GLP-1-based combination strategies for weight loss: Multi-target agents and combination therapies

Area of Science:

• Pharmacology
• Metabolic Diseases
• Drug Development

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized obesity pharmacotherapy.
• Single-target mechanisms of current GLP-1RAs present limitations for maximal weight loss.
• Combination strategies targeting multiple pathways are emerging as a key area in obesity drug development.

Purpose of the Study:

• To systematically review GLP-1RA-based combination weight-loss strategies.
• To examine the scientific rationale and research progress in single-agent multi-target and multi-drug combination therapies.
• To evaluate the efficacy and safety of these advanced weight-loss approaches.

Main Methods:

• Review of scientific literature on GLP-1RA combination therapies.
• Analysis of single-agent multi-target agonists (dual and triple agonists targeting receptors like GLP-1R, GIPR, GCGR, AMYR).
• Evaluation of multi-drug combination therapies (free and fixed-dose combinations).

Main Results:

• Single-agent multi-target agonists achieve superior weight loss via synergistic regulation of appetite, metabolism, and lipolysis.
• Multi-drug combinations, both free and fixed-dose, improve weight loss and metabolic parameters.
• Common side effects include gastrointestinal events; potential risks like increased heart rate and hypoglycemia require monitoring, alongside long-term thyroid and muscle safety.

Conclusions:

• GLP-1RA-based combination strategies represent a significant advancement in obesity pharmacotherapy.
• Personalized treatment, head-to-head comparisons, oral formulations, and long-term maintenance are crucial for future research.
• These approaches hold promise for comprehensive obesity management and improved cardiometabolic health.