Pancreatic Safety of Sitagliptin inthe TECOS StudyDiabetes Care 2017;40:164–170 | DOI: 10.2337/dc15-2780

OBJECTIVE

Weevaluated the incidence of acute pancreatitis and pancreatic cancer in patientswith type 2 diabetes and cardiovascular disease who were treated withsitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).

RESEARCH DESIGN AND METHODS

In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, acardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitisand pancreatic cancer were collected prospectively for 14,671 participantsduring a median follow-up time of 3 years, and were adjudicated blindly.

RESULTS

Baseline differences were minimal between participants confirmed to have nopancreatic events, acute pancreatitis, or pancreatic cancer. Among those partic-ipants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receiveplacebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96–3.88], P = 0.065;0.107 vs. 0.056/100 patient-years), with 25 versus 17 events, respectively. Severepancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin.Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%])versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28–1.51], P = 0.32; 0.042vs. 0.066 events/100 patient-years). Meta-analysis with two other DPP-4i cardio-vascular outcome studies showed an increased risk for acute pancreatitis (riskratio 1.78 [95% CI 1.13–2.81], P = 0.01) and no significant effect for pancreaticcancer (risk ratio 0.54 [95% CI 0.28–1.04], P = 0.07).

CONCLUSIONS

Pancreatitis and pancreatic cancer were uncommon events with rates that werenot statistically significantly different between the sitagliptin and placebo groups,although numerically more sitagliptin participants developed pancreatitis andfewer developed pancreatic cancer. Meta-analysis suggests a small absolute in-creased risk for pancreatitis with DPP-4i therapy.

Increased risks of pancreatitis and pancreatic carcinoma are linked to type 2 di-abetes, obesity, and insulin resistance in epidemiological studies and animal models(1). Dipeptidyl peptidase-4 inhibitors (DPP-4is) have become widely adopted aseffective and well-tolerated glucose-lowering agents since the introduction of sita-gliptin in 2006 (2). A potential association between DPP-4i treatment and pancre-atitis and pancreatic cancer was suggested in 2009, based on studies in rats carryingthe human islet amyloid polypeptide transgene treated with sitagliptin, in whichincreased pancreatic ductal turnover, ductal metaplasia, and isolated pancreatitiswere observed (3). Although subsequent preclinical studies have not confirmed this

1University of North Carolina School of Medicine,Chapel Hill, NC2Diabetes Trials Unit, Oxford Centre for Diabetes,Endocrinology and Metabolism, University ofOxford, Oxford, U.K.3Duke Clinical Research Institute, Duke Univer-sity School of Medicine, Durham, NC4Pontificia Universidad Javeriana, Hospital Uni-versitario San Ignacio, Bogota, Colombia5Centre Region CINVEC, Vi~na del Mar, Chile6University Specialized Hospital for Active Treat-ment in Endocrinology,Medical University, Sofia,Bulgaria7E. Wolfson Medical Center, Holon, Israel8St. Michael’s Hospital, University of Toronto,Toronto, Ontario, Canada9The George Washington University BiostatisticsCenter, Rockville, MD10Merck & Co., Inc., Kenilworth, NJ11Toronto Centre for Liver Disease, Division ofGastroenterology, University of Toronto HealthNetwork, Toronto, Ontario, Canada

Corresponding author: John B. Buse, jbuse@med.unc.edu.

Received 22 December 2015 and accepted 28July 2016.

Clinical trial reg. no. NCT00790205, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-2780/-/DC1.

This article is featured in a podcast available athttp://www.diabetesjournals.org/content/diabetes-core-update-podcasts.

© 2017 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

See accompanying articles, pp. 161and 284.

John B. Buse,1 M. Angelyn Bethel,2

Jennifer B. Green,3 Susanna R. Stevens,3

Yuliya Lokhnygina,3 Pablo Aschner,4

Carlos Raffo Grado,5 Tsvetalina Tankova,6

Julio Wainstein,7 Robert Josse,8

John M. Lachin,9 Samuel S. Engel,10

Keyur Patel,11 Eric D. Peterson,3 and

Rury R. Holman,2 for the TECOS Study

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finding (4,5), this potential associationhas triggered intense interest and clinicalassessment. Pharmacovigilance efforts,epidemiological studies, andmeta-analysisof randomized control studies with DPP-4is have suggested a small increase in orno increased risk of pancreatitis (6) or pan-creatic cancer (7), but they all have meth-odological limitations.The Trial Evaluating Cardiovascular

