Why do some people lose considerably more weight than others while taking the same obesity medication? A Mayo Clinic study suggests part of the answer may lie in biological differences that affect how long people feel full after eating.
Researchers identified a subgroup of adults with obesity who produced lower levels of appetite-regulating hormones, emptied food from their stomachs more quickly and experienced more hunger after meals. Participants with this pattern lost an average of 21.5% of their body weight after six months of tirzepatide treatment, compared with 11.7% among participants with other biological patterns.
The findings do not prove that the proposed “hungry gut” subtype can reliably predict an individual’s response to tirzepatide. The classification method still needs to be tested prospectively and independently before it can be used to select medications in routine care.
The researchers and Mayo Clinic also have commercial interests connected to the approach. Senior authors Andres J. Acosta and Michael Camilleri and Mayo Clinic are co-founders and inventors of intellectual property licensed to Phenomix Sciences, a company developing tests intended to identify obesity phenotypes. Several authors also reported consulting, advisory or research relationships with pharmaceutical and food companies.
The study, published in Gastroenterology, included 483 adults with obesity. Researchers measured biological characteristics related to appetite and digestion and identified three subgroups. About one-quarter of the participants had the pattern involving lower production of GLP-1 and other hormones that normally help signal fullness after eating.
“Obesity is a complex disease driven by different biological mechanisms,” Acosta said. “Our findings suggest we can begin identifying which patients are most likely to respond to specific therapies rather than treating obesity as a single disease.”
The researchers described the subgroup as a form of the “hungry gut” obesity phenotype. People with this pattern may eat ordinary portions at meals but become hungry again sooner, potentially leading to more frequent eating or snacking.
The term is a research label, not a diagnosis people can make based on their own hunger. Appetite can be influenced by sleep, stress, medications, food availability, meal composition, learned behavior and many other factors.
Tirzepatide mimics the actions of two hormones, GLP-1 and GIP, that influence appetite and blood sugar regulation. The medication can reduce hunger and help people feel full longer. It is approved under the brand name Zepbound for chronic weight management in certain adults and under the name Mounjaro for type 2 diabetes.
Researchers found that participants in the low-hormone subgroup experienced nearly twice the average percentage of weight loss seen in the other groups during six months of treatment.
That does not mean tirzepatide was ineffective for everyone else. An average loss of 11.7% of body weight can still be clinically meaningful, and averages cannot predict exactly how much any one person will lose.
The study also does not establish that tirzepatide is the best medication for everyone with this biological pattern. Researchers did not show that phenotype-guided prescribing produced better results than standard clinical decision-making or compare tirzepatide with other GLP-1-based medications for each subgroup.
Differences in dosage, side effects, adherence, eating patterns and clinical support may also influence treatment response. Longer follow-up will be needed to determine whether the difference between groups continues and whether participants maintain the weight change over time.
The researchers also investigated why participants in the subgroup had lower levels of appetite-regulating hormones. Their analysis pointed toward reduced production in the intestine rather than differences in the gut microbiome.
That finding adds to the idea that people can reach the same clinical diagnosis of obesity through different biological and behavioral pathways. One person may experience weaker fullness signals, while another may have stronger reward responses to food, lower energy expenditure or different emotional and environmental influences on eating.
Recognizing that variation could eventually help clinicians move beyond trial and error when choosing among medications, behavioral interventions and other treatments.
The practical challenge is determining whether the proposed categories can be measured accurately and affordably. Assessing hormone responses and stomach emptying may require specialized testing that is not widely available. Researchers would also need to show that the results remain consistent across different populations and clinical settings.
The authors cautioned that prospective studies are needed before the approach becomes part of routine obesity care.
The study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. One author also receives research support from the Mayo Clinic Center for Women’s Health Research and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Andres J. Acosta, Michael Camilleri and Mayo Clinic are co-founders and inventors of intellectual property licensed to Phenomix Sciences. Acosta has consulted for several pharmaceutical, biotechnology and food companies, including Amgen, General Mills, Boehringer Ingelheim and Nestlé, and has received research support or contracts from other pharmaceutical companies. Camilleri has consulted for Kallyope, received research support from Novo Nordisk and serves as an adviser to Eli Lilly, the manufacturer of tirzepatide. Maria D. Hurtado Andrade has consulted for Novo Nordisk, Roche and Verge Genomics and receives research funding from Eli Lilly, Endogenex and Phenomix Sciences.