Diabetes Care Volume 37, September 2014 2435

Itamar Raz,1 Deepak L. Bhatt,2 of Pancreatitis and Boaz Hirshberg,3 Ofri Mosenzon,1 CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL CLIN 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 (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 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 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 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. Each report and all patients gave written informed pancreatitis. The diagnosis of acute pan- was reviewed for accuracy and com- consent before enrollment. The full creatitis was regarded as definite when pleteness by blinded study physicians care.diabetesjournals.org Raz and Associates 2437

of both the TIMI Study Group and the group was performed. SAS version 8.2 12,917 (78.3%); aspirin, 12,404 (75.2%); sponsor. and above (SAS Institute Inc., Cary, NC) ACE inhibitors/angiotensin receptor was used for all analyses. P , 0.05 was blockers, 12,995 (78.8%); and b-blockers, Statistical Analysis considered statistically significant. 10,162 (61.6%). Overall, the SAVOR-TIMI All analyses were performed with an in- 53 patients had a high of CV tention to treat all patients who under- RESULTS risk factors, including dyslipidemia went randomization. Continuous variables Between May 2010 and December (71.2%), hypertension (81.8%), BMI $30 are expressed as mean 6 SD, median 2011, 16,492 patients were randomized kg/m2 (53.6%), BMI $40 kg/m2 (7.5%), and interquartile range, or minimum and participated in the trial (12,959 pa- estimated glomerular filtration rate and maximum values; categorical varia- tients with established CV disease [78% #50 mL/min (15.6%), and current bles are expressed as frequencies and vs. 79% in the saxagliptin vs. placebo smoking (13.5%). percentages. x2 or Fisher exact tests for arms, respectively] and 3,533 with mul- The total observation time was categorical variables and Wilcoxon rank tiple risk factors [22% vs. 21% in the 16,884 person-years in the saxagliptin sum tests for continuous variables are saxagliptin vs. placebo arms, respec- group and 16,761 person-years in pla- reported. Incidence of pancreatitis was tively]). Baseline characteristics of ran- cebo group. The study drug was prema- calculated as the number of patients domized patients were well balanced turely discontinued less frequently in with pancreatitis divided by the total between treatment arms, as previously patients assigned to saxagliptin than population at risk in the beginning of published (17) (mean [SD] age 65.0 [8.5] to placebo (1,527 [18.4%] vs. 1,705 the study. In addition, the cumulative in- years, male sex 66.9%, BMI 31.2 [5.6] [20.8%], respectively, P , 0.001). A final cidence of pancreatitis at the end of kg/m2, median diabetes duration vital status was assessed in 99.1% of pa- study was reported by Kaplan-Meier 10.3 [8.9] years, mean HbA1c 8.0% tients. Twenty-eight patients were lost plots (Supplementary Fig. 1A–D). To [1.4] [64 (9.8) mmol/mol]). The num- to follow-up. The median follow-up was determine the of pancreati- bers of patients taking diabetic medi- 2.1 years (interquartile range 1.8–2.3 tis and pancreatic cancer between the cations at baseline were as follows: years), and maximum follow-up was 2.9 saxagliptin and placebo arms, Cox pro- insulin, 6,832 (41.4%); sulfonylurea, years. portional hazards modeling using profile 6,633 (40.2%); metformin, 11,473 Investigators reported a total of 35 likelihood estimations with stratification (69.6%); and none (antidiabetic drug– events of pancreatitis in 33 patients in by study design variables, baseline re- na¨ıve patients), 735 (4.5%). CV medica- the saxagliptin arm and 35 events in 30 nal impairment, and baseline CV risk tions at baseline included statins, patients in the placebo arm (hazard ratio