Outcomes with Sitagliptin (TECOS) as-sessed the long-term cardiovascularsafety of adding sitagliptin to usualcare, compared with usual care alone,in patients with type 2 diabetes and es-tablished cardiovascular disease duringa 3-year median follow-up period (8).We describe the presentation, features,and incidence of pancreatitis and pan-creatic cancer cases confirmed in TECOS,and perform a meta-analysis of theseevents with two recently reported DPP-4icardiovascular safety trials, the SaxagliptinAssessment of Vascular Outcomes Re-corded inPatientswithDiabetesMellitusdThrombolysis in Myocardial Infarction(SAVOR-TIMI) 53 trial (9,10) and the Ex-amination of Cardiovascular Outcomeswith Alogliptin versus Standard of Care(EXAMINE) trial (11).

RESEARCH DESIGN AND METHODS

The TECOS study (Clinical trial reg. no.NCT00790205, clinicaltrials.gov) ratio-nale and design (12) as well as its pri-mary outcomes and safety measures(6) have been reported previously.Briefly, 14,735 participants from 38countries were enrolled in the study be-tween December 2008 and July 2012.Eligible participants were $50 yearsold with type 2 diabetes, cardiovasculardisease, and HbA1c values of 6.5–8.0%(48–64 mmol/mol), and on stable-dose

monotherapy or dual-combination ther-apy with metformin, pioglitazone, orsulfonylurea, or insulin with or withoutmetformin. Study subjects were ran-domized double-blind to sitagliptin orplacebo at dosing appropriate for theirestimated glomerular filtration rate.Patients with an estimated glomerularfiltration rate of ,30 mL/min/1.73 m2

were not eligible for enrollment. Pa-tients with a history of pancreatitiswere not excluded from the study.Treatment for type 2 diabetes and itscomorbidities was provided by usualcare providers based on local guidelines.The addition of any antihyperglycemicagents, other than a glucagon-like pep-tide 1 receptor agonist or an open-labelDPP-4i, was permitted, but rosiglitazoneuse was discouraged. The intent-to-treat(ITT) population comprised 14,671 partic-ipants with a median follow-up period of3.0 years (interquartile range 2.3–3.8,maximum 5.7). Overall, 95.1% of partici-pants allocated to receive sitagliptin and94.1% allocated to receive placebo com-pleted the study, with premature studymedication discontinuation occurring in26.1% and 27.5% of participants, respec-tively. Vital status was determined atstudy end for 97.5% of participants. Thestudy was managed and all data were ad-judicated and analyzed by academic part-ners (Duke Clinical Research Institute andthe University of Oxford Diabetes TrialsUnit).

Event Ascertainment andAdjudicationA Clinical Events Committee (CEC) adju-dicated all cases of pancreatitis and can-cer reported by investigators, recordedas adverse events, or identified in sourcedocumentation for other events. The

CEC was independent of both the spon-sor and the TECOS Executive Commit-tee, and remained blinded to studytreatment assignment. Information re-lated to pancreatitis events was collectedsystematically in the trial database, in-cluding relevant symptoms, laboratoryand imaging data, concomitant medica-tion usage, and the investigator’s sus-pected etiology of the event. Relevanthospital and clinic records as well as lab-oratory and imaging reports were also re-quested for CEC review. All such caseswere first reviewed by a gastroenterol-ogist and then forwarded to the CEC fora second phase of independent reviewand finalization of adjudication. To con-firm a diagnosis of acute pancreatitis,medical records or a clinical narrative pre-pared by the study sites had to documentsymptoms (abdominal pain or vomiting)and objective evidence of pancreatic in-flammationdeither elevated pancreaticenzymes (amylase or lipase more thanthree times the upper limit of normal forthe assay or in patients with chronic pan-creatitis, enzyme elevations more thantwo times the upper limit of normal) orevidence of pancreatitis documented byimaging (abdominal computed tomogra-phy, magnetic resonance imaging, or ultra-sound showingdiffuse and inhomogeneousgland enlargement) (see SupplementaryData). Confirmed cases were further char-acterized as either “severe,” if there wasevidence of organ failure (i.e., systolic bloodpressure ,90 mmHg, partial pressure ofoxygen in arterial blood,60mmHg, serumcreatinine level .2 mg/dL after rehydra-tion, or estimated gastrointestinal bloodloss of.500 mL in 24 h) or local complica-tions demonstrated on imaging (i.e.,pancreatic necrosis, abscess, or acutepseudocyst), or “mild” (8).

