Case 3: Pancreatitis Risk with Incretin Therapies: Is It Real? Case: Pancreatitis Risk with Incretin Therapy 43-year-old obese woman Long-standing type 2 diabetes Currently treated with metformin 1000 mg BID and glyburide 10 mg BID History of dyslipidemia treated with atorvastatin 40 mg/day and fenofibrate 120 mg/day History of silent solitary gall stone discovered incidentally by ultrasound for fatty liver Rarely drinks alcohol A1C 7.8% Case: Pancreatitis Risk with Incretin Therapy No history of pancreatitis Heard from a friend, who also has diabetes, that exenatide is a drug that may help her in controlling her diabetes and may also help her to lose weight She is asking for your opinion about adding exenatide to her current medications but she is concerned about the pancreatitis risk 1
Conclusions: This study confirms prior findings that the incidence of acute pancreatitis is approximately two times higher in patients with type 2 diabetes. However, the authors did not find an increased risk for acute pancreatitis with exenatide or sitagliptin. The study has several limitations. Garg R, Chen W, Pendergrass M. Diabetes Care. 2010;33(11):2349-2354. Acute Pancreatitis The estimated risk for acute pancreatitis in the general population is 0.33 0.44 events per 1000 adults per year 20% of cases are considered to be severe (hemorrhagic or necrotizing), with 2 4% resulting in death 1 2% of the cases are drug induced Forsmark CE, Baillie J. Gastroenterology. 2007;132(5):2022-2044. Whitcomb DC. N Engl J Med. 2006;354(20):2142 2150. Etiology of Pancreatitis 60 80% of pancreatitis cases are attributed to Alcohol Gallstones Severe hypertriglyceridemia 2.8-fold increased risk of acute pancreatitis in patients with diabetes (3-fold in men and 2.6-fold in women) 5-fold increased risk in the 18- to 44-year-old population with diabetes 1.9-fold risk of biliary disease was reported in patients with diabetes (cholelithiasis is the basis in 50% of the cases) Noel RA, Patterson RE, Braun DK, Bloomgren GL. Diabetes Care. 2009;32(5):834-838. 2
Drug-Induced Pancreatitis Of the top 100 prescribed drugs in the United States, 44 have been associated with acute pancreatitis These include acetaminophen, erythromycin, trimethoprim/sulfamethoxazole, agents used to treat human immunodeficiency virus, and oncologic agents No clear pathophysiologic basis connects the various agents Among diabetes medications, glyburide may be associated with an increased risk for pancreatitis, especially in patients with high BMI Trivedi CD, Pitchumoni CS. J Clin Gastroenterol. 2005;39(8):709-716. Blomgren KB, Steineck G, Sundstrom A, Wiholm BE. Diabetes Care. 2002;25(2):298-302. Incretins and Acute Pancreatitis In the exenatide development program: Six cases in 3489 subject-years of exenatide exposure (1.7/1000 subject-years) One case in 336 subject-years in placebo (3.0/1000 subjectyears) One case in 497 subject-years (2.0/1000 subject-years) for the insulin comparator Over 1 year, in 27,996 patients on exenatide and 16,276 on sitagliptin, the incidence of acute pancreatitis: 0.13% of exenatide users [RR 1.0; confidence interval (CI) 0.6 1.7)] 0.12% sitagliptin users [RR 1.0; CI 0.5 2.0)] Between 2006 and 2010, 88 cases of pancreatitis were reported in relation to sitagliptin (2 cases hemorrhagic or necrotizing) Amylin-Eli-Lilly report to the FDA. Dore DD, Seeger JD, Arnold Chan K. Curr Med Res Opin. 2009;25(4):1019-1027. Possible Etiology That Links Incretins to Acute Pancreatitis A few animal studies have shown incretin mimetic drugs to cause exocrine pancreatic duct hyperplasia that may eventually lead to acute or chronic pancreatitis or pancreatic carcinoma Matveyenko AV et al. Diabetes. 2009;58:1604-1615. Nachnani JS et al. Diabetologia. 2010;53:153-159. 3
Acute Pancreatitis: Crude Incidence Rates from Time-on-Drug Analysis Acute Pancreatitis Crude Incidence Rates per 100,000 Person-Years among Exenatide Initiators and Other Antidiabetic Drug* Initiators Incidence Rate/ 100,000 PY 1000 750 500 250 0 Exenatide N = 25,719 Other Antidiabetic Drugs* 218 *Includes initiators of 220 227 321 326 355 N = 234,536 metformin, thiazolidinediones, Current Use Exenatide vs Other Recent Use Adjusted Rate Ratio Past Use 95% CI insulins, sulfonylureas, nonsulfonylurea secretagogues, Antidiabetic sitagliptin, pramlintide, Drugs and α-glucosidase Current Use Recent Use 0.9 0.9 0.6 1.3 0.4 2.1 inhibitors; CI, confidence interval; PY, patient-years Past Use 1.4 0.9 2.3 Bloomgren et al. Presented at ADA, 69th Scientific Sessions; 2009; New Orleans, LA (158-OR). Acute Pancreatitis