GLP-1/GLP-2 Co-agonists: Multi-Receptor Strategies Reshape Metabolic Drug Development

The success of single-receptor GLP-1 agonists has set the stage for the next logical step: molecules that engage multiple receptors simultaneously to achieve synergistic metabolic effects. Among the most clinically advanced of these next-generation candidates are GLP-1/GLP-2 co-agonists.

The Biology of Dual Agonism

GLP-1 and GLP-2 are both cleaved from the proglucagon precursor in intestinal L-cells, but their physiological roles diverge significantly. GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and promotes satiety — the mechanisms exploited by semaglutide and tirzepatide. GLP-2, by contrast, is a potent intestinal growth factor: it stimulates crypt cell proliferation, increases villus height, enhances nutrient absorption, and improves gut barrier function.

The therapeutic rationale for combining GLP-1 and GLP-2 activity is compelling. Obesity and type 2 diabetes are associated with intestinal barrier dysfunction and low-grade endotoxemia — both of which GLP-2 agonism may ameliorate. A GLP-1/GLP-2 co-agonist could simultaneously address metabolic dysfunction and its gastrointestinal consequences.

Clinical Pipeline

Zealand Pharma’s dapiglutide (ZP7570) is the most advanced GLP-1/GLP-2 co-agonist, currently in Phase II for obesity. Data presented at ADA 2026 showed 14.8% mean body weight reduction at 26 weeks with significantly lower rates of nausea (22% vs. 44% for semaglutide 2.4 mg) — likely attributable to GLP-2-mediated intestinal adaptation that mitigates GLP-1-related gastrointestinal side effects. A key secondary endpoint, intestinal permeability, showed 31% improvement vs. placebo.

Eli Lilly’s GLP-1/GIP/GLP-2 triple agonist (retatrutide follow-on) entered Phase I in Q4 2025, and Novo Nordisk has disclosed a GLP-1/GLP-2 program in preclinical development. The race to establish multi-receptor agonism as the standard of care in metabolic disease is accelerating.

Regulatory and Commercial Considerations

Multi-receptor agonists face a higher regulatory bar than single-receptor agents. The FDA will require demonstration that each component of the molecule contributes to efficacy. However, the commercial prize is substantial: the obesity market is projected to reach $100 billion by 2030, and a molecule with superior tolerability and broader metabolic benefits could capture significant share.