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    2 Comments for this article
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    Acute pancreatitis and glucagon like peptide 1-based therapies – caution over what to conclude from observational studies
    Dr REJ Ryder MD FRCP, Dr A Blann PhD FRCPath, Dr KY Thong MBBS FRACP | Sandwell and West Birmingham Hospitals, UK. Diabetes(Dr. Ryder); Trust statistician(Dr. Blann); Rockingham General Hospital, Perth, Australia. Diabetes(Dr. Thong)
    In their observational study, Singh et al(1) concluded that treatment with the glucagonlike peptide1 (GLP1)-based therapies sitagliptin (a gliptin) and exenatide (a GLP1 receptor-agonist (GLP1RA)) was associated with increased risk of acute pancreatitis. Real-world patients do not get put on GLP1-based therapies randomly – they get put on them for a reason. GLP1RAs have weight losing, and gliptins weight neutral, properties. By contrast, other glycaemic medications, such as insulin, sulphylureas and thiazolidenediones cause weight increase. 

    Thus patients prescribed GLP1-based therapies are likely to be more obese than those not so treated. Obesity is associated with other risk factors
    for pancreatitis such as gall stones and hypertriglyceridaemia. In keeping with this it is noteworthy that the pancreatitis cases in the study of Singh et al were significantly more likely to have other risk factors for pancreatitis including obesity, gall stones and hypertrygliceridaemia (1).  Though Singh et al adjusted for these confounders in a multivariate analysis(1), there remains an insurmountable difficulty - patients treated with GLP1-based therapies are fundamentally different from those not so treated - like was not being compared with like, and no amount of adjustment for confounders can create matching samples. Furthermore, Singh et al accept that some factors, including obesity, were markedly under-recorded in their database. Thus we believe Singh et al would agree that the association they have found could be because diabetic patients with obesity are at the same time:i) more likely to have gall stones and hypertriglyceridaemia increasing their risk of pancreatitis ii) more likely to be treated with GLP1-based therapies. 

    The Association of British Clinical Diabetologists(ABCD) nationwide audits of exenatide and liraglutide in real clinical use, found clinically important benefits for patients - improvement in HbA1c and weight with reduction in other medications including insulin(2-4). Pancreatitis was specifically asked for in the exenatide audit, while “any possible side effects” were asked for in the liraglutide audit. In keeping with the above, most cases of pancreatitis reported in these audits, had another cause such that the GLP1RA did not need to be implicated(2,5). There was an unexplained case in each audit leading to rates of 0.030 and 0.027 cases/100 patient years exposure in the exenatide(2) and liraglutide(5) audits respectively. These occasional cases without any other cause might have been cases of “idiopathic” pancreatitis, this being common(5). With GLP1RAs, the possibility of a causal association with pancreatitis remains uncertain, whereas clinical benefits are considerable. 

    1. Singh S, Chang H-Y, Richards TM, et al. Glucagon like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus. JAMA Intern Med. 2013 Apr 8;173(7):534-9 

    2. Ryder REJ, Thong KY, Cull ML, et al. The Association of British Clinical Diabetologists (ABCD) nationwide exenatide audit. Practical Diabetes International 2010; 27(8): 352-357 

    3. Ryder REJ and Thong KY,on behalf of the ABCD nationwide exenatide and nationwide liraglutide audit contributors. Findings from the Association of British Clinical Diabetologists (ABCD) nationwide exenatide and liraglutide audits. In Hot topics in diabetes, Vora J, ed. Synergy, London, 2012.  

    4. Thong, KY, Jose, B, Sukumar, N, et al. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists (ABCD) nationwide exenatide audit. Diabetes, Obesity and Metabolism 2011; 13(8): 703-720 

    5. Ryder, REJ, Thong, KY, Blann, A, et al. Liraglutide and acute pancreatitis in the Association of British Clinical Diabetologists (ABCD) nationwide liraglutide audit. Poster 15 (late breaking), ABCD Spring Meeting 2013. http://www.diabetologists-abcd.org.uk/GLP1_Audits/Liraglutide_Pancreatitis_Poster_ABCD_Apr2013.pdf

