In a randomized, placebo-controlled phase I trial, researchers demonstrated that tirzepatide could produce substantial reductions in energy intake as early as 3 weeks of treatment, with participants consuming 524.6 kcal less during ad libitum lunch meals compared with placebo.
The 6-week study enrolled 114 adults without diabetes and a body mass index (BMI) ranging from 27 to 50 kg/m² across three treatment arms: once-weekly tirzepatide, once-weekly placebo, or open-label once-daily liraglutide. The primary endpoint assessed change from baseline to week 3 in energy intake during controlled lunch meal tests.
Rapid Onset of Appetite Suppression
At week 3, tirzepatide recipients showed a mean energy intake reduction of 523.2 kcal from baseline, whereas placebo recipients increased intake by 11.0 kcal. By week 6, the treatment difference expanded to 686.0 kcal (95% confidence interval [CI] = −830.7 to −541.4, P < .01), representing a 72.4% reduction in energy intake for the tirzepatide group compared with baseline.
"Tirzepatide reduced energy intake vs placebo at week 3 (estimated treatment difference = −524.6 kcal (95% [CI] = −648.1 to −401.0), P < .0001)," the study authors reported. "With regard to secondary outcomes vs placebo, tirzepatide decreased overall appetite, food cravings, tendency to overeat, perceived hunger, and reactivity to foods in the environment but did not impact volitional restriction of dietary intake," they added.
Comprehensive Appetite Assessment
Secondary analyses revealed broad effects across multiple dimensions of ingestive behavior. Using visual analog scales, tirzepatide decreased fasting overall appetite vs placebo at week 3 (estimated treatment difference = 20.6, 95% CI = 12.1–29.0, P < .01). The drug also reduced fasting hunger; prospective food consumption; and the desire for sweet, salty, and fatty foods—while increasing satiety and fullness.
Food craving assessments showed tirzepatide's effects extended beyond general appetite suppression. The Food Craving Inventory overall score decreased vs placebo (−0.4, 95% CI = −0.7 to −0.2, P < .01), with specific reductions in cravings for high-fat foods, sweets, carbohydrates/starches, and fast-food fats, but not for fruits and vegetables.
The Food Craving Questionnaire–State demonstrated similar patterns, with tirzepatide reducing overall state-dependent food craving scores (−0.9, 95% CI = −1.2 to −0.6, P < .01) and all subscale scores, including physiological hunger states, lack of control over eating, and anticipation of both positive and negative reinforcement from eating.
Neurobiological Mechanisms
Functional magnetic resonance imaging revealed that tirzepatide modulated brain responses to food cues in regions associated with appetite regulation and food reward. At week 3, tirzepatide was found to reduce blood oxygen–level-dependent activation to high-fat, high-sugar food images in the medial frontal gyrus (P = .03), cingulate gyrus (P = .03), hippocampus (P = .02), and orbitofrontal cortex (P = .03) compared with placebo.
"At week 3 vs placebo, tirzepatide did not statistically significantly impact blood oxygenation–level-dependent activation to highly palatable food photos (aggregated category of high-fat, high-sugar foods and high-fat, high-carbohydrate foods) but decreased activation to high-fat, high-sugar food photos in the medial frontal and cingulate gyri, orbitofrontal cortex, and hippocampus," the study authors noted.
Behavioral Disinhibition Effects
The Eating Inventory assessments revealed that tirzepatide reduced perceived hunger (−3.2, 95% CI = −4.6 to −1.8, P < .01) and disinhibition (−3.1, 95% CI = −4.5 to −1.8, P < .01) vs placebo at week 3, reflecting a decreased tendency to overeat in response to external and internal cues. Notably, cognitive restraint showed no statistically significant difference between groups, suggesting the effects occurred without requiring increased volitional dietary restriction.
The Power of Food Scale, measuring susceptibility to food environment cues, showed notable reductions in overall scores (−1.0, 95% CI = −1.3 to −0.7, P < .01) and all subscales (food available, food present, and food tasted) vs placebo, indicating decreased responsiveness to proximal food stimuli.
Safety and Tolerability
Treatment-emergent adverse events occurred in 81% (n = 30) of tirzepatide recipients, 66% (n = 25) of liraglutide recipients, and 44% (n = 17) of placebo recipients. The most common tirzepatide-related adverse events were gastrointestinal: nausea (51%), vomiting (30%), constipation (19%), and dyspepsia. Seven participants discontinued treatment as a result of adverse events: three in the tirzepatide group (nausea, pancreatitis, and vomiting), two in the liraglutide group, and two in the placebo group.
Body weight changes paralleled energy intake effects, with tirzepatide producing mean reductions of 3.7 kg at week 3 and 7.0 kg at week 6 compared with 0.5 kg and 0.6 kg reductions with placebo, respectively.
Comparison With GLP-1 Monotherapy
Tirzepatide demonstrated superior efficacy compared with liraglutide across multiple endpoints. Energy intake reduction with tirzepatide exceeded liraglutide by 233.1 kcal at week 3 (95% CI = −358.0 to −108.3, P < .01) and 343.3 kcal at week 6 (95% CI = −488.2 to −198.3, P < .01). Similar patterns emerged for appetite measures, food cravings, and behavioral assessments.
The study's 89% completion rate and robust statistical methodology, employing mixed-model repeated measures analyses with treatment, baseline BMI stratum, time point, and treatment-by-time interactions as fixed effects, strengthened confidence in the findings.
The results provided mechanistic insights into tirzepatide's clinical efficacy for obesity treatment, demonstrating rapid onset of action on both peripheral appetite signals and central nervous system food reward pathways within the first weeks of therapy.
Disclosures can be found in the study.
Source: Nature Medicine