Table 1—Confirmed pancreatitis and pancreatic cancer events in the TECOS Study

Patients Events

Sitagliptin (n = 7,332) Placebo (n = 7,339) HR (95% CI) P Sitagliptin Placebo

ITT analysisAcute pancreatitis 23 (0.107) 12 (0.056) 1.93 (0.96–3.88) 0.065 25 (0.113) 17 (0.077)Severe 4 0 4 0Mild 19 11 21 16Unknown 0 1 0 1

Pancreatic cancer 9 (0.042) 14 (0.066) 0.66 (0.28–1.51) 0.32

Per-protocol analysisAcute pancreatitis 20 (0.104) 11 (0.058) 1.80 (0.86–3.76) 0.12 21 (0.109) 12 (0.063)Pancreatic cancer 9 (0.047) 10 (0.054) 0.91 (0.37–2.25) 0.85 . . . . . .

Data are n (events per 100 patient-years of follow-up) or n, except where indicated. Some patients had more than 1 event.

care.diabetesjournals.org Buse and Associates 165

Information related to malignant/neoplastic events was also collected sys-tematically in the trial database. Investi-gators reported classification (malignancyvs. benign neoplasm), primary site, type,stage, and extent, as well as the date ofonset and whether the malignancy/neoplasm was clinically evident priorto randomization. Relevant hospital andclinic records, and laboratory, imaging,and pathology reports were requestedfor CEC review. All such cases were firstreviewed by an oncologist and then for-warded to the CEC for a second phase ofreview and finalization of adjudication.Charter-defined malignancies includednewmalignancy or first recurrence duringthe study period of a previously diagnosedmalignancy. All confirmed charter-definedmalignancies were categorized by site ortype. Confirmed pancreatic cancers werealso subcategorized as pancreatic endo-crine or exocrine tumors, or as uncertaintypes of pancreatic malignancy. No pa-tient had both pancreatitis and pancreaticcancer confirmed during the study.

Statistical AnalysisDescriptive statistics from the adjudica-tion process are presented to provide asense of the nature of these events inthe TECOS study. Definition of the per-protocol population is provided in thestudy protocol (8). Unless otherwisestated, continuous variables are sum-marized as the median (interquartilerange), and categorical variables are cat-egorized as number (percentage). Thebaseline characteristics of patients inwhom pancreatitis, pancreatic cancer,or neither were diagnosed were com-pared with Wilcoxon rank sum, x2, andFisher exact tests.The time-to-pancreatic-event analy-

ses used Cox proportional hazards re-gression models and are presented ashazard ratio (95% CI). Hazard ratiosand P values for treatment effect areprovided for both the ITT and per-protocol populations. The ITT popula-tion includes all events regardless oftreatment compliance. The per-protocolend points are those that occurredbefore a major protocol violation in pa-tients who took at least one dose ofstudy medication. Event rates areshown as the number and as eventsper 100 patient-years of follow-up.Kaplan-Meier rates over the first 3 yearsforpancreatic events areplotted separately

for the sitagliptin andplacebo groups in theITT population.

Meta-analyses were performed on datafromtheSAVOR-TIMI 53 trial, the EXAMINEtrial, and the TECOS study using random-effects models on summative data for pan-creatitis and pancreatic cancer outcomes.Heterogeneity among studieswas assessedusing the CochranQ test and I2 index. Oddsratios and 95% CIs are shown with forestplots. Comprehensive Meta Analysis ver-sion 2.0 software (Biostat, Inc., Englewood,NJ) was used for these analyses. Exceptwhere noted, data were analyzed usingSAS version 9.4.

RESULTS

The ITT population comprised 14,671 in-dividuals. Relevant baseline characteris-tics for the 14,613 participants whohad no reported pancreatic event,35 with confirmed pancreatitis, and23 with confirmed pancreatic cancerare presented in the SupplementaryAppendix (Supplementary Table 1).Differences in baseline characteristicsamong these participants were generallyminimal, but smoking history differed bycategory (P = 0.015). For those with pan-creatitis, pancreatic cancer, or no pancre-atic event, the proportions of participants

Figure 1—Cumulative proportion of participants with confirmed acute pancreatitis (A) andconfirmed pancreatic cancer (B) by treatment group as a function of time.

