title: Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  The combination of insulin and glucagon-like peptide-1 (GLP-1) receptor agonist therapy improves glycaemic control, induces weight loss, and reduces insulin dose needed in type 2 diabetes. We assessed the efficacy and safety of the GLP-1 receptor agonist liraglutide as an add-on therapy to insulin for overweight adult patients with type 1 diabetes.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled trial at Steno Diabetes Center (Gentofte, Denmark). Patients aged 18 years or older with type 1 diabetes, insufficient glycaemic control (HbA1c >8% [64 mmol/mol]), and overweight (BMI >25 kg/m(2)) were randomly assigned (1:1) to receive insulin treatment plus either liraglutide or placebo (saline solution) by subcutaneous injection once per day. Randomisation was done in blocks of four. Treatment assignment was masked to investigators and patients. Treatment lasted 24 weeks and liraglutide was started at a dose of 0·6 mg per day, escalated to 1·2 mg per day after 1 week, and then again to 1·8 mg per day after another week. Intervals between dose increments could be extended at the discretion of the investigator. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were changes in hypoglycaemic events, glycaemic variability, glycaemic excursions, insulin dose, bodyweight, postprandial plasma concentrations of glucagon and GLP-1, gastric emptying, blood pressure, heart rate, patient-reported outcome measures, time spent in hypoglycaemia, near-normoglycaemia, and hyperglycaemia, plasma fasting glucose, mean glucose, and cholesterol. Efficacy analyses were calculated by use of a mixed model, whereby a patient's data are used as long as the patient is in the study. The safety analyses were done in the intention-to-treat population, which consisted of all patients who received at least one dose of their randomly assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01612468.
  
  
  RESULTS
  Between July 10, 2012, and May 30, 2014, we enrolled 100 patients with type 1 diabetes, with 50 patients allocated liraglutide and 50 to placebo. Four patients from the liraglutide group and six patients from the placebo group discontinued treatment before 24 weeks. At the end of treatment, change in HbA1c from baseline did not differ between groups (-0·5%, 95% CI -0·8 to -0·4 [-6·0 mmol/mol, 95% CI -8·7 to -4·4] with liraglutide vs -0·3%, -0·6 to -0·2 [-4·0 mmol/mol, -6·6 to -2·3] with placebo; between-group difference -0·2% [-0·5 to 0·1; 2·2 mmol/mol, -5·5 to 1·1], p=0·1833). The number of hypoglycaemic events was reduced with liraglutide, with an incident rate ratio of 0·82 (95% CI 0·74 to 0·90). However, we detected no changes in glycaemic variability (continuous overall net glycaemic action per 60 min from 10·3 [95% CI 9·8 to 10·8] to 9·9 [9·2 to 10·6] in the liraglutide treated patients vs 10·2 [9·7 to 10·7] to 9·7 [9·1 to 10·3] in the placebo treated patients). Both bolus insulin (difference -5·8 IU, 95% CI -10·7 to -0·8, p=0·0227) and bodyweight (difference -6·8 kg, 95% CI -12·2 to -1·4, p=0·0145) decreased with liraglutide treatment compared with placebo. Heart rate increased with liraglutide, with a difference between groups of 7·5 bpm (95% CI 2·8-12·2, p=0·0019). Postprandial plasma glucagon and GLP-1 concentrations did not differ between groups (difference between groups at end of treatment: -408 mmol/L per 240 min [95% CI -941 to 125, p=0·1309] for glucagon and -266 mmol/L per 240 min [-1034 to 501, p=0·4899] for GLP-1). Gastric emptying was delayed after 3 weeks of treatment with liraglutide (19·9 min, 95% CI 0·8 to 39·0, p=0·0412), but we detected no difference after 24 weeks of treatment (-1·5 min, -20·5 to 17·6, p=0·8793). Patient-reported outcome measures differed between groups only with respect to perceived frequency of hypoglycaemia, which was higher with placebo, with a difference between groups of -0·6 (95% CI -1·1 to -0·07, p=0·0257). Liraglutide was associated with more frequent nausea (29 [58%] patients with liraglutide vs five [10%] with placebo), dyspepsia (11 [22%] patients with liraglutide vs one [2%] with placebo), diarrhoea (ten [20%] patients with liraglutide vs one [2%] with placebo), decreased appetite (seven patients [14%] with liraglutide vs none with placebo), and vomiting (seven [14%] patients with liraglutide vs one [2%] with placebo).
  
  
  CONCLUSIONS
  In patients with type 1 diabetes, overweight, and insufficient glycaemic control, the reduction in HbA1c did not differ between insulin plus placebo and insulin plus liraglutide treatment. Liraglutide was associated with reductions in hypoglycaemic events, bolus and total insulin dose, and bodyweight, and increased heart rate.
  
  
  BACKGROUND
  Novo Nordisk.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. Electronic address: tfde@steno.dk.
authors.forename: Thomas Fremming
authors.initials: TF
authors.lastname: Dejgaard
authors.affiliation: Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
authors.forename: Christian Seerup
authors.initials: CS
authors.lastname: Frandsen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Tanja Stenbæk
authors.initials: TS
authors.lastname: Hansen
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Almdal
authors.affiliation: Department of Endocrinology, Frederiksberg Hospital, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Urhammer
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology, University of Copenhagen, Hillerød, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Pedersen-Bjergaard
authors.affiliation: Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tonny
authors.initials: T
authors.lastname: Jensen
authors.affiliation: Department of Clinical Research, Nordsjællands Hospital Hillerød, University of Copenhagen, Hillerød, Denmark; Section of Biostatistics, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas Kryger
authors.initials: AK
authors.lastname: Jensen
authors.affiliation: The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Clinical Research, Nordsjællands Hospital Hillerød, University of Copenhagen, Hillerød, Denmark; Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Filip Krag
authors.initials: FK
authors.lastname: Knop
authors.affiliation: Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
authors.forename: Sten
authors.initials: S
authors.lastname: Madsbad
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Henrik Ullits
authors.initials: HU
authors.lastname: Andersen
mesh_terms: D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D000069450:Liraglutide / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000150:complications*; D016896:Treatment Outcome; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists