title: Latest approaches for the treatment of obesity.
abstract: BACKGROUND
  Obesity is a body weight disorder characterized by excess adiposity that increases the risk for developing co-morbidities such as type 2 diabetes. A large medical need exists for new anti-obesity treatments capable of promoting 10% or greater weight loss, with minimal side effects.
  
  
  METHODS
  The authors describe the application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery. Furthermore, they review in detail several pathways and pharmacological targets in the central nervous system (e.g., the leptin-melanocortin axis, the opioid system, GLP-1/GLP-1 system, and FGF21/FGFR1c/β-Klotho axis) that play an important role in the regulation of feeding behavior and energy homeostasis. Special focus is given to new strategies that engage well-known targets via novel mechanisms in order to circumvent issues seen with previous drug candidates that failed in the clinic. Finally, the authors discuss the recent developments around fixed-dose combinations, targeted polypharmacology, and non-traditional combinations of drugs and devices.
  
  
  CONCLUSIONS
  The future for new weight-loss approaches to treat obesity looks promising. Current therapies have shown modest effects on weight loss in the general obese population but will have greater impact in smaller homogeneous sub-populations of obese subjects using personalized medicine. Drug combinations that target multiple, complementary pathways have the potential to promote double-digit weight loss in a broader, heterogeneous patient population. Furthermore, the development of advanced subcutaneous delivery technologies has opened up opportunities to develop breakthrough peptide and biologic agents for the treatment of obesity.
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer PharmaTherapeutics , 610 Main Street, Cambridge, MA 02139 , USA.
authors.forename: V Margaret
authors.initials: VM
authors.lastname: Jackson
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Fortin
authors.forename: Alice
authors.initials: A
authors.lastname: Liou
authors.forename: J Brent
authors.initials: JB
authors.lastname: Kuzmiski
authors.forename: A Katrina
authors.initials: AK
authors.lastname: Loomis
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Rives
authors.forename: Bhavik
authors.initials: B
authors.lastname: Shah
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D004359:Drug Therapy, Combination; D006801:Humans; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents
keywords: FGF21; FGFR1c/β-Klotho; GLP-1; GLP-1R; LepRb; MC4R; central nervous system; devices; leptin system; melanocortin system; microbiome; obesity