Impaired incretin secretion may contribute to insulin secretion defects in pancreatic insufficient cystic fibrosis (PI-CF). We hypothesized that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy would increase glucagon-like peptide-1 (GLP-1) and improve insulin secretion in glucose intolerant CF. We conducted a randomized, double blind, placebo-controlled trial in 24 subjects with PI-CF and abnormal glucose tolerance who received the DPP-4 inhibitor sitagliptin 100 mg (n = 12) or matched-placebo (n = 12) for 6 months. Randomization was stratified by oral glucose tolerance. Mixed-meal tolerance tests (MMTT) and glucose-potentiated arginine (GPA) tests were performed at baseline and after 6 months intervention. Incremental area-under-the-curves were calculated for GLP-1 (AUCGLP-1) post meal. Insulin secretory rates (ISR), derived by parametric deconvolution of C-peptide kinetics, were modeled using linear mixed effects models. Acute insulin and glucagon response to arginine were calculated under fasting, 230, and 340 mg/dL hyperglycemic clamp conditions. Subjects in the sitagliptin vs. placebo groups were similar in age (median 24 [range 18-43] vs. 28 [18-43] years), sex (5 females each), and BMI (24 [19-34] vs. 22 [17-24] kg/m2). HbA1c, similar at baseline (5.6 [4.8-6.1] vs. 5.7 [5.4-5.9] %), improved after 3 months of sitagliptin (-0.2 %, 95% CI -0.4- -0.2, P = 0.02). AUCGLP-1 was higher after sitagliptin vs. placebo (1400 pmol·min/L, 95% CI 750-2050, P < 0.001). ISR after sitagliptin showed a faster rise through 60 min post meal (9.1 µU·mL-1·min-1, 95% CI 4.4-13.9, P < 0.001) and returned to baseline faster vs. placebo (-12.0 µU·mL-1·min-1, 95% CI -16.9- -7.2, P < 0.001). Acute insulin responses did not differ between groups, but acute glucagon responses were lower after sitagliptin vs. placebo (P = 0.03). In glucose intolerant CF, six-month therapy with sitagliptin resulted in modest improvement in glycemic control and islet function.


S. Sheikh: None. A. Kelly: None. D. Stefanovski: None. A.J. Peleckis: None. S. Nyirjesy: None. J.N. Eiel: None. A. Sidhaye: None. D.D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc. D. Hadjiliadis: Other Relationship; Self; AstraZeneca. R.C. Rubenstein: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc.


National Institutes of Health (R01DK97830, K23DK107937, UL1TR001878, P30DK19525, T32 DK007314); Merck & Co., Inc. (MISP50512)

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