Tirzepatide Twists Appetite and Beats Calorie Intake in New Obesity Trial

Tirzepatide Twists Appetite and Beats Calorie Intake in New Obesity Trial

A new clinical trial shows tirzepatide's ability to curb hunger and alter the brain's responses to food, marking a new era in the treatment of obesity.

In a study recently published in the journalNatural medicineResearchers 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 influence of tirzepatide on eating behavior with that of liraglutide (dose-escalated daily from 0.6 mg to 3 mg) and an equivalent placebo.

Study results showed that cases (tirzepatide-using participants) consumed an average of 658 kcal less (-72.4%) after 6 weeks than during baseline lunch alone.

The drug has been observed to effectively curb appetite, hunger, impulsivity, cravings, and food reactivity, particularly with respect to high sugar and high-fat foods, suggesting potential early mechanisms underlying tirzepatide's potent weight loss effects.

However, tirzepatide did not significantly affect cognitive restraint (extensive restriction of food intake), an important distinction from some other interventions.

background

Obesity (BMI ≥ 30 kg/m²) is a chronic disease characterized by excessive fat accumulation. It remains a major public health problem, with the World Health Organization (WHO) estimating that 2.3 billion children and adults are either overweight (BMI ≥ 25 kg/m²) or obese. Alarmingly, this number will increase significantly in the coming years, reflecting recent suboptimal trends in health behaviors (sleep, physical activity, diets).

Obesity has been linked to a spectrum of potentially fatal comorbidities, prompting decades of research into the condition and mitigating interventions. Unfortunately, the neurobiological and behavioral mechanisms that underpin the development and progression of the disease remain poorly understood.

Recent research using drugs called "glucagon-like peptide-1 (GLP-1) receptor agonists (RAS)" suggests that they may influence ingestive behavior by modifying central nervous system (CNS) pathways involved in food and appetite. Tirzepatide, a dual GIP/GLP-1 receptor agonist, has been tentatively shown to reduce weight after a 72-week intervention 20.9% found.

Unfortunately, while tirzepatide's appetite and energy intake reduction effects are established, studies evaluating these metrics have not captured measures of brain function and have adhered to inadequate behavioral intake assays, thereby limiting their ability to elucidate tirzepatide's CNS mechanisms.

About the study

The present study addressed these knowledge gaps through a six-week phase 1 study of adults with overweight or obesity to examine tirzepatide's short-term, weight-associated behavioral effects. The study compared the effects of tirzepatide with those of liraglutide (another GLP-1 RA) and an equivalent placebo.

The study used data from adults (18 to 65 years old) with a stable, clinically validated body mass index (BMI) between 27 and 50 kg/m². Participants with a glycated hemoglobin level ≥6.5% or a positive diagnosis of diabetes were excluded from downstream analysis.

Participants were stratified by BMI from the baseline stratum 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, escalated with dose), or equivalent placebo for the 6-week study period.

Outcome data were collected at baseline, week 3, and week 6 of the study. It included: 1. Visual Analog Scale (VAS) ratings for hunger and appetite assessment, 2. Questionnaires such as craving measurement measures such as the Food Craving Inventory (FCI) and the Food Craving Questionnaire (FCQ-S), 3. Food/Energy Intake Intake Assay. 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 dietary intake. The safety of tirzepatide and liraglutide was continually monitored.

Study results

The study utilized a total of 114 non-diabetic adult 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 reduction in intake of 532 kcal (week 3) and 658 kcal (week 6) during an Adlitum 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 values ​​support these findings by suggesting that tirzepatide causes a decrease in patients' appetite and food cravings. FCI/FCQ and BIS evaluations highlight the craving, disinhibition, and impulsivity-curbing ability of tirzepatide and further demonstrate that tirzepatide consumers have an easier time resisting eating foods.

The fMRI results showed that key brain regions associated with food-searching behaviors (medial frontal gyrus, cingulate gyrus, orbitofrontal cortex and hippocampus) showed significantly reduced activation compared to tirzepatide treatment, particularly in response to high-value, 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 exaggerating these fMRI findings due to multiple comparisons and the short study duration. Further replication is required. Encouragingly, both drugs were generally well tolerated, with adverse events, primarily mild to moderate gastrointestinal symptoms, being 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 the dramatic short-term weight loss effects of tirzepatide. Consumption of the drug has been observed to powerfully suppress energy intake, appetite, cravings, impulsivity, and neural responses to palatable foods. While liraglutide demonstrated similar results, tirzepatide was observed to outperform it by a significant margin across multiple measures.

Importantly, tirzepatide did not increase cognitive retention, 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 gender distribution between groups. These findings show that tirzepatide does more than just lower blood sugar. It modulates eating behavior and provides a robust defense against overeating.

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