Table 1—Investigator-reported and adjudication-confirmed pancreatitis in SAVOR-TIMI 53 Saxagliptin overall Placebo overall P value (n =8,280) (n =8,212) (Fisher exact test) HR (95% CI) Investigator-reported pancreatitis Patients with pancreatitis events 33 (0.40) 30 (0.37) 0.80 1.09 (0.66–1.79) Number of events of pancreatitis 35 35 0.99 (0.90–1.10) Adjudication-confirmed pancreatitis Patients with any pancreatitis event 24 (0.29) 21 (0.26) 0.77 1.13 (0.63–2.06) Number of events of pancreatitis 26 25 1.03 (0.93–1.15) Patients with definite acute pancreatitis events 17 (0.2) 9 (0.1) 0.17 1.88 (0.86–4.41) Patients with acute pancreatitis, definite or possible 22 (0.3) 16 (0.2) 0.42 1.36 (0.72–2.64) Patients with chronic pancreatitis events 2 (0.02) 6 (0.07) 0.18 0.33 (0.05–1.44) Patients with any pancreatitis event* Duration of events (days) n 21 22 dd Mean (SD) 13.7 (28.3) 38.5 (103.4) dd Median (minimum, maximum) 7.0 (3.0, 135.0) 12.0 (2.0, 494.0) dd Action taken to study drug Not applicable 4 (15.4) 5 (20.0) dd Dose not changed 16 (61.5) 13 (52.0) dd Drug interrupted 2 (7.7) 1 (4.0) dd Drug withdrawn 4 (15.4) 6 (24.0) dd Outcome of the AE Resolved 21 (80.8) 21 (84.0) dd Recovering 3 (11.5) 1 (4.0) dd Not resolved 2 (7.7) 1 (4.0) dd Resolved with sequelae 0 1 (4.0) dd Fatal 0 1 (4.0) dd Data are n (%) unless otherwise indicated. HR and 95% CIs from a Poisson regression model. *Summary is at the event level; denominator is the total number of events for each treatment group. Eight pancreatic cases missing data on duration of events. 2438 SAVOR-TIMI 53dPancreatitis/Pancreatic Cancer Diabetes Care Volume 37, September 2014

[HR] 1.09 [95% CI 0.66–1.79]) (Table 1 the study drug. Preexisting risk factors pancreatitis cases in the saxagliptin and and Supplementary Table 1). Pancreati- for pancreatitis were identified in 18 placebo arms were similar (nine vs. nine, tis was adjudicated in 24 patients (26 (81.8%) patients with acute pancreatitis respectively), as was the frequency at events) receiving saxagliptin and 21 (25 (definite and possible) receiving saxa- which the study medication was discon- events) receiving placebo (HR 1.13 [95% gliptin and in 15 patients (93.8%) with tinued due to pancreatitis (six vs. seven, CI 0.63–2.06], Fisher exact test P =0.77) acute pancreatitis receiving placebo respectively). Adjudicated reports of se- (Table 1 and Supplementary Fig. 1A). (Fig. 1 and Supplementary Table 2). vere pancreatitis and deaths were simi- One case was adjudicated first as possi- Risk factors in general and the number lar between the saxagliptin and placebo ble acute pancreatitis and subsequently of risk factors per patient were distrib- arms (one case of severe pancreatitis in as chronic pancreatitis. Thirty-eight pa- uted similarly between the two treat- each arm, and no vs. one death in the tients were adjudicated to have either ment arms (Supplementary Table 2 saxagliptin vs. placebo arms, respec- definite or possible acute pancreatitis and Fig. 1). The blinded pancreatitis ad- tively) (Table 1). The mean (SD) duration (22 [0.3%] vs. 16 [0.2%], HR 1.36 [95% judication committee considered 19 of events was 13.7 (28.3) vs. 38.5 (103.4) CI 0.72–2.64], Fisher exact test P =0.42) cases as unlikely to be pancreatitis (9 days in saxagliptin- vs. placebo-treated in the saxagliptin and placebo arms, re- in the saxagliptin arm and 10 in the pla- patients, respectively. The recovery spectively (Table 1 and Supplementary cebo arm). All these cases did not rate from pancreatitis was similar be- Fig. 1B). Of these, 26 patients were ad- have typical abdominal pain, increased tween the two treatment arms (21 judicated to have definite acute pancre- pacreatic enzymes (more than three [80.8%] vs. 21 [84.0%] were resolved, 2 atitis (17 [0.2%] vs. 9 [0.1%], HR 1.88 times the upper limit of normal), or [7.7%] vs. 1 [4.0%] were not resolved, [95% CI 0.86–4.41], Fisher exact test imaging consistent with pancreatitis. and 0 vs. 1 [4%] were resolved with se- P = 0.17) in the saxagliptin and placebo The event was recovered in 16 (7 in quelae in the saxagliptin vs. placebo arms, respectively (Table 1 and