166 Pancreatic Safety of Sitagliptin in the TECOS Study Diabetes Care Volume 40, February 2017

who were current smokers were 23%,13%, and 11%, respectively. Participantswith pancreatic cancer were more likelyto have smoked previously (65%) thanthose with pancreatitis (31%) or no pan-creatic event (40%). Additionally, therewas a similar imbalance with respect toracial distribution, particularly a lowerrepresentation of pancreatic canceramong Asians and perhaps an increasein pancreatitis among blacks. The aver-age age of those with confirmed pancre-atic events was 66 years.Confirmed acute pancreatitis events

are shown in Table 1. The 7,332 partici-pants assigned to receive sitagliptin had21,508 patient-years of follow-up,whereas those assigned to receive placebohad 21,325 patient-years of follow-up.Among participants randomized to re-ceive sitagliptin, pancreatitis developed in23 participants (0.3% of the ITT popula-tion, 0.107/100 patient-years) comparedwith 12 participantswho received placebo(0.2% of the ITT population, 0.056/100patient-years; hazard ratio 1.93 [95% CI0.96–3.88], P = 0.065), with these par-ticipants having 25 and 17 events, respec-tively. Four participants in the sitagliptingroup experienced a severe pancreatitisevent (two fatal events), with no severeevents in the placebo group. One pancre-atitis event of unknown severity was re-ported for the placebo group, with allremaining cases adjudicated as “mild” inseverity.Figure 1A shows the cumulative pro-

portion of participants with acute pancre-atitis as a functionof time,with nonotabledifferences between groups in event ratesduring the first 9months. Through 3 yearsof follow-up, there appears to be a fairlylinear rate of cases for each treatmentassignment. The median times to the di-agnosis of acute pancreatitis were 1.42years (interquartile range 0.80–2.66years) and 1.44 years (interquartile range0.54–1.94 years), respectively, in the sita-gliptin and placebo groups.The characteristics of the confirmed

pancreatitis events for participants allo-cated to sitagliptin or placebo are listedin Table 2. The majority of case patientsin both groups had symptoms, elevatedpancreatic enzyme levels, and imagingevidence of pancreatitis. Investigatorsreported a suspected cause of pancrea-titis (alcohol, biliary disease, or a historyof pancreatitis) in 60.0% of events insitagliptin-treated participants compared

with 47.1% in placebo-treated partici-pants; biliary disease and/or a history ofpancreatitis were present in 11 of 23 pa-tients in the sitagliptin group (13 of25 events) comparedwith2 of 12patientsin the placebo group (7 of 17 events). Thenumber of patients without a suspectedcause was similar in the two treatmentgroups (10 and 9, respectively). Addi-tional characteristics for the four casepatients with severe pancreatitis in thesitagliptin group are also presented in Ta-ble 2. The characteristics of case patientswith suspected pancreatitis referred foradjudication but not confirmed are avail-able in the Supplementary Appendix(Supplementary Table 2).

Confirmed pancreatic cancer casesare shown in Table 1 for the ITT popula-tion with numerically fewer participantsin the sitagliptin group (N = 9, 0.1%,0.042 events/100 patient-years) com-pared with the placebo group (N = 14,0.2%, 0.066 events/100 patient-years)(hazard ratio 0.66 [95% CI 0.28–1.51],P = 0.32). Pancreatic cancer resulted indeath in seven of the sitagliptin case

patients and nine of the placebo casepatients. The median times to the diag-nosis of pancreatic cancer were 0.80years (interquartile range 0.48–2.36years) and 1.05 years (interquartilerange 0.59–1.27 years), respectively, inthe sitagliptin and placebo groups. Fig-ure 1B shows the cumulative proportionof participants with pancreatic canceras a function of time, with no notable dif-ferences among groups in event ratesduring the first 12 months.

The per-protocol analyses shown inTable 1 excluded relatively few con-firmed cases of pancreatitis or pancreaticcancer but tended to move the hazardratios toward unity for both of theseoutcomes.

