Effects of Tirzepatide on Central Reward and Appetite Circuits in the Brain

Introduction and Objective: Tirzepatide is a GIP/GLP-1 receptor agonist approved in the US for T2D and obesity treatment. Both GIP and GLP-1 receptors are found in brain areas involved in appetite regulation. We investigated tirzepatide’s effects on brain activation in response to food images using blood oxygenation level dependent (BOLD) functional MRI (fMRI). Methods: In this 6-week, phase 1 study, 114 participants with obesity were randomized to QW tirzepatide 5 mg or QW placebo (blinded), or QD liraglutide 1.8 mg (open label). Participants had fMRI scans when fasting at baseline and the primary endpoint, week 3, while viewing images of high-fat and high-sugar (HFHS) foods or high-fat and high-carbohydrate (HFHC) foods and non-food items. Changes in positive brain activation from baseline to week 3 to HFHS and HFHC images were assessed relative to non-food images within brain regions of interest shown in the Figure. Results: At week 3, only tirzepatide-treated participants showed statistically significant decreases in HFHS activation vs. placebo in four brain regions: medial frontal and cingulate gyri, hippocampus, and orbitofrontal cortex, see Figure. Changes in HFHC activation for tirzepatide or liraglutide were non-significant vs. placebo in all brain regions of interest. Conclusion: Tirzepatide reduced brain activation to images of high-fat high-sugar foods in multiple brain regions implicated in appetite regulation. Disclosure O. Carmichael: Research Support; Eli Lilly and Company. Advisory Panel; Novo Nordisk. C.K. Martin: Advisory Panel; EHE Health, Wondr Health. Other Relationship; Academy of Nutrition and Dietetics, ABGIL. Research Support; Foundation for Food and Agriculture Research; Kroger Co. Zero Hunger / Zero Waste Foundation, Weight Watchers International, Eli Lilly and Company, Evidation Health. Other Relationship; Obesity Action Coalition, The Bray Course. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. D.A. Kareken: Other Relationship; Eli Lilly and Company. S. Carnell: Research Support; Eli Lilly and Company. U. Dydak: Consultant; American Regent, Inc. R.D. Mattes: Research Support; Lilly Diabetes, Almond Board of California, Grain Food Foundation. Advisory Panel; Mars Foods, General Mills, Grain Food Foundation. Consultant; Bright Seed, Calorie Control Council, Medifast, Inc. D. Scott: None. D.O. Svaldi: Employee; Eli Lilly and Company. H. Nishiyama: None. L. Biernat: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly Diabetes. Stock/Shareholder; Lilly Diabetes. Z. Milicevic: Employee; Eli Lilly and Company. S. Shcherbinin: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company