title: Liraglutide and the preservation of pancreatic β-cell function in early type 2 diabetes: the LIBRA trial.
abstract: OBJECTIVE
  Clinical studies evaluating the effects of medications on β-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of β-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve β-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT.
  
  
  METHODS
  In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration and an A1C of 6.8 ± 0.8% (51 ± 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks.
  
  
  RESULTS
  The primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 ± 27.8 vs. 229.3 ± 28.4, P = 0.008). Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group (6.2 ± 0.1% vs. 6.6 ± 0.1%, P = 0.055) (44 ± 1.1 vs. 49 ± 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 ± 24.7 vs. 238.1 ± 25.2, P = 0.20).
  
  
  CONCLUSIONS
  Liraglutide provides robust enhancement of β-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada rretnakaran@mtsinai.on.ca.
authors.forename: Ravi
authors.initials: R
authors.lastname: Retnakaran
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Caroline K
authors.initials: CK
authors.lastname: Kramer
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Haysook
authors.initials: H
authors.lastname: Choi
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Balakumar
authors.initials: B
authors.lastname: Swaminathan
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007003:Hypoglycemia / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1