Obesity Subphenotype With Low GLP-1 Levels Shows Greater Weight Loss With Tirzepatide

Key Clinical Summary

• Investigators identified a distinct obesity subphenotype characterized by rapid gastric emptying, low postprandial glucagon-like peptide 1 (GLP-1) levels, and increased postprandial hunger.
• Patients with this subphenotype experienced significantly greater weight loss after 6 months of tirzepatide treatment than those with other obesity phenotypes (21.5% vs 11.7%).
• The findings suggest physiologic phenotyping may help identify patients most likely to benefit from GLP-1–based therapies and support a more personalized approach to obesity management.

Researchers have identified a biologically distinct obesity subphenotype associated with rapid gastric emptying, reduced endogenous GLP-1 production, and substantially greater weight loss with tirzepatide, offering new evidence that obesity is a heterogeneous disease with variable treatment responses.

The study sought to better understand why some individuals respond more favorably to GLP-1–based therapies by examining gastric emptying, appetite regulation, hormone secretion, and intestinal hormone production.

Three Obesity Clusters Identified

The analysis included 483 adults with obesity who underwent gastric emptying scintigraphy following a standardized solid meal, postprandial appetite assessment, and plasma enteroendocrine hormone profiling.

Using Gaussian mixed modeling, investigators identified 3 distinct obesity clusters based on gastric emptying and GLP-1 responses.

Approximately 27% of participants (n = 130) belonged to a subgroup characterized by rapid solid gastric emptying and discordantly low postprandial GLP-1 concentrations despite increased hunger after meals. Investigators designated this phenotype as discordant gastric emptying/GLP-1 (dc-GE/GLP-1).

The remaining 73% of participants (n = 353) demonstrated concordant gastric emptying and GLP-1 responses.

Hormonal Differences May Explain Increased Hunger

Compared with the concordant group, patients in the discordant phenotype exhibited significantly lower circulating concentrations of peptide YY and cholecystokinin, two hormones involved in appetite regulation and satiety.

Additional analyses demonstrated reduced colonic mucosal messenger RNA expression of both GCG, which encodes GLP-1, and peptide YY in biopsy specimens obtained from a separate patient cohort.

Although investigators observed higher circulating short-chain fatty acid concentrations among patients with the discordant phenotype, fecal microbiome composition did not differ significantly between groups, suggesting that reduced gut hormone production may occur independently of major microbial composition changes.

Tirzepatide Response Varied by Phenotype

The investigators also retrospectively evaluated treatment response among 61 participants who received tirzepatide.

After 6 months of therapy, patients with the discordant gastric emptying/GLP-1 phenotype experienced markedly greater weight loss than those in the concordant group.

Mean weight loss reached 21.5% among patients with low endogenous GLP-1 and rapid gastric emptying compared with 11.7% among participants with concordant physiologic findings.

The findings suggest that patients with reduced endogenous incretin production may derive greater benefit from incretin-based pharmacotherapy.

Implications for Managed Care

As utilization of GLP-1 receptor agonists and dual incretin therapies continues to expand, identifying patients most likely to benefit from treatment has become an important consideration for health plans and other managed care stakeholders.

The study supports the concept that obesity encompasses multiple biologically distinct subtypes rather than a single disease process. Physiologic markers such as gastric emptying rate and endogenous gut hormone production could eventually help guide treatment selection, improve clinical outcomes, and optimize use of high-cost obesity therapies.

Although additional validation is needed before these approaches can be incorporated into routine clinical practice, the findings highlight the potential role of precision medicine in obesity management.

Conclusion

Investigators identified a distinct obesity subphenotype characterized by rapid gastric emptying, reduced endogenous GLP-1 production, and increased postprandial hunger that was associated with significantly greater weight loss after tirzepatide treatment. The authors conclude that further research is needed to better understand the mechanisms underlying GLP-1 deficiency and to determine whether physiologic phenotyping can improve patient selection for incretin-based therapies.

Reference

Ticho A L, McRae A N, Cifuentes L, et al. A subphenotype of obesity with reduced enteroendocrine glucagon-like peptide 1 synthesis and enhanced tirzepatide response. Gastroenterology. 2026; ISSN 0016-5085. doi: 10.1053/j.gastro.2026.05.019