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Objective: To detail studies investigating the efficacy/safety of semaglutide as a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the treatment of type 2 diabetes mellitus. Data Sources: A literature search in MEDLINE and ClinicalTrials.gov (January 2013 to May 2018) using the terms semaglutide, SUSTAIN, oral, and PIONEER resulted in 10 published articles and 14 ongoing/unpublished articles. Study Selection and Data Extraction: All English language phase 2 and 3 clinical trials evaluating efficacy/safety of semaglutide were included. Data Synthesis: In 9 phase 3, multicenter SUSTAIN trials, the efficacy and safety of semaglutide have been compared with placebo and other pharmacologic therapy for diabetes (PTD). In these trials, semaglutide resulted in lower hemoglobin A1c (HbA1c; approximately −1.5%) and weight reductions (approximately −4.5 kg) as comparable with dulaglutide for HbA1c lowering (approximately −1.5%). Semaglutide also has cardiovascular (CV) outcomes data that show significant reduction in risk of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio = 0.74; 95% confidence interval = 0.58-0.95). A safety finding that emerged from the CV outcomes trial was an association of semaglutide treatment with an increased risk of retinopathy complications in patients with preexisting diabetic retinopathy. Phase 3 trial data assessing semaglutide oral formulation have shown similar HbA1c (approximately −1.5% for 14 mg dose) and body weight (approximately −4.1 kg for 14 mg dose) reductions as compared with placebo. Across these studies, semaglutide was generally well tolerated with the most common adverse event reported as gastrointestinal side effects as seen in all GLP-1 RAs. Conclusions: These results suggest that semaglutide may have a place in therapy as a GLP-1 RA add-on therapy with higher weight loss as compared with other GLP-1 RAs and PTD and CV benefit.