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New Dual-Action Drug Shows Promise in Diabetes and Obesity

An experimental two-hormone drug shows promise in diabetes and obesity…. 

Roche’s new dual action molecule targets the receptors for two hormones known as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both of these hormones play a critical role in regulating the body’s metabolism.

Both hormones are secreted from the intestine in response to ingested nutrients and lower postprandial glucose excursion through insulinotropic actions at pancreatic β cells. GLP-1 also suppresses appetite, resulting in reduced adiposity. Long-term glucose control with the currently available GLP-1 agonist on the market is less than perfect and a reduction in adiposity is insignificant. Increasing the dose to gain greater efficacy is not a viable option for most patients because GLP-1R agonists are a source of significant gastrointestinal side effects, most notably nausea and vomiting. Therefore, combination therapy appears to be the preferred path to enhanced efficacy while maintaining an appropriate tolerability and safety profile.

In vivo pharmacology studies were designed to assess the metabolic efficacy and safety of peptide analogs designed and confirmed to have co-agonistic properties at the GLP-1R and GIPR. Researchers observed that the dual-action peptide molecule increased insulin sensitivity and glycemic control in metabolically compromised rodent models of diet-induced obesity at a potency that was consistently enhanced 10-fold relative to comparably modified best in-class selective GLP-1R agonist. The pegylated co-agonist also caused a dose-dependent increase in HBA1c levels over time in type 2 diabetic patients with a maximal decrease of 1.11% from baseline. The dual action molecule was pharmacokinetically enhanced to lessen peak drug exposure and to have less dependence on the GLP-1 mediated pharmacology. Thus the robust effect of this molecule was seen without causing adverse gastrointestinal side effects in these patients.

The authors conclude that the discovery and validation of this dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

Practice Pearls: 
  • Dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
  • The pegylated co-agonist also caused a dose-dependent increase in HBA1c levels over time in type 2 diabetic patients.
  • The robust effect of this molecule was seen without causing adverse gastrointestinal side effects in these patients.

Science Translational Medicine, October 2013