title: Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin.
abstract: OBJECTIVE
  To determine the incidence of pancreatitis and pancreatic cancer in the SAVOR-TIMI 53 trial.
  
  
  METHODS
  A total of 16,492 type 2 diabetic patients ≥40 years old with established cardiovascular (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.
  
  
  RESULTS
  Trial investigators reported 35 events of pancreatitis in each treatment arm in 63 patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in control arm), with a hazard ratio (HR) of 1.09 (95% CI 0.66-1.79, P = 0.80). Adjudication confirmed pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and 21 patients (25 events) in placebo arm (0.26%), with an HR of 1.13 (0.63-2.06, P = 0.77). Cases of definite acute pancreatitis were confirmed in 17 (0.2%) vs. 9 (0.1%) (HR 1.88 [0.86-4.41], P = 0.17), definite plus possible pancreatitis in 22 vs. 16 (HR 1.36 [0.72-2.64], P = 0.42), and chronic pancreatitis in 2 vs. 6 (HR 0.33 [0.05-1.44], P = 0.18) in the saxagliptin and placebo arms, respectively. No differences in time to event onset, concomitant risk factors for pancreatitis, investigator-reported causality from study medication or disease severity, and outcome were found between treatment arms. The investigators reported 5 and 12 cases of pancreatic cancer in the saxagliptin and placebo arms, respectively (HR 0.42 [0.13-1.12], P = 0.09).
  
  
  CONCLUSIONS
  In the SAVOR-TIMI 53 trial, within 2.1 years of follow-up, risk for pancreatitis in type 2 diabetic patients treated with saxagliptin was low and apparently similar to placebo, with no sign of increased risk for pancreatic cancer. Further studies are needed to completely resolve the pancreatic safety issues with incretin-based therapy.
authors.affiliation: Diabetes Unit, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel ntv502@netvision.net.il.
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: AstraZeneca Research and Development, Wilmington, DE.
authors.forename: Boaz
authors.initials: B
authors.lastname: Hirshberg
authors.affiliation: Diabetes Unit, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Ofri
authors.initials: O
authors.lastname: Mosenzon
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Amarachi
authors.initials: A
authors.lastname: Umez-Eronini
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: KyungAh
authors.initials: K
authors.lastname: Im
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Stahre
authors.affiliation: Diabetes Unit, Department of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Buskila
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Nayyar
authors.initials: N
authors.lastname: Iqbal
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Norton
authors.initials: N
authors.lastname: Greenberger
authors.affiliation: University Medicine Greifswald, Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004151:Dipeptides / Q000009:adverse effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D010195:Pancreatitis / Q000139:chemically induced / Q000453:epidemiology*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane