Background Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1•73 m², and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete.

Background Single-stranded DNA aptamers are oligonucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts. Methods To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically-relevant perturbational model of “planned” myocardial injury (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples obtained before, at 10 and 60 minutes after PMI, and protein changes were assessed by repeated measures ANOVA. The generalizability of our PMI findings was evaluated in a spontaneous MI (SMI) cohort (Wilcoxon rank-sum). We then tested the platform’s ability to detect associations between proteins and Framingham Risk Score (FRS) components in the Framingham Heart Study (FHS); performing regression analyses for each protein versus each clinical trait. Results We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P < 5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P < 2.30E-4); > 85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf related protein 4, a WNT pathway inhibitor (peak increase 124%, P = 1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P = 1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with SMI (n=46; P < 0.05). Our FHS studies revealed 156 significant protein associations with the FRS (n=899), including aminoacylase 1 (β = 0.3386, P = 2.54E-22) and trigger factor 2 (β = 0.2846, P = 5.71E-17). Further, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity. Conclusions Our results highlight an emerging proteomics tool capable of profiling over one thousand low abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies as well as large human cohorts.