A new clinical trial reveals tirzepatide’s ability to curb hunger and alter brain responses to food, marking a new era in obesity treatment.
Study: Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial. Image Credit: Pixel-Shot / Shutterstock
In a recent study published in the journal Nature Medicine, researchers conducted a randomized, parallel-group, 6-week phase 1 clinical trial to estimate the early effects of Tirzepatide (5 mg once weekly for 2 weeks, then 10 mg once weekly for 4 weeks) on hunger and energy intake.
A randomized cohort of 114 adults without diabetes compared the impact of tirzepatide on eating behavior with that of Liraglutide (dose-escalated daily from 0.6 mg to 3 mg) and an equivalent placebo.
Study findings revealed that after 6 weeks, cases (Tirzepatide-consuming participants) consumed a mean of 658 kcal less (−72.4%) than they did at baseline during lunch alone.
The drug was observed to effectively curb appetite, hunger, impulsivity, cravings, and food cue responsiveness, particularly with regard to high-sugar and high-fat foods, suggesting potential early mechanisms underlying Tirzepatide’s powerful weight-loss effects.
However, tirzepatide did not significantly affect cognitive restraint (volitional restriction of dietary intake), an important distinction from some other interventions.
Background
Obesity (BMI ≥ 30 kg/m²) is a chronic condition characterized by excessive fat accumulation. It remains a major public health concern, with the World Health Organization (WHO) estimating that 2.3 billion children and adults suffer from either overweight (BMI ≥ 25 kg/m²) or obesity. Alarmingly, this number is expected to substantially rise in the coming years, driven by recent suboptimal trends in health behaviors (sleep, physical activity levels, diets).
Obesity has been associated with a spectrum of potentially lethal comorbidities, prompting decades of research into the condition and mitigatory interventions. Unfortunately, the neurobiological and behavioral mechanisms underpinning disease genesis and progression remain poorly understood.
Recent research using drugs called ‘glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)’ suggests that they can influence ingestive behaviors by modifying central nervous system (CNS) pathways implicated in food rewards and appetite. Tirzepatide, a dual GIP/GLP-1 receptor agonist, has been preliminarily found to result in a 20.9% weight reduction after a 72-week intervention.
Unfortunately, while Tirzepatide’s appetite- and energy-intake-reducing effects are established, investigations evaluating these metrics have failed to collect brain functioning measurements and used insufficient ingestive behavior assays, limiting their ability to elucidate Tirzepatide's CNS mechanisms.
About the study
The present study addressed these knowledge gaps by conducting a six-week, phase 1 trial of adults with overweight or obesity to explore Tirzepatide’s short-term, weight-associated behavioral effects. The study compared the impacts of Tirzepatide with those of Liraglutide (another GLP-1 RA) and an equivalent placebo.
The study leveraged data from adult humans (age 18-65 years) with a stable, clinically validated body mass index (BMI) between 27 and 50 kg/m². Participants with a glycated hemoglobin level of≥6.5% or a positive diabetes diagnosis were excluded from downstream analysis.
Participants were stratified by baseline BMI and randomly assigned to one of three groups: case (Tirzepatide 5 mg once weekly for 2 weeks, then 10 mg once weekly for 4 weeks), Liraglutide (0.6 mg to 3 mg daily, with dose escalation), or an equivalent placebo for the 6-week study duration.
Outcome data were collected at baseline, week 3, and week 6 of the study. It included: 1. Visual Analogue Scale (VAS) assessments for hunger and appetite evaluation, 2. Craving-measuring questionnaires such as the Food Craving Inventory (FCI) and the Food Craving Questionnaire-State (FCQ-S), 3. Food/energy intake via the Eating Inventory assay for disinhibition and hunger, 4. The Barrett Impulsiveness Scale, and 5. Food-environment sensitivity using the Power of Food Scale.
Additionally, a subset of the sample cohort underwent functional Magnetic Resonance Imaging (fMRI) to assess changes in brain activation in response to images of high-fat and high-sugar foods compared to control images. All statistical models were controlled for sociodemographic variables, BMI, and relative food intake. The safety of Tirzepatide and Liraglutide was constantly monitored.
Study findings
The study leveraged a total of 114 adult non-diabetic participants (randomized 1:1:1 to tirzepatide [n=37], liraglutide [n=38], or placebo [n=39]). Energy intake assessments revealed that Trizepatide consumption was associated with a 532 kcal (week 3) and 658 kcal (week 6) reduction in intake from baseline during an ad libitum lunch. In contrast, placebo showed negligible change (−8 kcal at week 3, +28 kcal at week 6), and Liraglutide achieved smaller reductions (~−299 and −315 kcal).
VAS and Eating Inventory scores substantiate these findings by suggesting that Tirzepatide causes drops in patients’ appetites and cravings. FCI/FCQ and BIS evaluations underscore the cravings, disinhibition, and impulsivity-curbing ability of Tirzepatide, further demonstrating that Tirzepatide consumers have an easier time resisting food rewards in food-rich environments.
fMRI results revealed that key brain regions associated with food-seeking behaviors (medial frontal gyrus, cingulate gyrus, orbitofrontal cortex, and hippocampus) demonstrated significantly reduced activation under Tirzepatide treatment, particularly in response to high-fat, high-sugar foods at week 3 compared to placebo.
These results were not replicated in Liraglutide, suggesting a mechanism specific to Tirzepatide. However, the journal cautions against overinterpreting these fMRI findings due to multiple comparisons and the short study duration; further replication is necessary. Encouragingly, both drugs were generally well-tolerated, with adverse events, primarily mild to moderate gastrointestinal symptoms, more common in the tirzepatide group (81%) compared to the liraglutide group (66%) and the placebo group (44%).
Conclusions
The present study provides mechanistic insights into Tirzepatide’s dramatic short-term weight loss effects. Consumption of the drug was observed to powerfully suppress energy intake, appetite, cravings, impulsivity, and neural responses to palatable foods. While Liraglutide demonstrated similar outcomes, Tirzepatide was observed to outperform it across multiple measures by a significant margin.
Importantly, tirzepatide did not increase cognitive restraint, distinguishing it from some other interventions. The study also had several limitations, including an open-label design for liraglutide, a relatively short intervention period, and an imbalance in sex distribution among groups. These insights reveal that Tirzepatide doesn’t just lower blood sugar; it modulates eating behavior, providing a robust defense against overeating.
Journal reference:
- Martin, C.K., Carmichael, O.T., Carnell, S. et al. Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial. Nat Med (2025), DOI: 10.1038/s41591-025-03774-9, https://www.nature.com/articles/s41591-025-03774-9