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

Area of Science:

• Metabolic and Neural Regulation
• Obesity Pathophysiology

Background:

• Obesity is an energy dysregulation disease involving complex metabolic, hormonal, and neural interactions.
• The "gut-brain axis" describes the interconnectedness of these factors influencing energy balance.

Purpose of the Study:

• To review clinical evidence on eating behavior changes with gut hormone analogs and NB-ER.
• To explore the mechanistic rationale for combining these medications to target the gut-brain axis.
• To identify treatment strategies for patients not achieving goals with single medications.

Main Methods:

• Review of clinical evidence on physiological and behavioral changes.
• Analysis of mechanistic pathways targeted by gut hormone analogs and NB-ER.
• Examination of the gut-brain axis and its role in energy homeostasis and reward.

Main Results:

• Gut hormone analogs (liraglutide, semaglutide, tirzepatide) target GLP-1 and GIP receptors, impacting the hypothalamus and brainstem to reduce energy intake.
• Evidence on the effects of gut hormone analogs on the reward system is inconsistent.
• Naltrexone/bupropion extended-release (NB-ER) targets hypothalamic and mesolimbic systems, reducing food intake and reward-based eating.

Conclusions:

• Gut hormone analogs and NB-ER have distinct yet complementary effects on gut-brain pathways.
• These complementary effects provide a mechanistic rationale for combining these agents in obesity treatment.
• Combined therapy may offer a more comprehensive approach to managing obesity by targeting satiety, hunger, and reward pathways.