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

Faillie J-L, Azoulay L, Patenaude V, Hillaire-Buys D, Suissa S. Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. BMJ. 2014;348:g2780. doi 10.1136/bmj.g2780.

No increased risk of acute pancreatitis was seen with the incretin-based therapies, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, compared with sulfonylureas in a population-based cohort study of patients with type 2 diabetes.

Primary analysis
Results for the main analysis, which explored hazard ratios and 95% CI for acute pancreatitis among subjects who used incretin-based therapies vs sulfonylureas:

  • Of 153,983 total users of antidiabetic therapies after 2007, 20,748 were using incretin-based therapies and 51,712 were using sulfonylureas.
  • Mean treatment time was 1.4 years, which equated to 99,497 person-years of follow-up.
  • A total of 146 cases of acute pancreatitis were identified, an overall incidence rate of 1.47 per 1,000 person-years.
  • Among patients who received incretin-based therapies (N=20,748), there were 27 events over 18,682 person years. The acute pancreatitis incidence rate was 1.45 (95% CI, 0.99–2.11).
  • There were 119 events over 80,815 person years in sulfonylurea-treated patients (N=51,712). The acute pancreatitis incidence rate was 1.47 (95% CI, 1.23–1.76) for sulfonylureas.
  • After adjustment*, there was no increased risk of acute pancreatitis seen with incretin-based therapies (HR, 1.00; 95% CI, 0.59–1.70 for incretin-based therapies; sulfonylurea HR 1.00 [reference]).
  • No significant difference in Kaplan-Meier curves, which compared the cumulative incidence of acute pancreatitis, was seen between groups (log rank P=0.36).

The authors noted that study findings for the upper bound of the confidence interval for the hazard ratio do not rule out a possible modest increase in acute pancreatitis risk with incretin-based therapies.

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Acute Pancreatitis Risk With Incretin-Based Therapies Vs Sulfonylureas in Patients With Type 2 Diabetes 
Acute Pancreatitis Risk With Incretin-Based Therapies
Vs Sulfonylureas in Patients With Type 2 Diabetes 

Secondary analyses
Duration of use

Results for secondary analyses showed that there was no difference in acute pancreatitis risk based on duration of use of incretin-based therapies vs sulfonylureas.
Duration of use: incidence rate per 1,000 person-years; Adjusted HR (95% CI)*  

  • 0-1 years
    • Incretin-based therapies (N=20,748): 1.76 (1.15–2.69); 1.08 (0.57–2.03)
    • Sulfonylureas (N=51,712): 2.08 (1.66–2.62); 1.00 (reference)
     
  • 1-2 years
    • Incretin-based therapies (N=6,814): 0.89 (0.33–2.36); 1.06 (0.31–3.60)
    • Sulfonylureas (N=24,412): 1.27 (0.85–1.90); 1.00 (reference)
     
  • >2 years
    • Incretin-based therapies (N=2,824): 0.92 (0.23–3.66); 0.51 (0.09–2.86)
    • Sulfonylureas (N=14,659): 0.80 (0.52–1.22); 1.00 (reference)
     

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Acute Pancreatitis Risk With Incretin-Based Therapies Vs Sulfonylureas in Patients With Type 2 Diabetes By Duration of Use 
Acute Pancreatitis Risk With Incretin-Based Therapies
Vs Sulfonylureas in Patients With Type 2 Diabetes 
By Duration of Use
 

Gender
Secondary analyses showed a nonsignificant increase in the hazard ratio for acute pancreatitis in men vs women.
Men vs women: incidence rate per 1,000 person-years; Adjusted HR (95% CI)*  

  • Men
    • Incretin-based therapies (N=11,897): 1.99 (1.31–3.02); 1.41 (0.75–2.63)
    • Sulfonylureas (N=30,091): 1.61 (1.28–2.01); 1.00 (reference)
     
  • Women
    • Incretin-based therapies (N=8,851): 0.66 (0.27–1.57); 0.45 (0.15–1.31)
    • Sulfonylureas (N=21,621): 1.28 (0.95–1.73); 1.00 reference

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Acute Pancreatitis Risk With Incretin-Based Therapies Vs Sulfonylureas in Patients With Type 2 Diabetes By Gender    
Acute Pancreatitis Risk With Incretin-Based Therapies
Vs Sulfonylureas in Patients With Type 2 Diabetes 
By Gender
 

About this study
This population-based cohort study compared risk of acute pancreatitis with the incretin-based therapies, GLP-1 receptor agonists and DPP-4 inhibitors, versus sulfonylureas in patients with type 2 diabetes. Data were culled from a base cohort of subjects aged ≥18 years with type 2 diabetes newly treated with noninsulin antihyperglycemic therapy from the UK Clinical Practice Research Datalink and the hospital episodes statistics database. Patients who received an incretin as monotherapy or in combination with other agents (GLP-1 receptor agonists exenatide and liraglutide, and DPP-4 inhibitors linagliptin, sitagliptin, saxagliptin, and vildagliptin; N=20,748) were compared with patients who received sulfonylureas as monotherapy or in combination with other agents (N=51,712). Patients with history of pancreatic cancer or pancreatic disorders, as well as those with cystic fibrosis, lupus, polycystic ovarian syndrome, and bariatric surgery were excluded.

Starting from 2007, subjects were followed until first occurrence of: acute pancreatitis, death from any cause, end of registration with their general practice, or end of the study period (March 2013). The main analysis explored hazard ratios and 95% CI for acute pancreatitis among incretin users. Two secondary analyses examined whether pancreatitis risk varied with duration of therapy or between men and women. The analyses were based on “as treated” exposure: subjects were considered continually exposed if the duration of one prescription overlapped with the prescribing of the next prescription. A 30-day grace period was allowed between two successive prescriptions; termination of treatment was whichever came first: lack of a new prescription by the end of the grace period or switch to insulin therapy. 

Incretin users were younger, had higher A1C and longer duration of antihyperglycemic treatment, were more likely to be obese, and were more likely to have used antihyperglycemic therapy in the year prior to study analysis compared to those who received sulfonylureas. Fewer patients received incretin-based therapies as monotherapy (13.5%) compared with sulfonylurea (28.7%); 76% of subjects received incretin-based therapy in combination with metformin vs 67% who received sulfonylurea plus metformin. 


Click on slide thumbnail to view larger. Slide available for download in the slide library.
Acute Pancreatitis Risk With Incretin-Based Therapies Vs Sulfonylureas in Type 2 Diabetes: Design   
Acute Pancreatitis Risk With Incretin-Based Therapies
Vs Sulfonylureas in Type 2 Diabetes: Design 
 

*Adjusted for tenths of high dimensional propensity score and year of cohort entry
Not FDA approved for use in the United States

Related content: 

Conference coverage from EASD 2013: No Pancreatic Risk in DPP-4 Cardiovascular Safety Studies (Login required)

  

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. 

May 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: 8/4/2014