Emerging Combinatorial Hormone Therapies for the Treatment of Obesity and T2DM

Nat Rev Endocrinol. 2013 Jul;9(7):425-33. doi: 10.1038/nrendo.2013.47. Epub 2013 Mar 12.

Abstract

Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.

Publication types

  • Review

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Central Nervous System / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Gastric Inhibitory Polypeptide / therapeutic use
  • Glucagon / therapeutic use
  • Glucagon-Like Peptide 1 / therapeutic use
  • Humans
  • Leptin / therapeutic use
  • Obesity / drug therapy*

Substances

  • Blood Glucose
  • Leptin
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucagon