Keywords: GLP-1R, GIPR, GCGR, triple agonist, tirzepatide, retatrutide, ASC37, multi-target agonist, obesity, type 2 diabetes

Glucagon-like peptide-1 receptor (GLP-1R) agonists have revolutionized the treatment of type 2 diabetes and obesity over the past decade. However, the efficacy ceiling and gastrointestinal tolerability issues of single-target drugs have prompted researchers to explore more complex multi-target synergistic strategies. GLP-1R, GIPR, and GCGR form a natural metabolic regulatory receptor network—each modulating energy balance from distinct dimensions: appetite suppression, energy expenditure, and lipid mobilization. Multi-target agonists targeting this combination are emerging as one of the most active frontiers in metabolic disease drug development.

GLP-1R, GIPR, and GCGR all belong to the class B G protein-coupled receptor family and exert biological effects through the cAMP signaling pathway, but their physiological functions exhibit intricate division and complementarity.

GLP-1R is the most mature target in current metabolic drug development. GLP-1 is secreted by intestinal L cells, and its receptors are widely distributed in pancreatic β cells, the hypothalamus, the gastrointestinal tract, and other tissues. GLP-1R activation promotes glucose-dependent insulin secretion, inhibits glucagon release, delays gastric emptying, suppresses appetite, and offers multi-organ benefits such as cardiovascular and renal protection.

GIPR is activated by glucose-dependent insulinotropic polypeptide (GIP) secreted by intestinal K cells and is another important incretin receptor. GIPR promotes insulin secretion in pancreatic β cells, facilitates lipid storage and fatty acid uptake in adipose tissue, and participates in appetite regulation in the central nervous system. The unique feature of GIPR is its "state-dependent" metabolic effects—promoting fat synthesis under normoglycemia and enhancing insulin secretion under hyperglycemia. This characteristic makes it a critical regulatory dimension in multi-target design.

GCGR is the receptor for glucagon, primarily expressed in the liver. Unlike GLP-1R and GIPR, GCGR activation promotes hepatic glycogenolysis and gluconeogenesis, increasing blood glucose. This effect appears counterintuitive to glycemic control goals, but in multi-target designs, GCGR activation can significantly enhance energy expenditure, fat oxidation, and lipid mobilization, thereby amplifying weight loss. Balancing GCGR's thermogenic and lipolytic effects without inducing hyperglycemia is a core challenge in multi-target agonist design.

GLP-1R single-target agonists (e.g., semaglutide) have demonstrated robust glycemic and weight loss effects in clinical practice, but a significant proportion of patients exhibit suboptimal responses or poor tolerability. Researchers subsequently turned to dual-target combinations:

GLP-1R/GIPR dual-target agonists are exemplified by tirzepatide. Tirzepatide is a 39-amino acid linear peptide with C20 fatty diacid modification to enable protein binding and extend its half-life to 5 days. It exhibits GIPR pharmacology similar to native GIP while displaying biased cAMP signaling activation at GLP-1R. Tirzepatide has been approved for type 2 diabetes and obesity, becoming the first commercially successful dual-target incretin drug.

GLP-1R/GCGR dual-target agonists, represented by survodutide, are currently in Phase III clinical trials for obesity and MASH. The inclusion of GCGR complements GLP-1R's appetite suppression by increasing energy expenditure, showing synergistic advantages in weight loss and hepatic fat reduction.

Building on these dual-target validations, GLP-1R/GIPR/GCGR triple agonists have become the focus of next-generation development. The design goal of triple agonists is to harness the complementary effects of all three pathways—GLP-1R for appetite suppression and delayed gastric emptying, GIPR for enhanced insulin secretion and fat distribution modulation, and GCGR for increased energy expenditure and lipid oxidation. However, triple agonist design is far more complex than dual-target approaches: the three receptors have distinct structural and sequence requirements for ligands, and achieving "balanced" or "optimal ratio" activation demands precise molecular engineering.

