Targeting Multiple Gut‐Brain Pathways in Obesity: Rationale for Combination Pharmacotherapy

Background: As a disease of energy dysregulation, obesity involves metabolic, hormonal, and neural factors, the interconnection of which is referred to as the “gut‐brain axis.” Objective: This review aimed to provide an overview of the clinical evidence of physiological and objective or subjective changes in eating behavior with gut hormone analogs and NB‐ER, as well as a mechanistic rationale for the combined use of these medications to target multiple pathways along the gut‐brain axis, particularly for patients who have not achieved their health goals with a single medication. Findings: Peripheral hormones such as glucagon‐like peptide‐1 (GLP‐1) are released in response to food consumption. Peripheral signals are integrated in the hypothalamus and hindbrain to promote energy homeostasis. These brain regions also interact with other systems such as the mesolimbic dopamine system, which promotes food intake for its rewarding properties. Thus, medical interventions for obesity, such as pharmacotherapy and bariatric surgery, aim to regulate various components of this gut hormone–hedonic brain axis. Gut hormone analog medications such as liraglutide, semaglutide, and tirzepatide target the GLP‐1 receptor, with tirzepatide also targeting the glucose‐dependent insulinotropic polypeptide receptor. These gut hormone analog medications primarily exert their effects on the hypothalamus and brainstem to reduce energy intake. Evidence on their effects on the reward system and reward‐based eating is inconsistent. The fixed‐dose, extended‐release combination of naltrexone and bupropion (NB‐ER) acts via the hypothalamic and mesolimbic systems to reduce food intake and reward‐based eating. Conclusion: The distinct yet complementary effects of gut hormone analog medications and NB‐ER on gut‐brain pathways regulating satiety, hunger, and reward provide a mechanistic rationale for their combination in obesity treatment.