title: Exposure-response analyses of liraglutide 3.0 mg for weight management.
abstract: OBJECTIVE
  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 ∼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.
authors.affiliation: Department of Obesity and Endocrinology, University of Liverpool, Liverpool, UK.
authors.forename: J P H
authors.initials: JP
authors.lastname: Wilding
authors.affiliation: Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: R V
authors.initials: RV
authors.lastname: Overgaard
authors.affiliation: Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: L V
authors.initials: LV
authors.lastname: Jacobsen
authors.affiliation: Medical Affairs, GLP-1 and Obesity, Novo Nordisk A/S, Søborg, Denmark.
authors.forename: C B
authors.initials: CB
authors.lastname: Jensen
authors.affiliation: Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland.|Investigative Science, Imperial College London, London, UK.
authors.forename: C W
authors.initials: CW
authors.lastname: le Roux
mesh_terms: D001067:Appetite Depressants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015992:Body Mass Index; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000628:therapy; D004038:Diet, Reducing; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015444:Exercise; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054795:Incretins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069450:Liraglutide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000628:therapy; D050177:Overweight / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000628:therapy; D011236:Prediabetic State / Q000150:complications / Q000628:therapy; D012727:Sex Characteristics; D015431:Weight Loss / Q000187:drug effects; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001067:Appetite Depressants; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: body weight; glucagon-like peptide-1; incretin; pharmacokinetic
references.citation: J Neurosci. 2011 Mar 9;31(10 ):3904-13
references.pmid: 21389245
references.citation: J Diabetes Complications. 2014 May-Jun;28(3):399-405
references.pmid: 24561125
references.citation: Circ Res. 2014 May 23;114(11):1788-803
references.pmid: 24855202
references.citation: N Engl J Med. 2015 Jul 2;373(1):11-22
references.pmid: 26132939
references.citation: Curr Clin Pharmacol. 2012 Aug;7(3):214-28
references.pmid: 22432846
references.citation: Endocr J. 2010;57(5):359-72
references.pmid: 20424341
references.citation: Lancet. 2009 Jul 4;374(9683):39-47
references.pmid: 19515413
references.citation: J Clin Pharmacol. 2012 Dec;52(12):1815-23
references.pmid: 22174428
references.citation: JAMA. 2015 Aug 18;314(7):687-99
references.pmid: 26284720
references.citation: Lancet. 2010 Jun 26;375(9733):2234-43
references.pmid: 20609969
references.citation: Eur J Neurosci. 1995 Nov 1;7(11):2294-300
references.pmid: 8563978
references.citation: Diabetes Care. 2005 Jun;28(6):1526-7
references.pmid: 15920086
references.citation: Lancet. 2014 Oct 11;384(9951):1349-57
references.pmid: 25018121
references.citation: Nature. 1996 Jan 4;379(6560):69-72
references.pmid: 8538742
references.citation: Diabetologia. 1993 Aug;36(8):741-4
references.pmid: 8405741
references.citation: Lancet. 2009 Nov 7;374(9701):1606-16
references.pmid: 19853906
references.citation: Prog Neurobiol. 2010 Nov;92(3):442-62
references.pmid: 20638440
references.citation: J Clin Invest. 1998 Feb 1;101(3):515-20
references.pmid: 9449682
references.citation: J Comp Neurol. 1999 Jan 11;403(2):261-80
references.pmid: 9886047
references.citation: J Pers Soc Psychol. 1986 Dec;51(6):1173-82
references.pmid: 3806354
references.citation: Int J Obes (Lond). 2014 May;38(5):689-97
references.pmid: 23942319
references.citation: Int J Obes Relat Metab Disord. 2001 Jun;25(6):781-92
references.pmid: 11439290
references.citation: Diabetes Technol Ther. 2015 Jan;17 (1):35-42
references.pmid: 25375397
references.citation: Diabetes Care. 1987 Sep-Oct;10(5):563-6
references.pmid: 3677974
references.citation: J Med Chem. 2000 May 4;43(9):1664-9
references.pmid: 10794683