Amylase, Lipase, and Acute Pancreatitis In
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Diabetes Care 1 William M. Steinberg,1 John B. Buse,2 Amylase, Lipase, and Acute Marie Louise Muus Ghorbani,3 David D. Ørsted,3 Michael A. Nauck,4 and Pancreatitis in People With Type 2 the LEADER Steering Committee, on behalf Diabetes Treated With Liraglutide: of the LEADER Trial Investigators* Results From the LEADER Randomized Trial https://doi.org/10.2337/dc16-2747 OBJECTIVE To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5–5.0 years. RESEARCH DESIGN AND METHODS A total of 9,340 patients with type 2 diabetes were randomized to either liraglutide or placebo (median observation time 3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in a blinded manner. PATHOPHYSIOLOGY/COMPLICATIONS RESULTS Compared with the placebo group, liraglutide-treated patients had increases in se- rum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 1George Washington University Medical Center, 6 months and then remained stable. During the study, 18 (0.4% [1.1 events/1,000 Washington, DC 2 patient-years of observation] [PYO]) liraglutide-treated and 23 (0.5% [1.7 events/ University of North Carolina School of Medicine, fi Chapel Hill, NC 1,000 PYO]) placebo patients had acute pancreatitis con rmed by adjudication. Most 3Novo Nordisk A/S, Bagsvaerd, Denmark acute pancreatitis cases occurred ‡12 months after randomization. Liraglutide-treated 4St. Josef-Hospital, Ruhr University, Bochum, patients with prior history of pancreatitis (n = 147) were not more likely to develop Germany acute pancreatitis than similar patients in the placebo group (n = 120). Elevations of Corresponding author: William M. Steinberg, amylase and lipase levels did not predict future risk of acute pancreatitis (positive [email protected]. predictive value <1.0%) in patients treated with liraglutide. Received 23 December 2016 and accepted 3 April 2017. CONCLUSIONS Clinical trial reg. no. NCT01179048, clinicaltrials In a population with type 2 diabetes at high cardiovascular risk, there were numer- .gov. ically fewer events of acute pancreatitis among liraglutide-treated patients (regard- This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ less of previous history of pancreatitis) compared with the placebo group. Liraglutide suppl/doi:10.2337/dc16-2747/-/DC1. was associated with increases in serum lipase and amylase, which were not pre- *The full list of LEADER Trial Investigators dictive of an event of subsequent acute pancreatitis. and Committee Members can be found in the Supplementary Data online. Glucagon-like peptide 1 (GLP-1) receptor agonists are established glucose-lowering © 2017 by the American Diabetes Association. Readers may use this article as long as the work drugs for treating type 2 diabetes (1). However, incretin-based therapies (GLP-1 re- is properly cited, the use is educational and not ceptor agonists and dipeptidyl peptidase 4 [DPP-4] inhibitors) are associated with for profit, and the work is not altered. More infor- increased levels of serum lipase and amylase, and a potential for an increased risk of mationisavailableathttp://www.diabetesjournals acute pancreatitis has previously been raised (2–6). Current assessments from regula- .org/content/license. tory agencies in Europe and the U.S. indicate that pancreatitis should be considered a See accompanying article, p. XXX. Diabetes Care Publish Ahead of Print, published online May 5, 2017 2 Amylase, Lipase, and Pancreatitis in LEADER Diabetes Care risk associated with incretin-based drugs were repeated annually until the trial the liver enzyme profile alanine ami- until further data are available (7). Sub- ended. No measurement was performed notransferase/aspartate transaminase) sequently, analyses of pooled data from after the planned end-of-treatment visit. (11). In addition, characteristics of the shorter phase III clinical trials of GLP-1 re- Serum pancreatic lipase and total amylase events not confirmed by adjudication ceptor agonists have noted an associa- were measured in the fasting state in all were evaluated in a post hoc review by tion with 38 cases of acute pancreatitis patients using an enzymatic colorimetric the sponsor. among 17,775 patient-years of observa- assay (Roche Diagnostics, Mannheim, Ger- tion (PYO) (event rate 2.1/1,000 PYO) many) performed by a central laboratory Statistical Analysis compared with 9 cases after 5,863 PYO (ICON PLC, Dublin, Ireland). No patients All analyses were prespecified (before da- (event rate 1.5/1,000 PYO) (8). For DPP-4 had symptoms suggesting acute pancrea- tabase lock) unless marked otherwise. inhibitors, though meta-analysis of shorter titis at baseline blood