Supple- the saxagliptin arm and 9 in the placebo arms, respectively). The number of pa- mentary Fig. 1C). Repeated cases of pan- arm)andnotrecoveredin2inthe tients who continued on the study med- creatitis were reported in two patients saxagliptin arm (1 had hepatic cellular car- ication despite pancreatitis was 16 in the saxagliptin arm and three patients cinoma) and 1 in the placebo arm (who (61.5%) in the saxagliptin arm compared in the placebo arm. Of these five pa- had metastatic pancreatic cancer). with 13 (52.0%) in the placebo arm (Ta- tients, one in the saxagliptin arm was After inclusion in the study, the time ble 1). The proportion of patients with permanently discontinued from the to onset of symptoms of all adjudicated more than two on-treatment AEs of study drug after the first event, yet he definite or possible acute pancreatitis, pancreatitis was generally similar be- had another occurrence of pancreatitis, definite acute pancreatitis, or chronic pan- tween the two treatment groups (one and the second patient was continued creatitis did not differ between treatment [,0.1%] patient in the saxagliptin group on the study drug. In the placebo arm, arms. Events occurred at various time and two [,0.1%] in the placebo group). two patients were permanently discon- points during the treatment period, with Chronic pancreatitis was reported by tinued from the study drug after the first no cluster of events in either treatment the investigators in five patients receiv- event, yet one had two recurrent arm (Fig. 2). Investigators’ assessments ing saxagliptin and four receiving pla- events, and one was continued on of study medication causality in all cebo; adjudication confirmed chronic

Figure 1—Most common risk factors for pancreatitis identified in patients with pancreatitis, intention-to-treat population. Con., control; HyperTG, hypertriglyceridemia. care.diabetesjournals.org Raz and Associates 2439

Figure 2—Scatter plots of adjudication-confirmed pancreatitis, ITT population by category. Subject E7836013 (saxagliptin) was confirmed as having definite acute pancreatitis after possible acute pancreatitis and is presented twice in the figure. ITT, intention to treat. pancreatitis in two patients receiving pancreatitis in type 2 diabetic patients, regarding the subtypes of pancreatitis. saxagliptin (0.02%) and six receiving pla- particularly regarding incretin-based In the saxagliptin arm, more cases of cebo (0.07%) (HR 0.33 [95% CI 0.05–1.44], therapy. To increase sensitivity for definite acute pancreatitis were found Fisher exact test P = 0.18)] (Sup- milder cases of pancreatitis, we used (17 vs. 9, HR 1.88 [95% CI 0.86–4.41]) plementary Fig. 1D). Pancreatic cancer both the definite and the possible defi- and fewer cases of possible (5 vs. 7, HR was reported in 5 patients in the nition. However, because amylase and 0.85 [95% CI 0.27–2.56]) and chronic (2 saxagliptinarmand12intheplacebo lipase levels were not routinely exam- vs.6,HR0.33[95%CI0.05–1.44]) pan- arm (HR 0.42 [95% CI 0.13–1.12], Fisher ined throughout the trial, and clinical creatitis. None of these differences exact test P = 0.09), including 1 patient visits were performed every 6 months reached statistical significance, how- with a neuroendocrine tumor in the pla- (with a telephone call visit every 3 ever. The meaning of statistical non- cebo arm. months in between), subclinical pancre- significance with such a small number atitis might have been missed. Post hoc of cases is limited. In addition, the nu- CONCLUSIONS analysis of studies that examined the merical imbalance in the cases of defi- The frequency of pancreatitis cases pre- levels of lipase and amylase in over- nite acute pancreatitis that were also viously reported in epidemiological weight/obese patients versus type 2 di- observed in the EXAMINE (Examination studies of diabetic patients aged .40 abetic patients found a higher incidence of Cardiovascular Outcomes: Alogliptin years versus the general population of