 (4.9) 71 (5.7) 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) * Includes contribution from 20 100 mg saxagliptin in Phase 2b Study (-008) 32

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 33

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

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.

Kaplan-Meier curve of acute pancreatitis in exenatide, sitagliptin, and diabetes control groups.

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

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.

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).

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).

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

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

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

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

Pancreatitis cases in completed liraglutide diabetes trials, as per 10 July 2012 Pancreatitis (n=13) Acute (n=9) Chronic (n=4) Liraglutide (n=8) Comparator (n=1) Liraglutide 1.8 mg (n=6) 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 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 Liraglutide 0.5 5.6 cases/1000 PYE 2 5 Active comparator Estimated reporting rate ratio (95% CI) p value Reported incidence of acute 2.1 pancreatitis 1.6 0.7 0.6948 (0.3, 95.3) (number of cases/1000 PYE) 1 Reporting rates: low and within predicted range for a T2D population 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 trials 1 using i3 Aperio and the Clinical Practice Research Datalink LEADER will study pancreatitis safety in >9000 patients 2 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

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.

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).

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.

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

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.

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.

Morphological stages in the transition from normal healthy ducts through intermediate premalignant pancreatic intraepithelial neoplasia (PanIN) lesions and invasive pancreatic cancer.

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.