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Savor-Timi 53 Diabetes Care Volume 37, September 2014 2435 Itamar Raz,1 Deepak L. Bhatt,2 Incidence of Pancreatitis and Boaz Hirshberg,3 Ofri Mosenzon,1 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Benjamin M. Scirica,2 Pancreatic Cancer in a Amarachi Umez-Eronini,2 KyungAh Im,2 Christina Stahre,4 Alona Buskila,1 Randomized Controlled Nayyar Iqbal,5 Norton Greenberger,2 and Multicenter Trial (SAVOR-TIMI Markus M. Lerch6 53) of the Dipeptidyl Peptidase-4 Inhibitor Saxagliptin Diabetes Care 2014;37:2435–2441 | DOI: 10.2337/dc13-2546 OBJECTIVE To determine the incidence of pancreatitis and pancreatic cancer in the SAVOR- TIMI 53 trial. RESEARCH DESIGN AND METHODS A total of 16,492 type 2 diabetic patients ‡40 years old with established cardio- vascular (CV) disease or CV risk factors were randomized to saxagliptin or placebo and followed for 2.1 years. Outcome measures were investigator reported with blinded expert adjudication of total pancreatitis (acute and chronic) and reported cases of pancreatic cancer. 1Diabetes Unit, Department of Medicine, Hadassah RESULTS Hebrew University Hospital, Jerusalem, Israel 2TIMI Study Group, Cardiovascular Division, Trial investigators reported 35 events of pancreatitis in each treatment arm in 63 Brigham and Women’s Hospital and Harvard patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in control arm), with a Medical School, Boston, MA 3 hazard ratio (HR) of 1.09 (95% CI 0.66–1.79, P = 0.80). Adjudication confirmed AstraZeneca Research and Development, Wilmington, DE pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and 21 4AstraZeneca Research and Development, patients (25 events) in placebo arm (0.26%), with an HR of 1.13 (0.63–2.06, P = Molndal,¨ Sweden 0.77). Cases of definite acute pancreatitis were confirmed in 17 (0.2%) vs. 9 5Bristol-Myers Squibb, Princeton, NJ 6 (0.1%) (HR 1.88 [0.86–4.41], P = 0.17), definite plus possible pancreatitis in 22 University Medicine Greifswald, Greifswald, Germany vs. 16 (HR 1.36 [0.72–2.64], P = 0.42), and chronic pancreatitis in 2 vs. 6 (HR 0.33 Corresponding author: Itamar Raz, ntv502@ [0.05–1.44], P = 0.18) in the saxagliptin and placebo arms, respectively. No differ- netvision.net.il. ences in time to event onset, concomitant risk factors for pancreatitis, investigator- Received 31 October 2013 and accepted 8 May reported causality from study medication or disease severity, and outcome 2014. were found between treatment arms. The investigators reported 5 and 12 Clinical trial reg. no. NCT01107886, clinicaltrials cases of pancreatic cancer in the saxagliptin and placebo arms, respectively .gov. (HR 0.42 [0.13–1.12], P = 0.09). This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ CONCLUSIONS suppl/doi:10.2337/dc13-2546/-/DC1. In the SAVOR-TIMI 53 trial, within 2.1 years of follow-up, risk for pancreatitis in A slide set summarizing this article is available type 2 diabetic patients treated with saxagliptin was low and apparently similar to online. placebo, with no sign of increased risk for pancreatic cancer. Further studies are © 2014 by the American Diabetes Association. Readers may use this article as long as the work needed to completely resolve the pancreatic safety issues with incretin-based is properly cited, the use is educational and not therapy. for profit, and the work is not altered. 2436 SAVOR-TIMI 53dPancreatitis/Pancreatic Cancer Diabetes Care Volume 37, September 2014 Several clinical features associated with eligibility criteria have been previously at least two of the following three crite- type 2 diabetes and obesity are recog- published (16). In short, eligible patients ria from internationally accepted guide- nized risk factors for acute pancreatitis had a documented history of type 2 di- lines (18) were met: 1) acute onset of (1). Recently, concerns have been raised abetes, had an HbA1c between 6.5% and persistent, severe, epigastric pain often regarding long-term consequences of 12.0% (48–108 mmol/mol) during the 6 radiating to the back; 2) elevation in se- incretin therapy in type 2 diabetic pa- months before enrollment in the study, rum lipase or amylase to three times or tients. These concerns include possible and were taking any antidiabetic drug more the upper limit of normal at the triggers for acute pancreatitis and initi- except incretin-based therapy. To qualify respective institution; and 3) character- ation or acceleration of histological for the established CV disease criteria, istic findings of acute pancreatitis on di- changes, suggesting silent or clinical study subjects had to be at least 40 years agnostic imaging (transabdominal chronic pancreatitis with preneoplastic old and have a history of a clinical event ultrasound, contrast-enhanced com- lesions and potentially pancreatic can- secondary to atherosclerosis involving puted tomography, or magnetic reso- cer (2,3). Although some reports have the coronary, cerebrovascular, or pe- nance imaging). To allow for greater supported the linkage of type 2 diabetes ripheral vascular system. To qualify sensitivity