increased enzyme levels and higher vs. Standard of Care in Patients with was 54.0 vs. 30.1 per 100,000 person- variability within the same patient, Type 2 Diabetes Mellitus and Acute Cor- years, respectively (adjusted rate ratio among type 2 diabetic patients (21). onary Syndrome) trial (12 [0.4%] vs. 8 1.77 [95% CI 1.46–2.15]) (7). These num- The use of DPP-4 inhibitors might lead [0.3%] unadjudicated cases of pancrea- bers, however, are imprecise because of to a further increase and fluctuation in titis in the alogliptin vs. placebo arm, investigators’ reliance on epidemiologi- levels of amylase and lipase in asymp- respectively) (9) should not be dis- cal data rather than on prospective clin- tomatic patients (22). The clinical im- missed without further investigation. ical studies. The SAVOR-TIMI 53 trial is pact, however, of a diabetes-related as A possible slight increase in the risk the first prospective study in which pan- well as a drug-induced increase in amy- for pancreatitis should be balanced creatitis was predefinedasanEOSI. lase and lipase levels and their relation with the favorable course and outcome We systematically collected informa- to subclinical pancreatitis are unclear. of the rare pancreatitis cases. Both tion regarding all pancreatitis events, The predefined end point of all cases study arms had similar clinical outcomes using a similar process to that for the of pancreatitis was similarly distributed as expressed by the length of hospitali- CVendpoints,andusedanindepen- between treatment arms (26 vs. 25 in zation and similar high rates of recovery dent, blinded adjudication committee the saxagliptin vs. placebo arms, respec- regardless of continuation or discon- to ensure the quality of these adju- tively; HR 1.03 [95% CI 0.93–1.15]). tinuation of study drug, and no fatali- dicated end points. This rigorous pro- However, there were numerical differ- tiesoccurredinthesaxagliptinarm. cess provides important data regarding ences between the treatment arms The investigators’ perception of most 2440 SAVOR-TIMI 53dPancreatitis/Pancreatic Cancer Diabetes Care Volume 37, September 2014

pancreatitis events as mild might ex- saxagliptin arm and 12 (including 1 and Andromeda Biotech Ltd.; and speaker’s plain the high continuation rate of study with neuroendocrine tumor) in the pla- bureau for Novo Nordisk, AstraZeneca/BMS, fi drug in both the saxagliptin (61.5%) cebo arm (Fisher exact test P = 0.09). Sano ,MSD,EliLilly,andNovartis.D.L.B. discloses the following relationships: advisory and the placebo (52%) arms. Finally, Although a reduction in pancreatic can- board for Elsevier PracticeUpdate Cardiology, the low rate of recurrent events (two cer risk has been suggested for antidia- Medscape Cardiology, and Regado Biosciences; in the saxagliptin arm and three in the betic drugs like metformin (32,33), board of directors for Boston VA Research In- placebo arm), regardless of continua- such a protective effect is not assumed stitute and Society of Cardiovascular Patient tion or discontinuation of study drug, for saxagliptin. However, concerns about Care; chair of the American Heart Association Get With The Guidelines Steering Committee; is also reassuring. an increased pancreatic cancer or neuro- data monitoring committees for Duke Clinical Patients with type 2 diabetes have an endocrine tumor risk, as proposed by Research Institute, Harvard In- increased risk of developing acute pan- others in patients under relatively short stitute, Mayo Clinic, and Population Health Re- creatitis, chronic pancreatitis, and pan- exposure to DPP-4 inhibitors (2), could search Institute; honoraria from the American creatic cancer (1,23) compared with the not be confirmed in the current study. It College of Cardiology (editor, CardioSource clin- ical trial summaries), Belvoir Publications (edi- general population and even more so should be noted that the median follow- tor in chief, Harvard Heart Letter), Duke Clinical when known confounders, such as