PMID- 26833744
OWN - NLM
STAT- MEDLINE
DCOM- 20170106
LR  - 20220408
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Print)
IS  - 1462-8902 (Linking)
VI  - 18
IP  - 5
DP  - 2016 May
TI  - Exposure-response analyses of liraglutide 3.0 mg for weight management.
PG  - 491-9
LID - 10.1111/dom.12639 [doi]
AB  - AIMS: Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight 
      management, lowers body weight through decreased energy intake. We conducted 
      exposure-response analyses to provide important information on individual 
      responses to given drug doses, reflecting inter-individual variations in drug 
      metabolism, absorption and excretion. METHODS: We report efficacy and safety 
      responses across a wide range of exposure levels, using data from one phase II 
      (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity 
      and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, 
      placebo-controlled trials (n = 4372). RESULTS: There was a clear exposure-weight 
      loss response. Weight loss increased with greater exposure and appeared to level 
      off at the highest exposures associated with liraglutide 3.0 mg in most 
      individuals, but did not fully plateau in men. In individuals with 
      overweight/obesity and comorbid type 2 diabetes, there was a clear 
      exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased 
      with higher plasma liraglutide concentration (plateauing at  approximately 21 nM); however, for 
      individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No 
      exposure-response relationship was identified for any safety outcome, with the 
      exception of gastrointestinal adverse events (AEs). Individuals with gallbladder 
      AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not 
      have higher liraglutide exposure compared with the overall population. 
      CONCLUSIONS: These analyses support the use of liraglutide 3.0 mg for weight 
      management in all subgroups investigated; weight loss increased with higher drug 
      exposure, with no concomitant deterioration in safety/tolerability besides 
      previously known gastrointestinal side effects.
CI  - (c) 2016 John Wiley & Sons Ltd.
FAU - Wilding, J P H
AU  - Wilding JP
AD  - Department of Obesity and Endocrinology, University of Liverpool, Liverpool, UK.
FAU - Overgaard, R V
AU  - Overgaard RV
AD  - Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Soborg, Denmark.
FAU - Jacobsen, L V
AU  - Jacobsen LV
AD  - Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Soborg, Denmark.
FAU - Jensen, C B
AU  - Jensen CB
AD  - Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Soborg, Denmark.
FAU - le Roux, C W
AU  - le Roux CW
AD  - Diabetes Complications Research Centre, Conway Institute, University College 
      Dublin, Dublin, Ireland.
AD  - Investigative Science, Imperial College London, London, UK.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20160301
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Appetite Depressants)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Incretins)
RN  - 839I73S42A (Liraglutide)
SB  - IM
MH  - Appetite Depressants/*administration & dosage/adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Body Mass Index
MH  - Cohort Studies
MH  - Combined Modality Therapy/adverse effects
MH  - Diabetes Mellitus, Type 2/complications/drug therapy/therapy
MH  - Diet, Reducing
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Exercise
MH  - Female
MH  - Glucagon-Like Peptide-1 Receptor/*agonists/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/therapeutic use
MH  - Incretins/*administration & dosage/adverse effects/pharmacokinetics/therapeutic 
      use
MH  - Liraglutide/*administration & dosage/adverse effects/pharmacokinetics/therapeutic 
      use
MH  - Male
MH  - Middle Aged
MH  - Obesity/blood/complications/*drug therapy/therapy
MH  - Overweight/blood/complications/*drug therapy/therapy
MH  - Prediabetic State/complications/therapy
MH  - Sex Characteristics
MH  - Weight Loss/drug effects
PMC - PMC5069568
OTO - NOTNLM
OT  - body weight
OT  - glucagon-like peptide-1
OT  - incretin
OT  - pharmacokinetic
EDAT- 2016/02/03 06:00
MHDA- 2017/01/07 06:00
PMCR- 2016/10/19
CRDT- 2016/02/03 06:00
PHST- 2015/12/16 00:00 [received]
PHST- 2016/01/21 00:00 [revised]
PHST- 2016/01/28 00:00 [accepted]
PHST- 2016/02/03 06:00 [entrez]
PHST- 2016/02/03 06:00 [pubmed]
PHST- 2017/01/07 06:00 [medline]
PHST- 2016/10/19 00:00 [pmc-release]
AID - DOM12639 [pii]
AID - 10.1111/dom.12639 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2016 May;18(5):491-9. doi: 10.1111/dom.12639. Epub 2016 Mar 
      1.