title: The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight From the LIBRA Trial.
abstract: BACKGROUND
  In patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM. Design/Setting/Participants/Intervention: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks.
  
  
  METHODS
  The glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test.
  
  
  RESULTS
  As expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48-week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 ± 34.9 vs 65.4 ± 36.4 pg/mL · 2 hours, P = .04), 36 weeks (162.2 ± 27.9 vs 55.7 ± 30.4 pg/mL · 2 hours, P = .01), and 48 weeks (155.5 ± 26.5 vs 45.7 ± 27.0 pg/mL · 2 hours, P = .006).
  
  
  CONCLUSIONS
  In contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM.
authors.affiliation: Leadership Sinai Centre for Diabetes (C.K.K., B.Z., H.C., R.R.) and Lunenfeld-Tanenbaum Research Institute (B.Z., R.R.), Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Division of Endocrinology (C.K.K., B.Z., P.W.C., R.R.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; and Keenan Research Centre for Biomedical Science of St Michael's Hospital (P.W.C.), Toronto, Ontario M5B 1W8, Canada.
authors.forename: Caroline K
authors.initials: CK
authors.lastname: Kramer
authors.affiliation: Leadership Sinai Centre for Diabetes (C.K.K., B.Z., H.C., R.R.) and Lunenfeld-Tanenbaum Research Institute (B.Z., R.R.), Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Division of Endocrinology (C.K.K., B.Z., P.W.C., R.R.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; and Keenan Research Centre for Biomedical Science of St Michael's Hospital (P.W.C.), Toronto, Ontario M5B 1W8, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.affiliation: Leadership Sinai Centre for Diabetes (C.K.K., B.Z., H.C., R.R.) and Lunenfeld-Tanenbaum Research Institute (B.Z., R.R.), Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Division of Endocrinology (C.K.K., B.Z., P.W.C., R.R.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; and Keenan Research Centre for Biomedical Science of St Michael's Hospital (P.W.C.), Toronto, Ontario M5B 1W8, Canada.
authors.forename: Haysook
authors.initials: H
authors.lastname: Choi
authors.affiliation: Leadership Sinai Centre for Diabetes (C.K.K., B.Z., H.C., R.R.) and Lunenfeld-Tanenbaum Research Institute (B.Z., R.R.), Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Division of Endocrinology (C.K.K., B.Z., P.W.C., R.R.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; and Keenan Research Centre for Biomedical Science of St Michael's Hospital (P.W.C.), Toronto, Ontario M5B 1W8, Canada.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Connelly
authors.affiliation: Leadership Sinai Centre for Diabetes (C.K.K., B.Z., H.C., R.R.) and Lunenfeld-Tanenbaum Research Institute (B.Z., R.R.), Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada; Division of Endocrinology (C.K.K., B.Z., P.W.C., R.R.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; and Keenan Research Centre for Biomedical Science of St Michael's Hospital (P.W.C.), Toronto, Ontario M5B 1W8, Canada.
authors.forename: Ravi
authors.initials: R
authors.lastname: Retnakaran
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000097:blood*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D000069450:Liraglutide / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D005934:Glucagon