Meta-analysis of the data from thethree cardiovascular outcome trialswith DPP-4i reported to date (Fig. 2)shows a statistically significant in-creased risk of acute pancreatitis forDPP-4i therapy (risk ratio 1.78 [95% CI1.13–2.81], P = 0.01) without evidenceof heterogeneity. Meta-analysis for pan-creatic cancer showed a nonsignificant

Table 2—Characteristics of pancreatitis events among sitagliptin- and placebo-treated participants in the TECOS study

CharacteristicSitagliptin(N = 25)

Placebo(N = 17)

SymptomsAbdominal pain 22 (88) 17 (100)Vomiting 11 (44) 5 (29)

Evidence of pancreatic inflammationElevated pancreatic enzymes 15 (60) 14 (82)Amylase or lipase .33 upper limit of normal 13 13In patients with chronic pancreatitis, amylase, or

lipase .23 upper limit of normal2 1

Documented by imaging 18 (72) 7 (41)

Investigator reported pancreatitis etiologyKnown or suspected etiology* 15 (60) 8 (47)Alcohol 2 0Biliary 9 3History of pancreatitis 6 6Other 1 1

Unknown† 10 (40) 9 (53)

Severity indicesSevere pancreatitis 4 (16) 0 (0)Evidence of organ failure‡ 1 0Local complications on imaging 4 0

Pancreatic necrosis 3 0Pancreatic abscess 2 0Pancreatic pseudocyst 1 0

Pancreatitis resulting in death§ 2 0

Data are n (%) or n. *Investigator reported. †Events where study drug was reported as a possiblecause are included in the category for unknown. ‡The patient with evidence of organ failurehad renal failure (serum creatinine .2 mg/dL after rehydration), pulmonary insufficiency(PAO2 ,60 mmHg), and shock (systolic blood pressure,90 mmHg). §The deaths resulting frompancreatitis occurred in one patient with a history of alcohol use and one with a known historyof chronic biliary pancreatitis.

care.diabetesjournals.org Buse and Associates 167

effect of DPP-4i (risk ratio 0.54 [95% CI0.28–1.04], P = 0.07) without evidenceof heterogeneity.

CONCLUSIONS

The TECOS study was a global, double-blind, placebo-controlled clinical trialof sitagliptin in individuals $50 years ofage with type 2 diabetes and establishedcardiovascular disease. The TECOS studydemonstrated, on a background of usualcare, that there was no difference be-tween treatment groups in the rates ofmajor cardiovascular events, heart fail-ure, or death from any cause. This studyexamined whether there was an associ-ation between the use of sitagliptin andpancreatic disease.The overall rate of confirmed acute

pancreatitis was low (0.095 events/100patient-years)with anumerically increased

but not statistically significant risk foracute pancreatitis with sitagliptin therapy(0.107/100 patient-years for sitagliptintreatment vs. 0.056/100 patient-years forplacebo treatment). The clinical presenta-tion of acute pancreatitis with regard tosymptoms and onset during the study pe-riod was similar in the two treatmentgroups. Recurrent episodes of pancreatitisoccurred in two participants treated withsitagliptin (both had one recurrence) andtwo participants treated with placebo(one with a single recurrence and onewith four recurrences). Cases of confirmedsevere acute pancreatitis were rare, butnumerically greater with sitagliptin treat-ment compared with placebo treatment(four vs. zero, including two fatal cases).For both fatal cases, an etiology otherthan study treatmentwas suspected. Pan-creatitis is often associated with multiple

risk factors, and it is unclear towhat extentsitagliptin contributed to the pancreatitisin each case. That said, the finding of otherpotential etiologies should not provide re-assurance that treatment with sitagliptinwas perhaps not a contributor, as the alter-native hypothesis would be that treatmentwith sitagliptin magnifies the penetranceof risk factors on pancreatitis develop-ment and severity.

The per-protocol analysis of individualswith recent or ongoing treatment withstudymedication provides a similar resultfor the ITT analysis with a modestlylower point estimate for risk and widerCI (hazard ratio 1.80 [95% CI 0.86–3.76],P=0.12).With the small numberof events,it is not possible to ascribe particular riskfactors for acute pancreatitis for the pop-ulation as a whole (see SupplementaryAppendix). Although a history of pancrea-titis was not a TECOS exclusion criterion,the risk of acute pancreatitis with sitaglip-tin exposure in those participants with ahistory of pancreatitis cannot be esti-mated as this information was not re-corded systematically at baseline.