obe- up period in the SAVOR-TIMI 53 trial Research Institute (clinical trial steering com- sity (24) and CV disease (25), exist. was 2.1 years. Larger studies with longer mittees), Harvard Clinical Research Institute Moreover, medications often used to follow-up periods are needed to confirm (clinical trial steering committee), HMP Com- treat diabetes comorbidities have been the findings. munications (editor in chief, Journal of Invasive Cardiology), Population Health Research Insti- shown in population-based case-control The SAVOR-TIMI 53 trial did not com- tute (clinical trial steering committee), Slack studies to increase the risk of develop- pletely resolve the issue of whether Publications (chief medical editor, Cardiology To- ing pancreatitis, including statins (odds DPP-4 inhibitors are associated with a day’s Intervention), WebMD (continuing medical ratio [OR] 1.44), ACE inhibitors (OR 1.5), slight increase in the risk of pancreatitis education steering committees); other editorial ac- tivities for Clinical Cardiology (associate editor) and antidepressants (OR 2.8), and nonste- (mainly milder cases). The possible risk the Journal of the American College of Cardiology roidal anti-inflammatory drugs (OR 2.7) should be properly judged in the context (section editor, pharmacology); research grant (26). Previously published retrospective of the favorable outcome of these cases funding from Amarin, AstraZeneca/BMS, Eisai, studies suggested that the relationship and the overall proven safety record of Ethicon, Medtronic, Roche, Sanofi,andThe between incretin-based therapy and this group of drugs. This question will be Medicines Company; and unfunded research for FlowCo, PLx Pharma, and Takeda. B.H. and pancreatitis was nonrandomized and further determined by the results of C.S. are employees of AstraZeneca. O.M. discloses therefore uncontrolled for baseline other ongoing DPP-4 inhibitors prospec- the following relationships: research grant sup- known and unknown risk factors for tive outcome trials (34,35). port through Hadassah University Hospital pancreatitis. Pancreatitis cases were The SAVOR-TIMI 53 data do not funded by Novo Nordisk; speaker’s bureau for not blindly adjudicated, which may support a pancreatic cancer signal. It is AstraZeneca/BMS, Novo Nordisk, Eli Lilly, Sanofi, Novartis, and MSD; advisory board for have led to a bias of overreporting unlikely, however, that the effect of AstraZeneca/BMS, Novo Nordisk, Eli Lilly, Sanofi, among the incretin-treated patients DPP-4 inhibitors on cancer risk and pro- and Novartis; and grants paid to her institution (4,5,27). The current study is the first gression, particularly at specificcancer as study physician by AstraZeneca/BMS. B.M.S. in our knowledge to prospectively adju- sites, will be fully addressed with ran- discloses the following relationships: research dicate pancreatitis, and therefore, it domized controlled clinical trials be- grant support through Brigham and Women’s Hospital from AstraZeneca/BMS, Daichi-Sankyo, provides a more precise estimate of cause of the follow-up time limitation. GlaxoSmithKline, Johnson & Johnson, Gilead, the actual rate. The combination of the ongoing large Eisai, Arena, and Merck; consulting fees from Whereas acute pancreatitis must be outcome studies with a well-balanced Gilead, Arena, Eisai, Lexicon, BMS, and St. Jude’s regarded as an incident condition that meta-analysis and continued large Medical; and editorial board for Elsevier occurred during the treatment period data-based surveys might further clarify (PracticeUpdate Cardiology). A.U.