Strategies to maintain satiety and metabolic stability after GLP-1/GIP pharmacotherapy cessation identified

While GLP-1 receptor agonists and dual GLP-1/GIP agonists have revolutionized obesity treatment, enabling significant weight loss and cardiometabolic improvements, cessation of these therapies often leads to biologically driven weight regain. This phenomenon highlights the chronic nature of obesity and the limited durability of pharmacotherapy alone. A critical gap exists in structured clinical frameworks for maintaining satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation, leaving patients vulnerable to regaining lost weight and metabolic benefits.

This narrative review aimed to synthesize current understanding of mechanisms driving weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy. The authors discussed persistent metabolic adaptations and alterations in the hunger-satiety axis. They also presented strategies to support long-term metabolic stabilization, drawing from existing literature on nutrition, exercise, and gut microbiota modulation. The review did not involve experimental protocols, specific patient cohorts, or quantitative data analysis, but rather a comprehensive discussion of established and emerging concepts.

Weight regain post-GLP-1/GIP therapy is primarily driven by persistent metabolic adaptations. These include a reduction in resting energy expenditure (adaptive thermogenesis), and significant alterations in the hunger-satiety axis, characterized by increased ghrelin and reduced leptin signaling. Weight loss itself often leads to a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. The review highlights that pharmacological appetite suppression may not result in sustained normalization of endogenous satiety regulation, and its effects on gut microbiota function remain uncertain. Key strategies proposed for metabolic stabilization include:

Preserving muscle mass through adequate protein intake and resistance training, maintaining dietary nutrient density, stabilizing postprandial glycaemia, and ensuring sufficient intake of fermentable fiber to support short-chain fatty acid production. These interventions collectively aim to counteract the biological drivers of weight regain and support long-term metabolic health.