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Related Concept Videos

Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

424
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
424
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

262
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
262
Oral Hypoglycemic Agents: Glinides01:06

Oral Hypoglycemic Agents: Glinides

268
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
268

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From In Vitro Efficacy to Long-Term HbA1c Response for GLP-1R/GlucagonR Agonism Using the 4GI-HbA1c Systems Model.

Rolien Bosch1,2, Marcella Petrone3, Rosalin Arends4

  • 1LAP&P Consultants, Leiden, the Netherlands.

CPT: Pharmacometrics & Systems Pharmacology
|July 16, 2025
PubMed
Summary

A new systems model accurately predicts glucose and HbA1c levels in Type 2 Diabetes patients treated with Glucagon-like peptide 1 (GLP-1) agonists. This tool aids in selecting effective diabetes drugs and supports clinical development for novel therapies.

Keywords:
4GIGLP‐1R agonistsQSPcotadutidediabetessystems pharmacology

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Area of Science:

  • Pharmacology
  • Systems Biology
  • Endocrinology

Background:

  • Glucagon-like peptide 1 (GLP-1)-based therapies are crucial for managing Type 2 Diabetes.
  • Predicting treatment outcomes using early data can optimize drug development.
  • A previously developed glucose homeostasis model (4GI) quantifies drug effects on glucose.

Purpose of the Study:

  • To couple the 4GI model with an integrated glucose-red blood cell-HbA1c (IGRH) model.
  • To predict the effects of GLP-1 and dual receptor agonists on glucose and HbA1c.
  • To validate the predictive capability of the combined 4GI-HbA1c model.

Main Methods:

  • Coupling the 4GI model with the IGRH model.
  • Validating the 4GI model using Phase 2a continuous glucose monitoring (CGM) data for 24-h glucose prediction.
  • Using predicted glucose levels as input for the HbA1c model to assess overall predictiveness.
  • Applying the combined model to predict glucose and HbA1c dynamics for cotadutide's Phase 2b study.

Main Results:

  • The 4GI model showed good prediction of 24-h glucose with minimal calibration.
  • The combined 4GI-HbA1c model adequately predicted fasting plasma glucose and HbA1c for cotadutide and liraglutide.
  • Root Mean Square Percent Errors (RMSPE) were 5.9% for glucose and 13% for HbA1c.

Conclusions:

  • The 4GI-HbA1c systems model is a valuable tool for predicting clinical outcomes of GLP-1 and/or glucagon agonists.
  • This model supports compound selection and aids in the clinical development of novel diabetes therapies.