OBJECTIVE -The objective of this study was to assess the risk of acute pancreatitis in patients with type 2 diabetes compared with that in patients without diabetes. We also examined the risk of biliary disease (defined as occurrence of cholelithiasis, acute cholecystitis, or cholecystectomy), which is a major cause of pancreatitis.RESEARCH DESIGN AND METHODS -We conducted a retrospective cohort study using a large, geographically diverse U.S. health care claims database. Eligible patients (Ն18 years) were enrolled for at least 12 continuous months (1999 -2005), with no incident events of pancreatitis or biliary disease during that 1 year baseline period. ICD-9 codes and prescription data were used to identify patients with type 2 diabetes; ICD-9 codes were also used to identify cases of pancreatitis and biliary disease. Overall, 337,067 patients with type 2 diabetes were matched on age and sex with 337,067 patients without diabetes. Incidence rates of disease and 95% CI were calculated per 100,000 person-years of exposure.RESULTS -The type 2 diabetic cohort had a 2.83-fold (95% CI 2.61-3.06) greater risk of pancreatitis and 1.91-fold (1.84 -1.99) greater risk of biliary disease compared with the nondiabetic cohort. Relative to patients of corresponding age without diabetes, younger type 2 diabetic patients had the highest risk of pancreatitis (Ͻ45 years: incidence rate ratio [IRR] CONCLUSIONS -These data suggest that patients with type 2 diabetes may have an increased risk of acute pancreatitis and biliary disease.

Exenatide use was not associated with an increased risk of acute pancreatitis.

Word count: 3,668 without Acknowledgements or 4,089 with Acknowledgements Key messages Formal and transparent discussion of multiple viewpoints, interests and priorities facilitates mutual understanding of complex decision problems  Benefit-risk assessments of treatments should be undertaken in a structured way so that it is clear how a decision on the overall balance of a treatment's effects has been reached  Various structured approaches and singular methodologies/visual representations are available to support benefit-risk assessment of medicines, but so far universal agreement as to the most suitable method for structured benefit-risk assessment has been lacking  A team combining expertise from public and private institutions carried out a review of benefit-risk methods and visual representations, including application of the tools to case studies based on real regulatory scenarios  The project produced a clear set of practical recommendations for undertaking benefit-risk assessments, organised around a generic, five stage benefit-risk assessment roadmap /2007-2013) and EFPIA companies' in kind contribution.The processes described and conclusions drawn from the work presented herein relate solely to the testing of methodologies and representations for the evaluation of benefit and risk of medicines. This report neither replaces nor is intended to replace or comment on any regulatory decisions made by national regulatory agencies, nor the European Medicines Agency.The authors declare the following conflicts of interest: Dr Hughes has been employed by Pfizer Inc. for the duration of the project. Mr Downey reports that he is an employee of Amgen, a participant in the Innovative Medicines Initiative, which is a public-private partnership. The manuscript describes testing benefit-risk methodologies and visualizations using case studies of marketed products. No Amgen treatments were used in the work associated with this publication. Dr Juhaeri is an employee of Sanofi, the producer of rimonabant and telithromycin, which were used in the PROTECT project as case studies. Dr Juhaeri declares that he is an employee or Sanofi, the manufacturer of rimonabant which was studied in this project. Mr Lieftucht reports that he is an employee of GlaxoSmithKline, a participant in the Innovative Medicines Initiative, which is a public-private partnership. One of the case studies described in the manuscript is a GSK product but Mr Lieftucht did not work on that case study. Dr Metcalf reports that she is an employee of GlaxoSmithKline, a participant in the Innovative Medicines Initiative, which is a publicprivate partnership. One of the case studies described in the manuscript is a GSK product but Dr Metcalf did not work on that case study. To draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. MethodsEight case studies based on the benefit-risk balance of real medicines were ...

Aims Previously, a retrospective cohort study found no increased risk of acute pancreatitis with current or recent use of exenatide twice daily compared with use of other anti-diabetic drugs. This follow-up study investigated incident acute pancreatitis, with the use of a different data source and analytic method, in patients exposed to exenatide twice daily compared with patients exposed to other anti-diabetic medications.Methods A large US health insurance claims database was used. Eligible patients had ≥months continuous enrollment without a claim for pancreatitis and a claim for a new anti-diabetic medication on or after 1 June 2005 to 31 March 2009. Cases of acute pancreatitis were defined as hospitalized patients with an Internation Classification of Disease9 code of 577.0 in the primary position. A discrete time survival model was used to evaluate the relationship between exenatide twice daily and acute pancreatitis.Results Of 482034 eligible patients, 24237 initiated exenatide twice daily and 457797 initiated another anti-diabetic medication. Initiators of exenatide twice daily had more severe diabetes compared with initiators of other anti-diabetic medications. After adjustments for propensity score, insulin and use of medication potentially associated with acute pancreatitis, the odds ratio with exenatide twice daily exposure was 0.95 (95%CI 0.65–1.38). A secondary analysis that examined current, recent and past medication exposure found no increased risk of acute pancreatitis with exenatide twice daily, regardless of exposure category.Conclusion This study indicates that exposure to exenatide twice daily was not associated with an increased risk of acute pancreatitis compared with exposure to other anti-diabetic medications. These results should be interpreted in light of potential residual confounding and unknown biases.

The assessment of the benefits and risks associated with a medicine's use requires careful consideration of a wealth of information of varying format and quality, ranging from efficacy and safety data derived from randomized clinical trials to statistical results from health outcomes studies to spontaneously reported adverse events. Contrary to the expectations of patients, physicians, and regulators, the literature offers little guidance as to how to strike an appropriate balance between benefit and risk. Although a qualitative listing of a medicine's benefits and risks is useful, much could be gained from a systematic and transparent process to evaluate a medicine's pre- and postmarketing performance. The authors propose a representational model based on multicriteria decision analysis that can incorporate both evaluative judgments from different perspectives (e.g., physician, patient) and quantitative data to inform tradeoffs between multiple benefit and multiple risk elements in a logically consistent and transparent manner. The model is designed to highlight the relative merits and deficits of treatment alternatives in well-defined and specific contexts. It is intended to serve as a common platform to facilitate focused benefit-risk tradeoff discussions between scientists, physicians, regulatory authorities, and pharmaceutical companies, and to assist in the communication of clear and consistent messages regarding those tradeoffs.