for a potential association treatment with dipeptidyl peptidase-4 based on multiple risk factor criteria, with pancreatic disorders, we used a (DPP-4) inhibitors or GLP-1 receptor ag- study subjects had to be at least 55 second category of possible acute pan- onists and increased risk of pancreatitis (men) or 60 (women) years old and creatitis (18), which included patients in (4,5), others have not supported this have at least one of the following addi- whom reported atypical abdominal association (6–9). tional risk factors: dyslipidemia, hyper- symptoms were not characteristic of TheU.S.FoodandDrugAdministra- tension, or active smoking. Patients pancreatitis (but were without an alter- tion requires the investigation of cardio- were ineligible if they were currently or native explanatory diagnosis) plus at vascular (CV) safety of new drugs for previously (within 6 months) treated least one of the following: 1) elevated diabetes (10,11). Therefore, several ran- with an incretin-based therapy or had serum lipase or amylase levels to three domized controlled CV safety studies end-stage renal disease (long-term dial- times or more the upper limit of normal, with incretin-based therapies are ongo- ysis, renal transplant, or serum creati- 2) characteristic findings of acute pan- ing or have recently been completed nine level .6.0 mg/dL). The baseline creatitis on diagnostic imaging, or 3)a (12–15). These studies provide an op- characteristics of the SAVOR-TIMI 53 par- history of previous pancreatitis. Patients portunity to further evaluate additional ticipants were previously reported (17). were classified as having chronic pan- safety events of interest, including ef- Patients were followed at the study creatitis when either medical records fects on the pancreas. sites by a minimum of one office visit every documented or cross-sectional imaging 6 months with either an additional phone confirmed the diagnosis. Symptoms RESEARCH DESIGN AND METHODS call or office visit every 3 months. The pa- were regarded as unlikely to be pancre- The Saxagliptin Assessment of Vascular tients also continued their usual medical atitis when none of the these definitions Outcomes Recorded in Patients with Di- care with their respective treating physi- applied. Patients with definite or possi- abetes Mellitus–Thrombolysis in Myo- cians, and the sites were instructed to ble pancreatitis were assessed as having cardial Infarction 53 (SAVOR-TIMI 53) maintain contact with these physicians. severe disease when single or multiple trial evaluated the long-term CV safety Pancreatitis events were reported by organ failure persisted for .48 h and efficacy of saxagliptin in patients the investigator as an adverse event (19,20). Known risk factors for pancrea- with type 2 diabetes at high risk for CV (AE), a serious AE, and an event of spe- titis, including alcohol use, gallstone events (16). The TIMI Study Group and cial interest (EOSI). We systematically disease (including prior cholecystec- Hadassah Medical Organization de- collected all events, investigators re- tomy), hypertriglyceridemia, hypercal- signed the trial in collaboration with ceived specific training, and specificpro- cemia, recent endoscopic retrograde the sponsors. SAVOR-TIMI 53 was spective electronic case report forms cholangiopancreatography, trauma, and a randomized, double-blind, placebo- were used for event collection. concomitant drugs known to be associ- controlled, multicenter international Pancreatitis events were blindly adju- ated with pancreatitis, were also evalu- intervention trial conducted between dicated by an external expert commit- ated. In addition, investigators were May 2010 and June 2013 in 788 medical tee, which included two pancreatic instructed to treat pancreatitis according centers in 26 countries. Patients with disease experts (N.G. and M.M.L.). The to local guidelines and to continue or dis- type 2 diabetes .40 years of age with classification of the pancreatitis events continue the study drug according to established CV disease or $55 (men) and was decided on by an external expert their clinical judgment. Of note, history $60 (women) years of age with one or committee and was in accordance with of pancreatitis was not a contraindication more CV risk factors were randomized internationally accepted guidelines (18– for participation in the trial. 1:1 to receive 5 mg/day saxagliptin or 20). Reported cases were classified into Pancreatic cancer cases were col- placebo. In patients with moderate or four categories: definite acute pancrea- lected as AE and serious AE and, like all severe renal failure, the saxagliptin titis, possible acute pancreatitis, chronic cancer cases, as EOSI. We collected as dose was decreased to 2.5 mg/day. The pancreatitis, or unlikely to be pancreati- much information as possible on each protocol was approved by the ethics tis. The predefined end point was the case, including medical records and pa- committees of all participating centers, total number of adjudicated cases of thology and imaging results.
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