Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the DPP-4 inhibitor saxagliptin

Raz I, Bhatt DL, Hirshberg B, et al. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl-peptidase-4 (DPP-4) inhibitor saxagliptin. Diabetes Care. 2014. DOI:10.2337/dc13-2546.

Results from SAVOR-TIMI 531, which examined the cardiovascular efficacy and safety of saxagliptin vs placebo in patients with or at risk for cardiovascular disease, showed similar rates of pancreatitis in the saxagliptin and placebo groups and no excess of pancreatic cancer with saxagliptin. The current SAVOR-TIMI 53 analysis determined incidence of pancreatitis and pancreatic cancer.

Pancreatitis

Adjudication-confirmed pancreatitis for saxagliptin vs placebo, respectively:

  • Any pancreatitis event: 0.29% (n=24; 26 events) vs 0.26% (n=21; 25 events); HR, 1.13 (95% CI, 0.63-2.06); P=0.77
  • Definite acute pancreatitis events: 0.2% (n=17) vs 0.1% (n=9); HR, 1.88 (95% CI, 0.86-4.41); P=0.17
  • Definite or possible acute pancreatitis: 0.3% (n=22) vs 0.2% (n=16); HR, 1.36 (95% CI, 0.72-2.64); P=0.42
  • Chronic pancreatitis events: 0.02% (n=2) vs 0.07% (n=6); HR, 0.33 (95% CI, 0.05-1.44); P=0.18 

Investigator-reported pancreatitis was as follows: 35 events in 33 (0.40%) saxagliptin-treated patients (n=8,280) and 35 events in 30 (0.37%) placebo-treated patients (n=8,212); HR, 1.09 (95% CI, 0.66-1.79); P=0.80.  


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Adjucated Pancreatitis With Saxagliptin Vs Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53   
Adjucated Pancreatitis With Saxagliptin Vs Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53 


With regard to pancreatitis risk factors and causality:

  • Pancreatitis risk factors and risk factors in general were similar between groups
  • Preexisting pancreatitis risk factors in patients with acute pancreatitis: 81.8% (n=18) of saxagliptin-treated patients; 93.8% (n=15) of placebo-treated patients
  • No between-group differences in time to pancreatitis symptom onset*
  • Similar investigator assessment of (saxagliptin vs placebo, respectively)
    • Study medication causality for all pancreatitis cases (9 vs 9)
    • Frequency of medication discontinuation due to pancreatitis (6 vs 7)
     
  • Similar rates of adjudicated (saxagliptin vs placebo, respectively)
    • Severe pancreatitis (1 vs 1)
    • Death (0 vs 1)
     

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Pancreatitis Risk Factors Causality With Saxagliptin Vs Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53   
Pancreatitis Risk Factors Causality With Saxagliptin Vs Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53 


Pancreatic cancer
Data from SAVOR-TIMI 53 do not support a pancreatic cancer signal with saxagliptin. The investigator-reported number of patients with pancreatic cancer was 5 in the saxagliptin group (0.06%) vs 12 in the placebo group (0.15%) (HR, 0.42 [95% CI, 0.13-1.12]; P=0.09). 


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Data Do Not Support Pancreatic Cancer Signal With Saxagliptin in Patients With or At Risk for CVD in SAVOR-TIMI 53   
Data Do Not Support Pancreatic Cancer Signal With Saxagliptin in Patients With or At Risk for CVD in SAVOR-TIMI 53 

About this study
Pancreatitis history was not a contraindication for trial participation. Reported pancreatitis cases were classified as definite acute pancreatitis, possible acute pancreatitis, chronic pancreatitis, or unlikely to be pancreatitis. Outcome measures were the total number of adjudicated pancreatitis cases and reported pancreatic cancer cases. SAVOR-TIMI 53 study design1:

  • Double-blind, placebo-controlled trial
  • Examined CV safety, efficacy of DPP-4 inhibitor, saxagliptin
  • Subjects (N=16,492): type 2 diabetes, A1C 6.5% to 12%, and established CVD history or multiple CVD risk factors (≥1 of the following: dyslipidemia, hypertension, current smoking)
  • Randomization 1:1 to saxagliptin (n=8,280) or matched placebo (n=8,212)
  • Saxagliptin dose: 5 mg daily or 2.5 mg daily for patients with eGFR ≤50 ml/min; use of other CVD and antihyperglycemic therapies allowed
  • Primary endpoint: composite of CV death, nonfatal MI, or nonfatal ischemic stroke
  • Median follow-up: 2.1 years


Click on slide thumbnail to view larger. Slide available for download in the slide library.
Pancreatitis and Pancreatic Cancer With Saxagliptin or Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53   
Pancreatitis and Pancreatic Cancer With Saxagliptin or Placebo in Patients With or At Risk for CVD in SAVOR-TIMI 53 


*For all adjudicated definite or possible acute pancreatitis, definite acute pancreatitis, or chronic pancreatitis

P values are for Fisher exact test

Saxagliptin is not FDA approved for cardiovascular risk reduction.

SAVOR-TIMI 53=Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53
CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; MI=myocardial infarction

1. Scirica BM, Bhatt DL, Braunwald E, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
 

Related content:

Expert commentary: Silvio E. Inzucchi, MD on SAVOR-TIMI 53

Overview and slides:
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus

Overview and slides:
Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study

Conference coverage:
No Pancreatic Risk in DPP-4 Cardiovascular Safety Studies (login required)

Overview and slides:
Alogliptin after acute coronary syndrome in patients with type 2 diabetes  



 
  

Any pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

July 2014 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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Last Modified: 8/14/2014