-E. and K.I. dis- close research grant support to the TIMI Study of the study, the same argument does this issue. Group from AstraZeneca. A.B. is the Hadassah not hold for chronic pancreatitis University Hospital Diabetes Unit Project Man- because of the difficulty in excluding un- ager for the SAVOR-TIMI 53 trial. N.I. is an em- diagnosed, preexisting chronic pancrea- ployee of BMS. M.M.L. discloses the following titis; therefore, a possible association Acknowledgments. SAVOR-TIMI 53 Executive relationships: advisory board for Eli Lilly, Roche, Committee: Eugene Braunwald (study chair), Solvay, Abbott, MSD, and AstraZeneca; consul- withtherespectivetreatmentarmis Deepak L. Bhatt (co-principal investigator), tant for British Biotech, Bioserve, Centogene, less stringent (28). Following cases of Itamar Raz (co-principal investigator), Jaime A. Metanomics, Takeda, AstraZeneca/BMS, chronic pancreatitis is important be- Davidson, Robert Frederich (nonvoting), Boaz Sanochemia, Alpinia, and Novartis; and speaker’s cause data suggest that patients with Hirshberg (nonvoting), Ph. Gabriel Steg. bureau for Menarini, Recordati, Falk, Nordmark, chronic pancreatitis are at increased Funding and Duality of Interest. AstraZeneca Solvay, Abbott, AbbVie, and Roche. No other and Bristol-Myers Squibb (BMS) funded the – potential conflicts of interest relevant to this risk of pancreatic cancer (29 31). In study. article were reported. the SAVOR-TIMI 53 trial, eight cases of The sponsors were involved in the study design Author Contributions. I.R. contributed to the chronic pancreatitis were confirmed by and data collection and analysis. They were study concept, design, and supervision; data adjudication (two in the saxagliptin given the opportunity to review the manuscript analysis and interpretation; and drafting of the arm and six in the placebo arm), and but not to change any aspect. manuscript. D.L.B., B.H., and B.M.S. contributed . I.R. discloses the following relationships: advi- to the study concept, design, and supervision; all but one were reported after 300 sory board for Novo Nordisk, AstraZeneca/BMS, data analysis and interpretation; and critical days of exposure. Pancreatic cancer Sanofi, Merck Sharp & Dohme (MSD), and Eli revision of the manuscript for important in- was reported in 5 patients in the Lilly; consultant for AstraZeneca/BMS, Insuline, tellectual content. O.M. contributed to the data care.diabetesjournals.org Raz and Associates 2441

analysis and interpretation, drafting of the therapy: methodological deficiencies. Diabetes asymptomatic subjects with type 2 diabetes. Di- manuscript, and critical revision of the manu- Obes Metab. In press abetes Metab Syndr Obes 2012;5:419–424 script for important intellectual content. A.U.-E. 10. Food and Drug Administration, Center for 22. Tokuyama H, Kawamura H, Fujimoto M, and K.I. contributed to the statistical analysis. Drug Evaluation and Research. Guidance for in- et al. A low-grade increase of serum pancreatic C.S. and N.I. contributed to the study supervi- dustry: diabetes mellitusdevaluating cardio- exocrine enzyme levels by dipeptidyl peptidase-4 sion, data analysis and interpretation, drafting vascular risk in new antidiabetic therapies to inhibitor in patients with type 2 diabetes. Di- of the manuscript, and critical revision of the treat type 2 diabetes [article online], 2008. Avail- abetes Res Clin Pract 2013;100:e66–e69 manuscript for important intellectual content. able from http://www.fda.gov/downloads/Drugs/ 23. Giovannucci E, Harlan DM, Archer MC, et al. A.B. contributed to the administrative, techni- GuidanceComplianceRegulatoryInformation/ Diabetes and cancer: a consensus report. Dia- cal, and material support; data acquisition, Guidances/ucm071627.pdf. Accessed 19 January betes Care 2010;33:1674–1685 analysis, and interpretation; and critical revision 2011 24. Mart´ınez J, Johnson CD, Sanchez-Pay´ aJ,de´ of the manuscript for important intellectual 11. Hirshberg B, Raz I. Impact of the U.S. Food Madaria E, Robles-D´ıaz G, Perez-Mateo´ M. content. N.G. contributed to the data acquisi- and Drug Administration cardiovascular assess- Obesity is a definitive risk factor of severity tion, analysis, and interpretation. M.M.L. con- ment requirements on the development of tributed to the data acquisition, analysis, and novel antidiabetes drugs. 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