445 A Randomized Double-Blinded Placebo Controlled Trial of DPP-4 Inhibitor Therapy after Total Pancreatectomy with Islet Autotransplantation
Tuesday November 17, 2015 from 11:00 to 12:30
Plenary Room 1

Melena D Bellin, United States

Assistant Professor

Pediatric Endocrinology

University of Minnesota


A Randomized Double-Blinded Placebo Controlled Trial of DPP-4 Inhibitor Therapy after Total Pancreatectomy with Islet Autotransplantation

Melena Bellin1,2,3, Gregory J Beilman2, Ty B Dunn2, Timothy L Preutt2, Srinath Chinnakotla2, Joshua J Wilhelm3, Audrey Lane1, Peggy Ptacek1, K. Louise Berry2, Bernhard J Hering2,3, Antoinette Moran1.

1Pediatrics, University of Minnesota, Minneapolis, MN, United States; 2Sugery, University of Minnesota, Minneapolis, MN, United States; 3Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States

Total pancreatectomy with islet autotransplantation (TPIAT) relieves pain for patients with severe, intractable chronic pancreatitis, but under half have sustained insulin independence with euglycemia.  Barriers include substantial beta cell apoptosis after islet infusion. The incretin hormones, glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) have been proposed to reduce beta cell apoptosis and induce beta cell replication.  Dipeptidyl peptidase-4 (DPP-4) inhibitors slow metabolism of GLP-1 and GIP and thereby increase endogenous levels. Based on promising preclinical data, we postulated that post-operative treatment with a DPP-4 inhibitor (sitagliptin) would improve islet engraftment and thus improve long-term insulin independence.
From September 2010 to December 2013, 92 adults with chronic pancreatitis scheduled for TPIAT were screened for this single-center, randomized, blinded placebo-controlled trial of 1 year of sitagliptin therapy after TPIAT.  Of these, 83 met eligibility criteria; the other 9 were ineligible (islet mass <1,000 IEQ/kg or new diabetes mellitus diagnosed at screening).  Patients were randomized in a 2:1 ratio to either 100 mg sitagliptin daily (n=54) or placebo (n=29) from the day of TPIAT through 1 year post-TPIAT.  Patients were seen at baseline, 1 year, and 18 months after TPIAT to assess insulin independence and insulin dose and perform mixed meal tolerance testing (MMTT) and frequent sample intravenous glucose tolerance testing (FSIVGTT).  The 1 year visit was done while participants were on sitagliptin/placebo;   the 18 month visit followed a 6 month washout.  The primary endpoint of insulin independence was defined as no insulin for >2 weeks with HbA1c <6.5% and fasting plasma glucose <126 mg/dL.   Four patients were lost or withdrawn from the study at 1 year, and 6 at 18 months.
Sitagliptin and placebo groups did not differ in age, sex, BMI, or islet mass transplanted.  The proportion of patients insulin independent did not differ between sitagliptin and placebo at 1 year (42% vs 45% respectively, p=0.82) or at 18 months (36% vs 44%, p=0.48).  Average insulin dose (standard error) at 1 year was 9.0 (1.7) unit/day in the sitagliptin group and 7.9 (2.2) unit/day in the placebo group (p=0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) respectively (p=0.32).  Adjusting for age, sex, islet mass (IEq/kg), and BMI did not alter the results.  Average (SE) HbA1c was 6.2 (0.1) at 1 year and 6.4 (0.2) at 18 months in the sitagliptin group, and 6.1 (0.2) and 6.3 (0.3) respectively in the placebo group (p=0.62, p=0.77 respectively).  Peak C-peptide from MMTT, area under the curve (AUC) C-peptide from MMTT, and acute C-peptide response to glucose from FSIVGTT did not differ between groups at either follow up time (Table).  Fewer patients in the sitagliptin group experienced any severe adverse event (SAE, p=0.01), but considering per-person counts of SAEs, the SAE rate did not differ between groups (p=0.31).  Few AEs or SAEs were deemed related to the study treatment.
Sitagliptin could be safely administered but did not improve metabolic outcomes after autologous islet transplant.  These results do not support the addition of sitagliptin to the post-operative management of TPIAT recipients.  


[1] Kim SJ, Nian C, Doudet DJ, McIntosh CH. 2008; Diabetes 57:1331-1339.

© 2018 Melbourne2015