TOPLINE

More than 1 in 4 adults with obesity had a novel physiologic subtype marked by fast gastric emptying, discordantly low postmeal GLP‑1 levels, and increased postmeal hunger. In a retrospective analysis, participants with this subphenotype experienced nearly twice as much weight loss after 6 months of tirzepatide treatment as those with other obesity phenotypes.

METHODOLOGY

• Individuals with obesity show wide variability in gastric emptying and postmeal GLP-1 secretion, which can influence appetite, satiety, and response to GLP-1s.
• Researchers analyzed 483 adults with obesity (mean age, 40.93 years; 73.5% women) to characterize physiologic subtypes by examining gastric emptying, appetite regulation, and levels of postprandial plasma enteroendocrine hormones; they also assessed whether these subtypes were associated with differential weight-loss response to tirzepatide.
• After a standardized breakfast, participants underwent solid meal gastric emptying measured using scintigraphy and rated their postmeal hunger on a visual analog scale; levels of satiety hormones (GLP‑1, peptide YY, and cholecystokinin) were measured at fasting and at 15, 45, and 90 minutes after the meal. Participants were grouped by their gastric emptying speed and GLP-1 levels at 15 minutes to identify physiologic subtypes.
• Weight loss following tirzepatide treatment was assessed retrospectively in 61 participants from the distinct phenotypes who initiated the drug after phenotyping.
• In a separate group of 31 participants, colon mucosal biopsies were tested for gene expression of glucagon (proglucagon, a GLP-1 precursor) and peptide YY to infer hormone production.

TAKEAWAY

• The analysis identified three gastric emptying/GLP-1 phenotypes. About 26.9% (n = 130) of the participants belonged to the discordant group characterized by fast gastric emptying and low postmeal GLP-1 levels; the remainder belonged to two groups that had concordant gastric emptying/GLP-1 responses.
• The discordant group reported greater postmeal hunger than a specific cluster with average to slow gastric emptying and expected moderate levels of GLP-1; it also had lower fasting and postmeal levels of GLP-1 and peptide YY than the concordant groups; fasting and early postmeal levels of cholecystokinin were also lower, though this difference waned by 45 minutes (P < .05 for all).
• In colon biopsies, the discordant group had 45% lower glucagon expression (P = .017) and 50% lower peptide YY expression (P = .013).
• Among participants who later started tirzepatide, those in the discordant group lost nearly twice as much weight at 6 months as those in the two concordant groups (mean percent total body weight loss, 21.5% vs 12.1% and 10.8%; P = .0001), with differences already evident at 3 months.

IN PRACTICE

“The current study indicates that individuals with fast GE [gastric emptying] and low GLP-1 are superresponders to the GLP-1/GIP RA [glucose-dependent insulinotropic polypeptide receptor agonist] tirzepatide, highlighting that response to antiobesity therapies is influenced by the underlying physiology of an individual’s obesity phenotype,” the authors of the study wrote.

SOURCE

The study was led by Alexander L. Ticho, MD, PhD, Mayo Clinic, Rochester, Minnesota. It was published online in Gastroenterology.

LIMITATIONS

About 80 participants had GLP‑1 levels below the limit of detection. Colon mucosal biopsies were available from a relatively small cohort. Data on GLP‑1 degradation were not available.

DISCLOSURES

The study was supported by the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases. Some authors reported being cofounders and inventors of intellectual property, serving as consultants, and receiving research support or contracts from multiple companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.