draw. The upper Due to a right-skewed distribution, ob- regulatory trials failed to show an associ- limit of normal (ULN) for the assays was served geometric means for lipase and ationwithpancreatitis(8),meta-analysis 63 units/L for lipase and 100 units/L for amylase levels are presented. The differ- of the longer cardiovascular outcomes tri- amylase. Neither limit was adjusted for ences between treatment groups in als does suggest a small increased risk the distribution expected in patients with lipase and amylase were estimated (9,10). type 2 diabetes. More frequent tests for using a mixed effects model for repeated Due to the previous results and the lack lipase and amylase were allowed at the measurements adjusted for baseline co- of long-term data, pancreatitis continues discretion of the investigator. Baseline li- variates. Comparisons between groups to be of interest in studies of GLP-1 re- pase activity and amylase activity among were performed at 36 months, as this ceptor agonists, particularly in studies the study population have previously been was the last annual visit with laboratory where long-term safety data can be col- reported (14). Per protocol, participants testing for the majority of the patients, lected. Furthermore, serial amylase and diagnosed with pancreatitis should be given the minimum treatment period of lipase measurements have been sug- withdrawn from study medication by 42 months. An analysis using a linear gested to predict the development of their care team. model with repeated measures (Mixed acute pancreatitis (11). effect Model Repeat Measurement In the Liraglutide Effect and Action in Evaluation of Acute Pancreatitis [MMRM]) assuming an unstructured co- Diabetes: Evaluation of cardiovascular Pancreatitis was predefined by the trial variance matrix was performed to evalu- outcome Results (LEADER) trial, 9,340 protocol as a medical event of special in- ate the interaction between explanatory patients with type 2 diabetes and high terest. Revised Atlanta criteria were used factors at baseline and treatment in re- cardiovascular risk were randomized to for a confirmed diagnosis of acute pancre- lation to change from baseline for log- the GLP-1 analog liraglutide or match- atitis and classified by severity (15) transformed levels of lipase and amylase, ing placebo, both in addition to stan- (Supplementary Table 1). For the diagno- respectively, at each visit. Effects of each dard of care, and followed for 3.5–5.0 sis of acute pancreatitis, two or more of level in the factors were presented as the years. The aim of the current study was to the following three criteria had to be ful- treatment ratio between liraglutide ver- evaluate results from LEADER regarding filled: 1) severe acute upper abdominal sus placebo at the 36-month visit. Explan- the effects of liraglutide treatment on se- pain, 2) amylase and/or lipase threefold atory factors were age, sex, BMI, smoking rum lipase and amylase and the number or more above the ULN ($33 ULN), and status, diabetes duration, glycated hemo- of cases of acute pancreatitis confirmed 3) characteristic findings on imaging (ul- globin (HbA1c), baseline lipase and amy- by adjudication. trasound, computed tomography [CT], or lase levels, medical history (including MRI) of the pancreas. Chronic pancreatitis history of pancreatitis), estimated glo- RESEARCH DESIGN AND METHODS was defined by characteristic imaging merular filtration rate, lipid levels, and Detailed methods have previously been findings (ultrasound, CT, and MRI) with use of certain medications. The interac- published (12,13). Briefly, 9,340 patients abnormal pancreatic function tests or tion between baseline characteristics were enrolled at 410 sites in 32 countries. characteristic histological findings. All po- and allocated treatment (liraglutide vs. Patients with type 2 diabetes at high risk tential cases of pancreatitis were adjudi- placebo) on the development of acute for cardiovascular events were random- cated by an independent committee of pancreatitis was examined using logistic ized 1:1 double-blind to either subcutane- experts, which was blinded to treatment. regression. Correction for multiple com- ous liraglutide 1.8 mg daily (or maximum To ensure that potential events of pancre- parisons in the analyses of baseline char- tolerated dose) or placebo with a treat- atitis were not missed for adjudication, a acteristics was performed using the ment period of 3.5–5.0 years and a 30 day Medical Dictionary for Regulatory Activi- Bonferroni method. follow-up period. Patients with a history ties search of the clinical database was The analyses for risk of acute pancrea- of pancreatitis were not excluded. The performed