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

Abstract

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.

Once‐weekly semaglutide use in patients with type 2 diabetes: Results from the SURE France multicentre, prospective, observational study

“…In the SUSTAIN randomized controlled trials (RCT), semaglutide, a once‐weekly human GLP‐1 analogue, was associated with superior, clinically relevant improvements in glycaemic control (mean reduction in HbA1c of up to 1.8% point across the trials) and body weight (mean reduction across the trials of up to 6.5 kg) versus placebo or active comparators 15‐24 . The safety profile of semaglutide was similar to that of other GLP‐1RAs, in particular, gastrointestinal adverse events (AEs), which were most frequently non‐serious nausea, diarrhoea and vomiting 15‐25 . Semaglutide is reimbursed in France for the treatment of insufficiently controlled T2D, as dual therapy in combination with metformin and as triple therapy in combination with metformin and a sulphonylurea 26…”

“…[15][16][17][18][19][20][21][22][23][24] The safety profile of semaglutide was similar to that of other GLP-1RAs, in particular, gastrointestinal adverse events (AEs), which were most frequently non-serious nausea, diarrhoea and vomiting. [15][16][17][18][19][20][21][22][23][24][25] Semaglutide is reimbursed in France for the treatment of insufficiently controlled T2D, as dual therapy in combination with metformin and as triple therapy in combination with metformin and a sulphonylurea. 26 The SURE programme comprises nine non-interventional, singlearm, observational studies across 10 countries investigating onceweekly semaglutide in a diverse range of patients with T2D in a real-world setting.…”

Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

“…Despite the promising effects of SGLT2 inhibitors in HFpEF patients 5 and the impressive effects of GLP-1 agonists on symptom burden in obese HFpEF 64 , more treatment options are warranted for this highly prevalent and morbid disorder, especially considering the limited tolerability to GLP-1 agonists 65 . With a positive safety and tolerability profile, NO 2 -OA emerges as a potentially important drug for treating HFpEF and other cardiopulmonary diseases 66 .…”

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy

“…Long term studies of liraglutide in rodents and primates have not revealed increased pancreatitis risk ( 48 – 50 ). Moreover, systematic reviews and meta-analyses of randomised controlled trials have not shown increased incidence of pancreatitis in patients with type 2 diabetes treated with liraglutide, exenatide or semaglutide ( 51 – 53 ). Appropriate monitoring will be necessary for GLP-1R agonists use in the treatment of patients with lipodystrophy.…”