Dragoș Cozma, Cristina Văcărescu, Claudiu Stoicescu
Obesity remains a major global health challenge, with glucagon-like peptide-1 receptor agonists (GLP-1RAs) providing substantial yet sensitive benefits in weight reduction, glycemic control, and cardiovascular protection. Despite robust trial data, real-world persistence is limited by cost, tolerability, and hedonic adaptation. Intermittent fasting and time-restricted eating offer physiologically complementary, low-cost strategies that enhance fat oxidation, insulin sensitivity, and metabolic flexibility while engaging behavioral mechanisms of self-control and dietary regularity. This narrative review synthesizes current evidence and proposes a pragmatic, phased framework integrating GLP-1RA therapy with structured intermittent fasting and protein-optimized nutrition. The model emphasizes sequential initiation, transition, and maintenance phases designed to align pharmacologic appetite suppression with lifestyle-driven metabolic remodeling. Mechanistically, GLP-1RAs target vascular and neuroendocrine pathways, whereas fasting activates nutrient-sensing networks (AMPK, mTOR, sirtuins) associated with autophagy and longevity. Combined application may preserve lean mass, improve psychological autonomy, and reduce healthcare costs. Future research should validate this hybrid strategy in randomized trials assessing long-term weight durability, functional outcomes, and cost-effectiveness. By uniting pharmacologic potency with behavioral sustainability, phased GLP-1-fasting integration may represent an effective, affordable, and longevity-oriented paradigm for metabolic health.