Efficacy and Safety of the Off-Label Use of GLP-1 Receptor Agonists in Adults with Obesity or Overweight Without Diabetes

Abstract

This systematic review focused on evaluating the efficacy and safety of the off-label use of GLP-1 receptor agonists (such as Semaglutide and Tirzepatide) in adults with obesity or overweight who do not have a diagnosis of diabetes mellitus. The methodology included the analysis of eight studies published between 2017 and 2025, encompassing randomized clinical trials (e.g., the SELECT and SURMOUNT programs) and real-world studies. The results consistently indicate that these agents promote expressive and sustained weight reduction. Tirzepatide achieved average total losses of up to 25.3% over 88 weeks, while Semaglutide maintained a reduction of −10.2% after 208 weeks (nearly 4 years). Beyond weight loss, the treatment demonstrated crucial secondary cardiometabolic benefits, such as a 73% reduction in the risk of progression to biochemical diabetes over 156 weeks and the improvement of biomarkers like blood pressure (e.g., SBP reduced by −6.3 mmHg) and the lipid profile (e.g., triglycerides reduced by −38.4 mg/dL). The safety profile is deemed favorable for chronic use, with the most common adverse events being gastrointestinal in nature (nausea, diarrhea, vomiting), typically mild, transient, and manageable. The discontinuation of therapy results in substantial weight regain (approximately 14% of lost weight recovered upon cessation), reinforcing the need for chronic and continuous management of obesity. It is concluded that GLP-1 agonists and co-agonists are effective and safe therapeutic alternatives for this population.