SEMAGLUTIDE FOR WEIGHT MANAGEMENT: A COMPREHENSIVE NARRATIVE REVIEW OF MECHANISMS, EFFICACY, SAFETY, AND CLINICAL APPLICATIONS

Abstract

Background: Obesity is a global chronic disease affecting over 650 million adults and is associated with numerous comorbidities, including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Traditional weight management strategies often yield limited and unsustainable results, and while bariatric surgery is effective, it is inaccessible to most. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist initially developed for type 2 diabetes, has demonstrated substantial efficacy for chronic weight management and is now approved for this indication.

Aim: This narrative review aims to (i) elucidate the pharmacological mechanisms of semaglutide-induced weight loss; (ii) synthesize clinical evidence on its efficacy across diverse populations; (iii) evaluate its safety and tolerability profile; (iv) discuss practical implementation considerations; (v) examine cardiometabolic and other health outcomes; (vi) assess weight maintenance after discontinuation; (vii) analyze cost-effectiveness and accessibility; and (viii) identify key research gaps and future directions.

Methods: A comprehensive narrative review was conducted, drawing on data from pivotal clinical trials (notably the STEP program), cardiovascular and renal outcome studies (e.g., SELECT, FLOW), regulatory documents, and peer-reviewed literature. The review integrates findings on pharmacology, efficacy, safety, special populations (including adolescents), real-world implementation challenges, and health equity issues.

Results: Semaglutide promotes weight loss primarily through central appetite suppression, delayed gastric emptying, enhanced satiety signaling, and modulation of food reward pathways. In clinical trials, once-weekly subcutaneous semaglutide 2.4 mg produced mean weight losses of 14–17% over 68–104 weeks, surpassing placebo and other anti-obesity medications. Significant improvements were also observed in glycemic control, blood pressure, lipids, liver fat, and inflammatory markers. The SELECT trial confirmed a reduction in major adverse cardiovascular events in patients with obesity and established cardiovascular disease. Common adverse effects were gastrointestinal (nausea, vomiting, constipation, diarrhea), typically transient and manageable with dose titration. Serious but rare risks include pancreatitis, gallbladder disease, and contraindications in patients with personal or family history of medullary thyroid carcinoma. Discontinuation leads to substantial weight regain, supporting the need for long-term treatment. High costs, insurance barriers, and supply shortages limit equitable access.

Conclusion: Semaglutide represents a major advance in obesity pharmacotherapy, offering clinically meaningful weight loss and improvements in cardiometabolic health. Its efficacy is well-established, and its safety profile is generally favorable with appropriate patient selection and dose titration. However, long-term safety beyond two years, strategies for post-discontinuation weight maintenance, optimal patient stratification, comparative effectiveness against surgery, and equitable access remain critical challenges. Semaglutide should be integrated into comprehensive, multidisciplinary obesity care that includes lifestyle modification, behavioral support, and ongoing monitoring. Future research must address existing knowledge gaps to optimize its use in diverse clinical settings.