Effect of once-weekly subcutaneous semaglutide on arterial inflammation in people with type 2 diabetes and cardiovascular disease using PET-MRI: Primary results of a randomized, double-blind, placebo-controlled trial

Background Semaglutide has demonstrated cardiovascular benefits in people with type 2 diabetes (T2D) with cardiovascular disease (CVD). Inflammation plays a well-documented role in atherosclerosis and glucagon-like peptide-1 receptor agonists, like semaglutide, have shown anti-inflammatory effects in animal and clinical studies. This trial investigated the effect of semaglutide on atherosclerotic inflammation in the carotid arteries using positron emission tomography (PET)-magnetic resonance imaging (MRI). Methods Patients with T2D and CVD were randomized to double-blinded once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary and key secondary endpoints used PET-MRI with [ 18 F]FDG and [ 68 Ga]DOTATATE tracers to assess change from baseline to week 26 in plaque inflammation in the segments of the carotid arteries that were determined to be the most diseased and where plaque inflammation was quantified by the maximum target-to-background ratio (TBR max ) of the tracers. Additional secondary endpoints assessed plaque morphology and burden using MRI at week 52, including total wall volume, lipid-rich necrotic core volume, and fibrous cap thickness. Results Of 101 patients, 87.1% were male, mean age was 66 years and they were well-treated according to guidelines. No significant treatment differences were observed between semaglutide and placebo for change in plaque inflammation at week 26 with either tracer; TBR max of FDG (estimated treatment difference [ETD]: 0.033, 95% confidence interval [CI]: –0.118;0.184) and [ 68 Ga]DOTATATE (ETD: 0.045, 95% CI: –‍0.314;0.404). Conclusions This trial explored the feasibility of following plaque inflammation with PET-MRI using [ 18 F]FDG and [ 68 Ga]DOTATATE. A significant effect of semaglutide versus placebo on carotid plaque inflammation could not be detected through the methodology used in this trial, likely due to minimal baseline inflammation. However, this does not exclude an effect of semaglutide on inflammation seen in previous preclinical and clinical studies. Trial registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04032197.