Retatrutide is the world's first triple agonist to publish Phase II clinical data. In obese populations, it achieved an average weight loss of 24.2% after 48 weeks of treatment; in type 2 diabetes patients, it showed 16.9% weight loss and a 2.2% HbA1c improvement at 36 weeks, with 82% of patients achieving HbA1c ≤6.5%. Additionally, Retatrutide significantly improved multiple cardiometabolic indicators, including blood pressure, lipids, and waist circumference, with an 82% reduction in liver fat content. Its Phase III trials commenced in 2025, enrolling 586 patients to evaluate efficacy and safety over 80 weeks in obese or overweight patients with chronic low back pain. Data presented at the 2025 EASD Annual Meeting further demonstrated Retatrutide's efficacy in improving hepatic steatosis in MASH mouse models.

UBT-251 is another triple agonist entering Phase II trials, targeting GCGR, GIPR, and GLP-1R, with indications under investigation including metabolic dysfunction-associated steatohepatitis, chronic kidney disease, and type 2 diabetes.

ASC37, developed by Ascletis Pharma, represents the latest advancement in this field. In vitro experiments show that ASC37's agonistic activity at GLP-1R, GIPR, and GCGR is approximately 5-fold, 4-fold, and 4-fold stronger than Retatrutide, respectively. In head-to-head studies with non-human primates, ASC37 exhibited an average apparent half-life of ~17 days—7 times longer than Retatrutide—supporting once-monthly subcutaneous dosing. Ascletis plans to submit an IND application to the FDA in Q2 2026. ASC37 is also slated for co-development with ASC36, a once-monthly amylin receptor agonist, for obesity, diabetes, and other metabolic disorders.

From dual-target to triple-target, from weekly to monthly dosing, the pace of iteration in this field is accelerating. A 2025 study published in the Journal of Medicinal Chemistry further revealed that triple agonist design need not pursue "potent and balanced" activation of all three receptors—certain molecules with biased receptor activation profiles, even with significantly weaker GIPR activity, can achieve metabolic efficacy comparable to Retatrutide. This finding expands the chemical space and optimization flexibility for next-generation molecules.

The most critical scientific question in triple agonist development is: What is the optimal activation ratio for the three receptors?

Traditional views advocate "balanced" and potent activation of all three receptors. A 2026 study in RSC Medicinal Chemistry employed computer-aided drug design to develop 22 novel triple agonist structures, evaluating their receptor activity profiles using a "balanced triple agonism score." Most compounds exhibited highly balanced pharmacological features, with the most active analog (P2-L4) showing low-nanomolar potency across all three targets.

However, a 2025 Journal of Medicinal Chemistry study proposed an alternative design approach. Through sequence analysis, molecular dynamics simulations, and amino acid optimization, the researchers developed xGLP-1-based triple agonists characterized by potent GLP-1R and GCGR activity paired with weaker GIPR activation. Among these, xGLP/GCG/GIP-32 outperformed tirzepatide in weight loss and matched Retatrutide in metabolic efficacy. Preliminary mechanistic studies revealed biased activation at GIPR and GCGR. The researchers concluded that for biased triple agonists, there may be room to explore an "optimal receptor activation ratio" rather than uniformly pursuing balanced potent activation.

This finding has significant industrial implications—it suggests triple agonist design need not mimic native hormone activation patterns but can engineer "customized" signaling output spectra to strike a better balance between efficacy and safety.

GLP-1R/GIPR/GCGR triple agonists are at a critical juncture from proof-of-concept to large-scale clinical validation. Retatrutide's Phase III data will emerge over the next 1–2 years, while clinical initiation of next-gen molecules like ASC37 will provide further differentiated data. Key future research directions include: quantifying the relationship between optimal receptor activation ratios and clinical outcomes; extending dosing intervals and improving patient compliance via long-acting formulations (e.g., Ascletis' ULAP platform); exploring triple agonists in broader indications like MASH, chronic kidney disease, and cardiovascular diseases; and developing oral triple agonists to lower treatment barriers.

From GLP-1R single-target to GLP-1R/GIPR and GLP-1R/GCGR dual-target, and now to GLP-1R/GIPR/GCGR triple-target, metabolic drug development continues evolving along the "multi-target synergy" path. Triple agonists represent not just molecular design upgrades but a deeper understanding of energy metabolism networks—when the signals of three receptors are precisely orchestrated, the potential for weight loss and metabolic improvement may surpass the limits achievable by any single pathway.