Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, have emerged as effective therapies for glycaemic control and weight reduction in type 2 diabetes and obesity. Both injectable and oral formulations have been investigated in large phase III clinical trials, with growing interest in their long-term efficacy and safety. To review and compare the efficacy, safety, and tolerability of injectable and oral semaglutide formulations, with a focus on their role in chronic weight and glycaemic management. A narrative review was conducted based on data from pivotal clinical trials and real-world studies. Efficacy outcomes included changes in body weight and glycated haemoglobin (HbA1c). Safety profiles, adverse events, and patient adherence factors were also assessed. Injectable semaglutide (2.4 mg weekly) showed a mean weight reduction of 14.9% over 68 weeks in the STEP 1 trial, compared to 15.1% with oral semaglutide (50 mg daily) in the OASIS 1 study. Both formulations demonstrated significant improvements in HbA1c and cardiometabolic parameters. A real-world study found comparable efficacy between formulations. Gastrointestinal adverse events were most common, while serious events were rare. Long-term use was essential for sustained weight loss, as discontinuation led to significant weight regain. No consistent associations with increased cancer or psychiatric adverse events were confirmed. Both oral and injectable semaglutide are effective and generally well-tolerated options for chronic management of type 2 diabetes and obesity. Treatment adherence, long-term safety, and cost considerations should guide therapeutic choices. Ongoing monitoring is warranted to optimize outcomes and minimize risks.
