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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 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.
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Journal Title the lancet. diabetes & endocrinology
Publication Year Start




PMID- 26656289
OWN - NLM
STAT- In-Process
DA  - 20160227
LR  - 20160227
IS  - 2213-8595 (Electronic)
IS  - 2213-8587 (Linking)
VI  - 4
IP  - 3
DP  - 2016 Mar
TI  - 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.
PG  - 221-32
LID - 10.1016/S2213-8587(15)00436-2 [doi]
LID - S2213-8587(15)00436-2 [pii]
AB  - 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. FINDINGS: 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).
      INTERPRETATION: 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. FUNDING: Novo Nordisk.
CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
FAU - Dejgaard, Thomas Fremming
AU  - Dejgaard TF
AD  - Steno Diabetes Center, Gentofte, Denmark; Department of Endocrinology, Hvidovre
      Hospital, University of Copenhagen, Hvidovre, Denmark. Electronic address:
      [email protected]
FAU - Frandsen, Christian Seerup
AU  - Frandsen CS
AD  - Department of Endocrinology, Hvidovre Hospital, University of Copenhagen,
      Hvidovre, Denmark.
FAU - Hansen, Tanja Stenbaek
AU  - Hansen TS
AD  - Steno Diabetes Center, Gentofte, Denmark.
FAU - Almdal, Thomas
AU  - Almdal T
AD  - Center for Diabetes Research, Gentofte Hospital, University of Copenhagen,
      Hellerup, Denmark.
FAU - Urhammer, Soren
AU  - Urhammer S
AD  - Department of Endocrinology, Frederiksberg Hospital, University of Copenhagen,
      Frederiksberg, Denmark.
FAU - Pedersen-Bjergaard, Ulrik
AU  - Pedersen-Bjergaard U
AD  - Department of Cardiology, Nephrology and Endocrinology, University of Copenhagen,
      Hillerod, Denmark.
FAU - Jensen, Tonny
AU  - Jensen T
AD  - Department of Endocrinology, Rigshospitalet, University of Copenhagen,
      Copenhagen, Denmark.
FAU - Jensen, Andreas Kryger
AU  - Jensen AK
AD  - Department of Clinical Research, Nordsjaellands Hospital Hillerod, University of 
      Copenhagen, Hillerod, Denmark; Section of Biostatistics, Institute of Public
      Health, University of Copenhagen, Copenhagen, Denmark.
FAU - Holst, Jens Juul
AU  - Holst JJ
AD  - The NNF Center for Basic Metabolic Research, University of Copenhagen,
      Copenhagen, Denmark.
FAU - Tarnow, Lise
AU  - Tarnow L
AD  - Department of Clinical Research, Nordsjaellands Hospital Hillerod, University of 
      Copenhagen, Hillerod, Denmark; Department of Clinical Epidemiology, Aarhus
      University, Aarhus, Denmark.
FAU - Knop, Filip Krag
AU  - Knop FK
AD  - Center for Diabetes Research, Gentofte Hospital, University of Copenhagen,
      Hellerup, Denmark; The NNF Center for Basic Metabolic Research, University of
      Copenhagen, Copenhagen, Denmark.
FAU - Madsbad, Sten
AU  - Madsbad S
AD  - Department of Endocrinology, Hvidovre Hospital, University of Copenhagen,
      Hvidovre, Denmark.
FAU - Andersen, Henrik Ullits
AU  - Andersen HU
AD  - Steno Diabetes Center, Gentofte, Denmark.
LA  - ENG
SI  - ClinicalTrials.gov/NCT01612468
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151203
PL  - England
TA  - Lancet Diabetes Endocrinol
JT  - The lancet. Diabetes & endocrinology
JID - 101618821
SB  - IM
CIN - Lancet Diabetes Endocrinol. 2016 Mar;4(3):190-1. PMID: 26656291
EDAT- 2015/12/15 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/12/15 06:00
PHST- 2015/09/22 [received]
PHST- 2015/10/30 [revised]
PHST- 2015/11/02 [accepted]
AID - S2213-8587(15)00436-2 [pii]
AID - 10.1016/S2213-8587(15)00436-2 [doi]
PST - ppublish
SO  - Lancet Diabetes Endocrinol. 2016 Mar;4(3):221-32. doi:
      10.1016/S2213-8587(15)00436-2. Epub 2015 Dec 3.

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