1052-P: Investigation of the Extrapancreatic Effects of the DPP-4 Inhibitor Sitagliptin: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial in Totally Pancreatectomized Patients

Abstract

Dipeptidyl peptidase 4 (DPP-4) inhibitors increase circulating concentrations of the insulinotropic and glucagon-modulating gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). The multiorgan distribution of GIP and GLP-1 receptors suggests pleiotropic extrapancreatic effects of these hormones (and thus DPP-4 inhibition), but these have been difficult to disentangle from their potent effects on the endocrine pancreas. Here, we investigated postprandial effects of the DPP-4 inhibitor sitagliptin in totally pancreatectomized (PX) patients as compared to matched healthy controls (CTRLs). In a randomized, double-blinded, placebo-controlled crossover study, 10 PX patients (age 65.7±6.4 [mean±SD] years; BMI 23.8±4.3 kg/m2) and 10 CTRLs (age 65±7.8 years; BMI 24.3±3.5 kg/m2) underwent a 3-hour liquid mixed meal test (MMT) after two doses of 150 mg sitagliptin (administered the night before and on the morning of the MMT) and placebo, respectively. Basal insulin was administered as usual; no bolus insulin was administered during study days. Blood samples were drawn throughout the experimental days. Sitagliptin did not affect fasting plasma glucose compared to placebo in CTRLs (5.4±0.2 vs. 5.5±0.1 mmol/l, P=0.6) nor in PX patients (7.7±1.0 vs. 7.9±0.9 mmol/l, P=0.88). Also, sitagliptin did not affect postprandial plasma glucose excursions as assessed by peak values, time to peak values or area under the curve in any of the groups. In conclusion, the DPP-4 inhibitor sitagliptin has no effect on fasting plasma glucose or postprandial plasma glucose excursions in PX patients; suggesting that no or little extrapancreatic effects of GIP and GLP-1 are involved in the glucose-lowering action of DPP-4 inhibition in patients with diabetes. Disclosure M. Baekdal: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S.W. Nielsen: None. C. Hansen: None. J.H. Storkholm: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.