Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes

• Published in: Diabetes, obesity & metabolism Vol. 25; no. 5; pp. 1385 - 1397
• Main Authors: Aroda, Vanita R., Erhan, Umut, Jelnes, Peter, Meier, Juris J., Abildlund, Morten Tind, Pratley, Richard, Vilsbøll, Tina, Husain, Mansoor
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2023; Wiley Subscription Services, Inc
• Subjects: Acute Disease; antidiabetic drug; Antidiabetics; Cardiovascular diseases; Clinical trials; Congestive heart failure; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - epidemiology; Diabetic retinopathy; Diabetic Retinopathy - chemically induced; Gastrointestinal diseases; Gastrointestinal Diseases - chemically induced; Gastrointestinal Diseases - drug therapy; Gastrointestinal Diseases - epidemiology; GLP‐1; Glucagon; Glucagon-Like Peptides - adverse effects; Humans; Hypoglycemia; Hypoglycemic Agents - adverse effects; Pancreatitis; Pancreatitis - chemically induced; phase III study; Placebos; randomized trial; Retinopathy; Safety; type 2 diabetes; antidiabetic drug; GLP-1; type 2 diabetes; randomized trial; phase III study
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.14990

Aim Glucagon‐like peptide‐1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively. Materials and methods Adverse events (AEs) from 16 randomized placebo‐ or active‐controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once‐weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once‐daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480). Results In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non‐inferiority criteria were met with oral semaglutide. Conclusions The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.