GLP-1 DPP4 İnhibitörleri
Transkript
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 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 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.