Pancreatic cancer was also an uncom-mon event in the TECOS study (0.054events/100 patient-years). Numerically,there were fewer cases of pancreaticcancer with sitagliptin treatment thanwith placebo treatment, but the differ-ence was not statistically significant. Theper-protocol analysis for pancreatic can-cer essentially eliminates the discrep-ancy between arms. Although themedian 3-year follow-up period duringthe TECOS study is longer than in manyother diabetes outcome trials, it is insuf-ficient to permit a robust assessment ofthe long-term risk of pancreatic cancer.

SAVOR-TIMI 53 (9) and EXAMINE (11)are two recently reported, double-blind,placebo-controlled, cardiovascular safetytrials of DPP-4is that evaluated saxagliptinand alogliptin, respectively. These trialshave important differences with theTECOS study Both the SAVOR-TIMI53 and EXAMINE trials enrolled patientswith a wider range of HbA1c levels at di-agnosis and a shorter duration of studytreatment exposure. The SAVOR-TIMI53 trial used different criteria in the ad-judication of pancreatitis, whereas theEXAMINE trial did not adjudicate casesof pancreatitis and reported no cases ofpancreatic cancer. These factors precludehead-to-head comparisons of the ratesof pancreatitis and could impact on the

Figure 2—Meta-analysis of pancreatitis (A) and pancreatic cancer (B) in the SAVOR-TIMI 53 trial, theEXAMINE trial, and the TECOS study. It is noted that the SAVOR-TIMI 53 trial used different criteriathan the TECOS study for the adjudication of pancreatitis, and that in the EXAMINE trial pancreatitiswas not adjudicated and no pancreatic cancer cases were reported. *Ref. 9; †Ref. 11.

168 Pancreatic Safety of Sitagliptin in the TECOS Study Diabetes Care Volume 40, February 2017

meta-analysis presented here, whichmeans that these findings should there-fore be interpreted with caution.The primary goal of the Tecos study

was to examine the cardiovascularsafety of sitagliptin. The trial demon-strated unequivocal evidence for no in-creased risk of major cardiovascularevents, heart failure, or all-cause mor-tality. Sitagliptin was associated withgood tolerability and glycemic efficacy.These analyses of acute pancreatitisand pancreatic cancer from the TECOSstudy, and the meta-analysis with twoother large, well-conducted studies in-volving other members of the DPP-4iclass of drugs, provide prescribers andpatients greater precision around thequestion of pancreatic safety. Althoughconclusions are limited by the smallnumbers of events over a limited periodof follow-up, information collectedfrom these double-blind, randomized,placebo-controlled trials provide themost robust data available currently toquantify the risk of pancreatic out-comes associated with DPP-4i therapy.It may be that some cases of subclinicalpancreatitis could have been missed,but similar findings from the three trialssuggest that there is a small increasedrisk of acute pancreatitis with DPP-4itherapy. For sitagliptin, the magnitudeof excess risk based on the results of theTECOS study is estimated to be ;1 ad-ditional case/1,000 patient-years, al-though severe and fatal cases occurredin the sitagliptin group. If this differencehad been statistically significant, thenumber needed to harm would havebeen 1,974 to have 1 additional affectedindividual with pancreatitis. Pancreaticcancer, a condition that is almost uni-formly fatal, occurred in roughly half asmany participants as pancreatitis, and therisk did not appear to be increased withsitagliptin. Longer-term pharmacovigi-lance andpharmacoepidemiological stud-ies of DPP-4is will be required to providegreater insights into the pancreatic safetyof this drug class.

Acknowledgments. The authors thank theinvestigators, staff, and participants in theTECOS study, without whose efforts and collab-oration this work would not have been possible.The authors also thank the following academicpartners and contract research organizations fortheir assistance: Parexel International, JubilantClinsys, Clinogent, Canadian VIGOUR Centre,

