PMID- 31031702
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200225
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 10
DP  - 2019
TI  - The Discovery and Development of Liraglutide and Semaglutide.
PG  - 155
LID - 10.3389/fendo.2019.00155 [doi]
LID - 155
AB  - The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with 
      important effects on glycemic control and body weight regulation, led to efforts 
      to extend its half-life and make it therapeutically effective in people with type 
      2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor 
      agonists (GLP-1RAs) followed. Our article charts the discovery and development of 
      the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We 
      examine the chemistry employed in designing liraglutide and semaglutide, the 
      human and non-human studies used to investigate their cellular targets and 
      pharmacological effects, and ongoing investigations into new applications and 
      formulations of these drugs. Reversible binding to albumin was used for the 
      systemic protraction of liraglutide and semaglutide, with optimal fatty acid and 
      linker combinations identified to maximize albumin binding while maintaining 
      GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this 
      receptor, which is expressed in the pancreas, gastrointestinal tract, heart, 
      lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to 
      account for the respective improvements in glycemic control and body weight that 
      are evident with liraglutide and semaglutide. Both liraglutide and semaglutide 
      also positively affect cardiovascular (CV) outcomes in individuals with T2D, 
      although the precise mechanism is still being explored. Significant weight loss, 
      through an effect to reduce energy intake, led to the approval of liraglutide 
      (3.0 mg) for the treatment of obesity, an indication currently under 
      investigation with semaglutide. Other ongoing investigations with semaglutide 
      include the treatment of non-alcoholic fatty liver disease (NASH) and its use in 
      an oral formulation for the treatment of T2D. In summary, rational design has led 
      to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, 
      that have made a vast contribution to the management of T2D in terms of 
      improvements in glycemic control, body weight, blood pressure, lipids, beta-cell 
      function, and CV outcomes. Furthermore, the development of an oral formulation 
      for semaglutide may provide individuals with additional benefits in relation to 
      treatment adherence. In addition to T2D, liraglutide is used in the treatment of 
      obesity, while semaglutide is currently under investigation for use in obesity 
      and NASH.
FAU - Knudsen, Lotte Bjerre
AU  - Knudsen LB
AD  - Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark.
FAU - Lau, Jesper
AU  - Lau J
AD  - Global Research Technology, Novo Nordisk A/S, Malov, Denmark.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20190412
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
PMC - PMC6474072
OTO - NOTNLM
OT  - GLP-1
OT  - albumin
OT  - liraglutide
OT  - obesity
OT  - once-weekly
OT  - semaglutide
OT  - type 2 diabetes
EDAT- 2019/04/30 06:00
MHDA- 2019/04/30 06:01
PMCR- 2019/01/01
CRDT- 2019/04/30 06:00
PHST- 2018/12/04 00:00 [received]
PHST- 2019/02/21 00:00 [accepted]
PHST- 2019/04/30 06:00 [entrez]
PHST- 2019/04/30 06:00 [pubmed]
PHST- 2019/04/30 06:01 [medline]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2019.00155 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. 
      eCollection 2019.