    CONFLICT OF INTEREST: Dr. Ryder has received speaker fees, consultancy fees and/or educational sponsorship from a number of companies including in alphabetical order Eli Lilly, GlaxoSmithKline, Novo-Nordisk, Sanofi-Aventis and Takeda. Dr. Blann has no conflicts to report. Dr. Thong has received educational sponsorship from Eli Lilly and educational sponsorship and speaker fees from Novo-Nordisk.
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    Reply to the Study “Glucagonlike Peptide 1-Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus”
    Christian Hampp, Ph.D., Diane K. Wysowski, Ph.D., M.P.H., Solomon Iyasu, M.D., M.P.H | Division of Epidemiology-I, Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
    Singh and colleagues recently published a study on acute pancreatitis (AP) with GLP-1-based therapies (1). While we welcome research in this important area, we have concerns regarding the study’s methodology.First, case identification was not optimal. The investigators stated that they selected the best-performing claims-based algorithm with a positive predictive value of 60-80% from a review of algorithms (2). However, 4 out of 5 codes used by Singh et al. to identify AP (Appendix (1)) were not mentioned in the review, and their modified algorithm was not validated through medical charts. Also, since AP has been included in the study drugs’ labels for much of the study period, detection bias and differential misclassification may have contributed to the risk increase with GLP-1-based therapies. Second, as the authors noted, some important risk factors were markedly underascertained. Obesity was detected in only 9.77% of diabetic controls and alcohol use in only 0.24%, while codes for Alcohol dependence syndrome (ICD-9-CM codes 303.0x and 303.9x) were omitted. Other important risk factors including type, number, and duration of antidiabetic drug use were not included in the analysis. The authors used the DCSI score to adjust for diabetes severity; however, 65.1% of patients had a DCSI score of 0, indicating no comorbidities. This possible underascertainment may be related to short follow-up: more than 50% of cases had ≤12 months of history compared with an average of 3.5 years in the study that established the DCSI where only 32.1% were without comorbidities (3). Because the distribution of risk factors by exposure status was not shown, the extent and direction of residual confounding is not clear. Third, the categories of current and recent exposure were reportedly mutually exclusive and any use included current and recent use. However, the number of cases with any exposure to sitagliptin (n=47) was fewer than the sum of current (n=39) and recent users (n=38), suggesting substantial overlap. This could explain the similar ORs with recent and current use. Recent use is uninterpretable if it included current users. Lastly, despite potentially limited power, a separate analysis for sitagliptin and exenatide would have been interesting. Among current users, more controls (n=13) were exposed to exenatide than cases (n=10); this situation was reversed for sitagliptin. Because of its limitations, the study neither confirms nor refutes an increased risk of AP associated with GLP-1-based therapies. Thus, the assurance by Gier and Butler (4)(“clarity at last”) appears premature. References 1. Singh S, Chang HY, Richards TM, et al. Glucagonlike Peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med 2013;173:534-9. 2. Moores K, Gilchrist B, Carnahan R, et al. A systematic review of validated methods for identifying pancreatitis using administrative data. Pharmacoepidemiol Drug Saf 2012;21 Suppl 1:194-202. 3. Young BA, Lin E, Von KM, et al. Diabetes complications severity index and risk of mortality, hospitalization, and healthcare utilization. Am J Manag Care 2008;14:15-23. 4. Gier B, Butler PC. Glucagonlike Peptide 1-based drugs and pancreatitis: clarity at last, but what about pancreatic cancer? Comment on "glucagonlike Peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus." JAMA Intern Med 2013;173:539-41.This article reflects the views of the authors and does not necessarily represent FDA’s views or policies.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    April 8, 2013

    Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus: A Population-Based Matched Case-Control Study

    Author Affiliations

    Author Affiliations: Department of Medicine, The Johns Hopkins University School of Medicine (Drs Singh, Clark, and Segal), and Center for Public Health and Human Rights (Dr Singh) and Department of Health Policy and Management (Drs Chang and Weiner and Mr Richards), The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

    JAMA Intern Med. 2013;173(7):534-539. doi:10.1001/jamainternmed.2013.2720
    Abstract

    Importance Acute pancreatitis has significant morbidity and mortality. Previous studies have raised the possibility that glucagonlike peptide 1 (GLP-1)–based therapies, including a GLP-1 mimetic (exenatide) and a dipeptidyl peptidase 4 inhibitor (sitagliptin phosphate), may increase the risk of acute pancreatitis.

    Objective To test whether GLP-1–based therapies such as exenatide and sitagliptin are associated with an increased risk of acute pancreatitis. We used conditional logistic regression to analyze the data.

    Design Population-based case-control study.

    Setting A large administrative database in the United States from February 1, 2005, through December 31, 2008.

    Participants Adults with type 2 diabetes mellitus aged 18 to 64 years. We identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications.

    Main Outcome Measure Hospitalization for acute pancreatitis.

    Results The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.

    Conclusions and Relevance In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1–based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis.

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