Green Lane Coordinating Centre, and South Aus-tralian Health and Medical Research Institute.The authors thank Peter Hoffmann for excellenteditorial support. R.R.H. is aNational Institute forHealth Research Senior Investigator.Funding.This researchwas supportedbyMerckSharp & Dohme, a subsidiary of Merck & Co.,Inc. J.B.B. was supported by a grant from theNational Center for Advancing Translational Sci-ences, National Institutes of Health, throughgrant award number UL1TR001111.Duality of Interest. J.B.B. reports receivinggrants and fees for consultation to theUniversityof North Carolina (UNC) under contract, andtravel/meals/lodging for contracted activitiesfrom Merck during the conduct of the study;grants and fees for consultation to UNC undercontract, and travel/meals/lodging for con-tracted activities from Eli Lilly, GI Dynamics,Amylin, Orexigen, Merck, Novo Nordisk, vTvPharma, AstraZeneca, Takeda, Sanofi, and Lex-icon; fees for consultation to UNC under con-tract, and travel/meals/lodging for contractedactivities from Hoffmann-La Roche, Bristol-Myers Squibb, Liposcience, Elcylex, Metaven-tion, Dance Biopharm, and Quest; grants fromMedtronic Minimed, Tolerex, Osiris, Halozyme,Pfizer, Johnson&Johnson,Andromeda,Boehringer-Ingelheim, GlaxoSmithKline, Astellas, MacroGenics,Intarcia Therapeutics, and Scion NeuroStim;stock options in PhaseBio outside the submittedwork; and is or has been amember of a variety ofnonprofit boards, as follows: American DiabetesAssociation, DiabetesSisters, Taking Control ofYour Diabetes, AstraZeneca Healthcare Foun-dation, Bristol-Myers Squib Together on Diabe-tes Foundation, and the National DiabetesEducation Program.M.A.B. has received grants,personal fees, and other support from Merck,Sharp & Dohme; other support from Boehringer-Ingelheim, Novo Nordisk, and GlaxoSmithKline;and nonfinancial support from Bayer. J.B.G. hasreceived grants from Merck Sharp & Dohme,AstraZeneca, and GlaxoSmithKline; grants andpersonal fees fromMerck Sharp &Dohme;othersupport from Boehringer-Ingelheim; and personalfees from Bioscientifica and The Endocrine So-ciety. P.A. has received grants and personalfees from AstraZeneca, Boehringer-Ingelheim,Eli Lilly, GlaxoSmithKline, Janssen, Merck,Sharpe & Dohme, Novartis, and Sanofi. T.T.has received grants and personal fees fromMerck, Sharp & Dohme, Boehringer-Ingelheim,Novo Nordisk, Sanofi, Eli Lilly, Novartis, Servier,and AstraZeneca. R.J. has received grants orpersonal fees fromMerck, AstraZeneca, Janssen,and Eli Lilly. J.M.L. has received personal feesfrom Merck, Boehringer-Ingelheim, GileadPharmaceuticals, Janssen Pharmaceuticals, EliLilly, Novartis, and GlaxoSmithKline. S.S.E. isan employee of Merck Sharp & Dohme, a sub-sidiary of Merck & Co., Inc. E.D.P. has receivedgrants and personal fees from Janssen; grantsfrom Eli Lilly; and personal fees fromAstraZeneca,Bayer, and Sanofi. R.R.H. has received grantsand personal fees from Merck; grants fromBayer and AstraZeneca; personal fees fromAmgen, Bayer, Intarcia, Novartis, and NovoNordisk; and other support fromGlaxoSmithKline,Janssen, and Takeda. No other potential conflictsof interest relevant to this article were reported.

Author Contributions. J.B.B. contributed tothe study design, data analysis, and interpreta-tion; and drafted and edited the manuscript.M.A.B., P.A., C.R.G., T.T., J.W., R.J., J.M.L., S.S.E.,and E.D.P. contributed to the study design andedited the manuscript. J.B.G. contributed to thestudy design, event definition and adjudication,data collection, analysis, and interpretation; andedited themanuscript. S.R.S. and Y.L. performedthe statistical analyses and edited the manu-script. K.P. contributed to the study design, datainterpretation, and event adjudication; andedited the manuscript. R.R.H. edited the man-uscript, designed and ran the study, and con-tributed to the data analysis and interpretation.J.B.B. and R.R.H. are the guarantors of this workand, as such, had full access to all the data in thestudy and take responsibility for the integrity ofthe data and the accuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract form at the 75th ScientificSessions of the American Diabetes Association,Boston, MA, 5–9 June 2015; and the 51st EASDAnnual Meeting, Stockholm, Sweden, 14–18September 2015.

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