Crude Incidence Rate from the Intent-to-Treat Analysis Acute Pancreatitis Crude Incidence Rate per 100,000 Person-Years among Exenatide Initiators and Other Antidiabetic Drug* Initiators Incidence Rates per 100,000 PY 600 400 200 0 Intent-to-Treat 273 Exenatide vs Other Antidiabetic Drug Initiators 228 Adjusted 95% CI Rate Ratio 1.1 0.8 1.5 Exenatide initiators N = 25,719 Other antidiabetic drug* initiators N = 234,536 *Includes initiators of metformin, thiazolidinediones, insulins, sulfonylureas, nonsulfonylurea secretagogues, sitagliptin, pramlintide, and α-glucosidase inhibitors; CI, confidence interval; PY, patient-years Bloomgren et al. Presented at ADA, 69th Scientific Sessions; 2009; New Orleans, LA (158-OR). Back to the Article Method: A retrospective cohort of a large medical and pharmacy claims database Data for 786,656 patients were analyzed Cox proportional hazard models were built to compare the risk of acute pancreatitis between: Subjects with and without diabetes Exenatide, sitagliptin, and control diabetes medication Garg R, Chen W, Pendergrass M. Diabetes Care. 2010;33(11):2349-2354. 4
Kaplan-Meier Curve of Acute Pancreatitis in Combined Groups (Exenatide, Sitagliptin, Diabetes Control) with Diabetes and the Control Group without Diabetes Garg R et al. Diabetes Care. 2010;33:2349-2354. Copyright 2011 American Diabetes Association, Inc. Kaplan-Meier Curve of Acute Pancreatitis in Exenatide, Sitagliptin, and Diabetes Control Groups Garg R et al. Diabetes Care. 2010;33:2349-2354. Copyright 2011 American Diabetes Association, Inc. Study Limitations Retrospective nature of the study Patients on exenatide or sitagliptin might be selected from low-risk patients (exclusion of who is likely to develop pancreatitis) Dataset did not provide clinical details such as type and duration of diabetes, obesity, glycemic and lipid control, alcohol consumption, or history of pancreatitis Providers may have used the acute pancreatitis code when evaluating patients for rule-out pancreatitis The possibility of asymptomatic chronic pancreatitis and the potential for pancreatic carcinoma were not investigated in this study 5
Back to Our Patient 43-year-old obese woman Long-standing type 2 diabetes Currently treated with metformin 1000 mg BID and glyburide 10 mg BID History of dyslipidemia treated with atorvastatin 40 mg/day and fenofibrate 120 mg/day History of silent solitary gall stone discovered incidentally by ultrasound for fatty liver Rarely drinks alcohol A1C 7.8% Back to Our Patient No history of pancreatitis Heard from a friend, who also has diabetes, that exenatide is a drug that may help her in controlling her diabetes and may also help her to lose weight She is asking for your opinion about adding exenatide to her current medications but she is concerned about the pancreatitis risk Should You Add Exenatide? In general, this patient is at high risk for pancreatitis: Obese Type 2 diabetes Hypertriglyceridemia (as shown from her fenofibrate treatment) Gall stones Increased risk in her age category 6
What Studies Would Help Clarify the Situation? Animal studies in type 2 diabetes model randomized to either incretin mimetic or placebo Prospective randomized controlled study without selection bias Discussion Points with Patient The association between incretin therapies and acute pancreatitis is weak, based on the available retrospective data Limitations of current studies Regardless of diabetes medications, the patient is at increased risk for acute pancreatitis Exenatide may help in controlling her diabetes and may also help her to lose weight It is likely that incretin therapy may increase the risk of pancreatitis in her situation She may need to check her fasting triglycerides Other options to control her diabetes without the risk of pancreatitis may be considered, such as adding longacting insulin Summary Pancreatitis is common among patients with diabetes. The risk for pancreatitis is increased when a patient has gall stones, hypertriglyceridemia, or is drinking alcohol. Drug-induced pancreatitis accounts for 1 2% of the pancreatitis cases. GLP-1 analogs, DPP-4 inhibitors, and another 44 medications are linked to pancreatitis, but there is no pathophysiologic link between them. In a large retrospective observational study, the relative risk for pancreatitis in relation to exenatide and sitaglipitin was 1.0, indicating a weak relationship A prospective randomized clinical trial with no selection bias is needed to confirm or decline the relationship between GLP-1 analogs, DPP-4 inhibitors, and acute pancreatitis 7