Phase 3 clinical development of semaglutide (2015-2026): a comprehensive evidence-based review of trial designs, therapeutic outcomes and global clinical experience.

Abstract

Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has become an important therapeutic agent for type 2 diabetes mellitus (T2DM), obesity, and associated cardiometabolic complications. Its prolonged pharmacological activity and availability as subcutaneous and oral formulations have supported extensive clinical development across diverse populations. This review critically evaluates Phase 3, Phase 3a, and Phase 3b clinical trials (CTs) assessing the efficacy, safety and therapeutic utility of semaglutide, with an emphasis on the SUSTAIN, PIONEER, STEP, SELECT, FLOW, SOUL and related programmes. Eligible trials were assessed according to study design, registration, treatment duration, population characteristics, interventions, comparators, primary endpoints, adverse events (AEs) and clinical significance. Collectively, the evidence demonstrates clinically meaningful improvements in glycaemic control and body weight, as well as cardiovascular and renal benefits, in selected populations. Evidence from obesity and post-bariatric studies further supports its expanding therapeutic role beyond conventional glucose management. Gastrointestinal events, particularly nausea, vomiting, diarrhoea and constipation, were the predominant adverse effects, while overall tolerability remained consistent with the established GLP-1RA profile. However, differences in populations, treatment duration, comparators and endpoint definitions highlight important evidence gaps. This review synthesises Phase 3 clinical evidence to define the evolving therapeutic position, safety profile and future research priorities for semaglutide.