A Subphenotype of Obesity With Reduced Enteroendocrine Glucagon-Like Peptide 1 Synthesis and Enhanced Tirzepatide Response

Obesity includes a subphenotype marked by rapid gastric emptying, increased postprandial hunger, and unusually low GLP-1 levels despite reduced production of gut hormones. In a retrospective analysis, people with this subphenotype lost substantially more weight after 6 months of tirzepatide than those without it (21.5% vs 11.7%).

Journal article — Observational cohort with retrospective analysis. Population: Adults with obesity. Sample size: 483 adults with obesity. Follow-up: 6 months. Interventions: Tirzepatide.

Gaussian mixed modeling of gastric emptying and GLP-1 identified three clusters. One cluster (dc-GE/GLP-1; n=130, 26.9%) combined fast gastric emptying, increased postprandial hunger, and discordantly low postprandial GLP-1, together with lower peptide YY and cholecystokinin. This cluster had higher plasma short-chain fatty acids but no significant difference in fecal metagenomics compared with the concordant cluster (n=353, 73.1%). In colonic mucosal biopsies, dc-GE/GLP-1 showed reduced GCG and PYY mRNA expression. Among 61 participants treated with tirzepatide, the dc-GE/GLP-1 cluster lost more weight at 6 months than c-GE/GLP-1 (21.5% vs 11.7%).

This paper helps identify an obesity subphenotype that may respond particularly well to tirzepatide, based on gastric emptying and GLP-1 measures, supporting a precision-medicine approach. It does not establish tirzepatide as a specific treatment for this subphenotype, provides no dosing information, and does not prove that reduced GLP-1 synthesis causes the enhanced response.

Key findings

• A cluster of 130 participants (26.9%) had fast solid-meal gastric emptying, increased postprandial hunger, and discordantly low postprandial GLP-1 (dc-GE/GLP-1).
• dc-GE/GLP-1 had lower plasma peptide YY and cholecystokinin than concordant clusters.
• dc-GE/GLP-1 had higher plasma short-chain fatty acids, with no significant differences in fecal microbial composition.
• Compared with c-GE/GLP-1 (n=353, 73.1%), dc-GE/GLP-1 had reduced mucosal mRNA expression of GCG (GLP-1) and PYY.
• At 6 months of tirzepatide, dc-GE/GLP-1 was associated with greater weight loss than c-GE/GLP-1 (21.5% vs 11.7%).

Limitations

• Authors note further studies are needed to identify mechanisms contributing to GLP-1 deficiency.
• Retrospective tirzepatide analysis is non-randomized and may be confounded.
• Tirzepatide outcome data were available for only 61 of 483 participants.
• Six-month follow-up does not address long-term durability of weight loss.

The record

• Journal: Gastroenterology: S0016-5085(26)06942-8
• Published: 2026-06-05
• PMID: 42250890 — DOI: 10.1053/j.gastro.2026.05.019
• Funding: NIDDK NIH HHS; NIDDK NIH HHS; National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK NIH HHS

Peptide profiles: Tirzepatide.

All indexed evidence: Tirzepatide trials & papers.

Related studies: Peripheral nerve complications from medications utilised for weight loss: a systematic…, Incretin-Based Therapies in Doxorubicin-Induced Cardiotoxicity: A Systematic Review of…, Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory…, Comparative effects of drugs for adults with overweight or obesity: systematic review….