title: Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers.
abstract: BACKGROUND
  Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst₁₋₃ and sst₅. Clinical trials have demonstrated the efficacy of pasireotide in treating Cushing's disease and acromegaly but have also shown adverse effects on glucose metabolism.
  
  
  OBJECTIVE
  The aim of the study was to evaluate the mechanism of pasireotide-associated hyperglycemia.
  
  
  METHODS
  We conducted a randomized, single-center, open-label study.
  
  
  METHODS
  Forty-five healthy male volunteers were randomized to pasireotide 600 (n = 19), 900 (n = 19), or 1200 μg (n = 7) sc twice a day for 7 days. Randomization to 1200 μg was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test, and a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end.
  
  
  METHODS
  The effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity was measured. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption.
  
  
  RESULTS
  Pasireotide treatment resulted in significant decreases in insulin AUC0-180 min during both the hyperglycemic clamp test (-77.5%; P < .001 in both dose groups) and the OGTT (-61.9%; P < .001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the hyperinsulinemic-euglycemic clamp test. Additionally, significant increases in glucose AUC₀₋₁₈₀ min (+67.4%) and decreases in AUC₀₋₁₈₀ min glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected adverse events were observed.
  
  
  CONCLUSIONS
  Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity.
authors.affiliation: Center for Metabolic Research, Veterans Affairs San Diego Healthcare System, San Diego, California 92161, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Debra
authors.initials: D
authors.lastname: Armstrong
authors.forename: Paivi
authors.initials: P
authors.lastname: Burke
authors.forename: Monica
authors.initials: M
authors.lastname: Ligueros-Saylan
authors.forename: Sunder
authors.initials: S
authors.lastname: Mudaliar
mesh_terms: D000293:Adolescent; D000328:Adult; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C517782:pasireotide; D005947:Glucose